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Childhood derivatives of high and low reactivity in infancy
Kagan J, Snidman N, Arcus D. Child Dev. 1998 Dec;69(6):1483-93.
Department of Psychology, Harvard University, Cambridge, MA

Quote from article introduction: “The authors regard a shy or sociable response style with
strangers… as only one feature of two broader temperamental categories called inhibited and
uninhibited to the unfamiliar. Inhibited children react to unfamiliar incentives with an initial
avoidance, distress or subdued emotion… The complementary category called uninhibited is
characterized by a sociable and affectively spontaneous approach reaction to unfamiliar people,
situations and events… Infants who display vigorous motor activity combined with distress
vocalizations to visual, auditory, and olfactory stimulation are most likely to become inhibited.
These high reactive infants, who constitute about 20% of healthy European American
[children], are assumed to possess a low threshold of activation in the amygdala to sensory
stimulation and, as a result, move their limbs and fret or cry when their low threshold has been

Abstract: A group of 193 children, classified as high or low reactive to stimulation at 4 months
and observed again at 14 and 21 months, were observed at 4 1/2 years of age for behavioral
signs of inhibited or uninhibited behavior. Children who had been high reactive were less
spontaneous and less sociable than those who had been classified as low reactive, but only a
small proportion of children maintained a consistently inhibited or uninhibited phenotype at all

The preservation of two infant temperaments into adolescence
Kagan J, Snidman N et al. Monogr Soc Res Child Dev. 2007; 72(2):1-75
Harvard University, Cambridge, MA, USA.

Childhood derivatives of inhibition and lack of inhibition to the unfamiliar
Kagan J, Reznick JS et al. Child Dev. 1988 Dec;59(6):1580-9.
Department of Psychology, Harvard University, Cambridge, MA 02138.
Behavioral and physiological assessments of 41 7 1/2-year-old children who had been selected
to be inhibited or uninhibited at 21 months and observed again at 4 and 5 1/2 years revealed
that each of the 2 original behavioral profiles predicted theoretically reasonable derivatives. A
majority of the formerly shy, timid children became quiet and socially avoidant in unfamiliar
social situations, while a majority of the formerly sociable children became talkative and
interactive with peers and adults. Absolute heart-rate and cortisol level at 7 1/2 years were not
as discriminating of the 2 behavioral groups as they had been 2 years earlier.

Temperament and the reactions to unfamiliarity
Kagan J. Child Dev. 1997 Feb;68(1):139-43.
Harvard University, Department of Psychology, Cambridge, MA
The behavioral reactions to unfamiliar events are basic phenomena in all vertebrates. Four-
month-old infants who show a low threshold to become distressed and motorically aroused to
unfamiliar stimuli are more likely than others to become fearful and subdued during early
childhood, whereas infants who show a high arousal threshold are more likely to become bold
and sociable. After presenting some developmental correlates and trajectories of these 2
temperamental biases, I consider their implications for psychopathology and the relation
between propositions containing psychological and biological concepts.

Further evidence of an association between behavioral inhibition and anxiety disorders: results
from a family study of children from a non-clinical sample.
Rosenbaum JF et al. J Psychiatr Res. 1991; 25(1-2):49-65
Department of Psychiatry, Massachusetts General Hospital, Boston
Behavioral inhibition to the unfamiliar, identifiable in early childhood and reflecting the tendency
to exhibit withdrawal and excessive autonomic arousal to challenge or novelty, has been found
to be prevalent in young offspring of parents with panic disorder and agoraphobia and
associated with risk for anxiety disorders in these children. Using family study methodology,
we now examine psychopathology in first degree relatives of children from a non-clinical
longitudinal cohort identified at 21 months of age as inhibited (N = 22) or uninhibited (N = 19)
and followed through the age of seven years for a study of preservation of temperamental
characteristics in normal children. These assessments were compared with evaluations of the
first-degree relatives of 20 normal comparison children. Psychiatric assessments of parents (N
= 110) and siblings (N = 72) were based on structured interviews conducted blindly to the
temperamental classification of the index child. Parents of inhibited children, compared with
parents of uninhibited and normal controls, had significantly higher risks for multiple (greater
than or equal to 2) anxiety disorders, continuing anxiety disorders (both a childhood and
adulthood anxiety disorder in the same parent), social phobia, and childhood avoidant and
overanxious disorders. These findings provide additional support for the hypothesis linking
behavioral inhibition with risk for anxiety disorder.

Stable behavioral inhibition and its association with anxiety disorder
Hirshfeld DR et al. J Am Acad Child Adolesc Psychiatry. 1992; 31(1):103-11.
Clinical Psychopharmacology Unit, Massachusetts General Hospital, Boston
"Behavioral inhibition to the unfamiliar" is a temperamental construct reflecting the tendency to
be shy, timid, and constrained in novel situations. Previous work has suggested that it may be
associated with anxiety disorders in children. Psychopathology was assessed in children from
a nonclinical sample originally identified as behaviorally inhibited or uninhibited at 21 months
and followed through 7 1/2 years. Children who remained inhibited at 4, 5 1/2 and 7 1/2 years
(Stable Inhibited) had higher rates of anxiety disorders than children who were not consistently
inhibited. Their parents had higher rates of multiple childhood anxiety disorders and of
continuing anxiety disorder. These results suggest that the association between behavioral
inhibition and anxiety disorder is accounted for by children who have stable behavioral

Temperamental influences on reactions to unfamiliarity and challenge
Kagan J, Reznick JS, Snidman N. Adv Exp Med Biol. 1988;245:319-39.
Department of Psychology, Harvard University, Cambridge, MA.

Behavioral and physiological antecedents of inhibited and uninhibited behavior
Calkins SD, Fox NA, Marshall TR. Child Dev. 1996 Apr;67(2):523-40.
Department of Psychology, University of North Carolina, Greensboro
ABSTRACT: 4-month-old infants were specifically selected for patterns of affective and
motoric reactivity that were hypothesized to be associated with later inhibited and uninhibited
behavior. Infants were classified as high on motor activity and negative affect, high on motor
activity and positive affect, or low on motor activity and affect. Brain electrical activity was
assessed in these infants at 9 months of age, and behavior toward novelty was observed at 14
months of age. Infants who were high on motor activity and negative affect exhibited greater
right frontal EEG activation at 9 months of age and inhibited behavior at 14 months of age.
Infants classified as high motor/high positive at 4 months of age exhibited uninhibited behavior
at 14 months of age. No relations were found between frontal asymmetry at 9 months of age
and inhibited behavior at 14 months of age. However, greater activation in both the left and
right frontal hemispheres was associated with higher inhibition scores at 14 months of age.
These findings are discussed in terms of the role that affective and physiological reactivity may
play in the development of social behavior during toddlerhood.

Moving away from the world: Life-course patterns of shy children
Caspi, Avshalom; Bem, Daryl J. et al. Developmental Psychology 1988; 24 (6): 824-831
Abstract: What are the life-course sequelae of childhood shyness? Using archival data from the
Berkeley Guidance Study (Macfarlane, Allen, & Honzik, 1954), we identified individuals who
were shy and reserved in late childhood and traced the continuities and consequences of this
behavioral style across the subsequent 30 years of their lives. Shy boys were more likely than
their peers to delay entry into marriage, parenthood, and stable careers; to attain less
occupational achievement and stability; and--when late in establishing stable careers--to
experience marital instability. Shy girls were more likely than their peers to follow a
conventional pattern of marriage, childbearing, and homemaking. Results are compared with
those from our parallel study of childhood ill-temperedness (Caspi, Elder, & Bem, 1987).
Despite differences between shyness ("moving away from the world") and ill-temperedness
("moving against the world"), both persist across the life course through the progressive
accumulation of their own consequences (cumulative continuity) and by their tendency to
evoke maintaining responses from others during reciprocal social interaction (interactional

JE BATES & TD WACHS; American Psychological Association (APA); 1ST edition (April


The future of pediatric and adolescent endocrinology
Chrousos GP. Ann N Y Acad Sci. 1997 Jun 17;816:4-8.
Pediatric Endocrinology Section, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, Maryland

AUTHOR’S COMMENT: this is the cardinal article which widely introduced the concept of an
inborn, genetically based differential vulnerability to stress population wide.

Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral
Smoller JW, Slaugenhaupt SA et al. Biol Psychiatry 2003;54(12):1376-81.
Department of Psychiatry, Massachusetts General Hospital, Boston
BACKGROUND: Behavioral inhibition to the unfamiliar (BI), a heritable temperamental profile
involving an avoidant response to novel situations, may be an intermediate phenotype in the
development of anxiety disorders. Corticotropin-releasing hormone (CRH) is a key mediator of
the stress response through its effects on the hypothalamic-pituitary-adrenal axis and limbic
brain systems. Transgenic mice overexpressing CRH exhibit BI-like behaviors, implicating this
gene in the development of the phenotype. METHODS: We genotyped a marker tightly linked
to the CRH locus in 85 families of children who underwent laboratory-based behavioral
assessments of BI and performed family-based association analyses. RESULTS: We observed
an association between an allele of the CRH-linked locus and BI (p =.015). Among offspring of
parents with panic disorder, this association was particularly marked (p =.0009). We further
demonstrate linkage disequilibrium between this marker and single nucleotide polymorphisms
encompassing the CRH gene.

This is only one gene out of many that are responsible for producing a sensitive or insensitive
person. The evidence regarding CRH gene precedes evidence for the other genes involved in
the process due to the abundance of research funds pouring into this topic from both
corporate and governmental sources in an effort to produce pharmaceuticals for a variety of
components of the “neurotic” personality. Besides the impact of the environment, especially
early in life, has the power of suppressing or accentuating the effects of many of the genes
involved in sensitivity.

Heritability of daytime cortisol levels and cortisol reactivity in children
Steptoe A, Plomin R et al. Psychoneuroendocrinology 2008 Oct 18
[get actual citation later]
Psychobiology group, university college London
Summary: individuals differ widely in cortisol output over the day and cortisol reactivity to
challenge, both of which are relevant to disease risk. There is limited evidence concerning the
heritability of these differences, so we evaluated the heritability of cortisol levels in the
afternoon and cortisol reactivity using a twin design. The study involved 80 identical (MZ) and
70 non-identical (DZ) same-sex twin pairs aged 11.2 years on average. Salivary cortisol was
measured in the afternoon at home before and after playing a computer game. Ratings of
excitement and upset were also obtained, and objective task performance was assessed. There
were marked individual differences, with cortisol reactivity (difference between pre-task
baseline and post-task 1) ranging from +4.53 to -6.23 nmol/l. Intra-class correlations for all
cortisol parameters were substantially greater for MZ than for DZ twin pairs. Quantitative
genetic modeling confirmed significant heritability for pre-task baseline cortisol (58%), the two
post-task values (60 and 56%), and cortisol reactivity (44%). Subjective reports of excitement
were also somewhat heritable. These findings indicate that individual differences in children’s
cortisol levels recorded before tasks and cortisol reactivity to behavioral challenges are
influenced by genetic factors.

Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry
Eric M. Morrow, Christopher A. Walsh et al. Science 11 July 2008: Vol. 321. no. 5886, pp.
218 - 223
To find inherited causes of autism-spectrum disorders, we studied families in which parents
share ancestors, enhancing the role of inherited factors. We mapped several loci, some
containing large, inherited, homozygous deletions that are likely mutations. The largest
deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in
autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a
marker of genes involved in synaptic changes that underlie learning. A subset of genes
including NHE9 (Na+/H+ exchanger 9) showed additional potential mutations in patients with
unrelated parents. Our findings highlight the utility of "homozygosity mapping" in
heterogeneous disorders like autism but also suggest that defective regulation of gene
expression after neural activity may be a mechanism common to seemingly diverse autism

AUTHOR’S COMMENT: this study represents a breakthrough in the understanding and
openness of the mainstream medical community towards autism. In summary the study finds
that certain genes involved in preparing a child for learning new material are harder to activate.
This goes to explain the departure of autistic people from the culture of first impressions. This
also goes to partially explain why repetitive exposure to novel material may be the best way for
educating autistic children socially and academically. Besides it seems that these newly
discovered genes are related to the mechanisms underlying the behavioral curve ball discussed
earlier. It seems some genes involved in making connections in the brain necessary for learning
can only be activated at higher, more intense levels of stimulation. This is the right end of the
curve where autistic people gain clarity and focus while insensitive people freeze. This point is
discussed under the ‘tough love’ entry in the wholistic approach chapter. This study is
certainly not the last word on the genetic basis of the autistic personality. In fact, I believe we
will be able to find hundreds of genes if not that the whole genome functions differently in
autistic people than in the insensitive majority.

No one is supposed to comprehend the contents of the above abstract, not even the people
who wrote it! These types of reports are basically interim reports published for the purpose of
securing funds from the government in order to complete the search. There will be many more
reports about the topic until clarity and simplicity is accomplished. For the time being, the
search for a genetic basis for autism is underway. There is sufficient evidence to know that
there is a clear genetic component to the autistic personality. However the emerging evidence
may reveal something completely non-traditional. The autistic personality can present in the
offspring of two completely insensitive parents or two extremely sensitive parents. The laws
of genetics as they stand today will be challenged even maybe overturned. It seems that the
genetic makeup of 20% of newborns contains the requirements of the autistic personality to
varying degrees regardless of the parents basic personality. It seems that no matter who mates
with whom there is a 20% chance that the outcome is an autistic or sensitive baby. I believe in
this fascinating concept, which is yet to be proven. I also believe that this is a profound
adaptive measure that ensures the propagation of humanity.

Temperament, emotion, and cognition at fourteen months: the MacArthur
Longitudinal Twin Study
Plomin R, Zahn-Waxler C et al. Child Dev. 1992 Dec;63(6):1437-55.
Department of Psychiatry, University of Colorado Health Sciences Center
200 pairs of twins were assessed at 14 months of age in the laboratory and home. Measures
were obtained of temperament, emotion, and cognition/language. Comparisons between
identical and fraternal twin correlations suggest that individual differences are due in part to
heritable influences. For temperament, genetic influence was significant for behavioral
observations of inhibition to the unfamiliar, tester ratings of activity, and parental ratings of
temperament. For emotion, significant genetic influence was found for empathy and parental
ratings of negative emotion. The estimate of heritability for parental report of expression of
negative emotions was relatively high, whereas that for expression of positive emotions was
low, a finding consistent with previous research. For cognition and language, genetic influence
was significant for behavioral indices of spatial memory, categorization, and word
comprehension. Shared rearing environment appears influential for parental reports of language
and for positive emotions, but not for other measures of emotion or for temperament.

Genetic change and continuity from fourteen to twenty months: the MacArthur Longitudinal
Twin Study
Emde RN, Robinson J et al. Child Dev. 1993 Oct;64(5):1354-76.
Genetic change as well as continuity was investigated within the domains of temperament,
emotion, and cognition/language for 200 pairs of twins assessed at 14 and 20 months of age in
the laboratory and home. The second year of life is marked by change rather than continuity:
correlations from 14 to 20 months averaged about .30 for observational measures of
temperament and emotion, about .40 for language measures, and about .50 for mental
development. 2 types of genetic change were examined: changes in the magnitude of genetic
influence (heritability) and genetic contributions to change from 14 to 20 months. In general,
heritability estimates were similar at 14 and 20 months. Evidence for genetic influence on
change from 14 to 20 months emerged for several measures, implying that heritability cannot
be equated with stability. Analyses of continuity indicated that genetic factors are largely
responsible for continuity from 14 to 20 months.

FULKER, DW (1981) The genetic and environmental architecture of psychoticism,
extraversion and neuroticism. In HJ Eysenck (ED) A Model for Personality (pp 88-122)
Heidelberg, Springer-Verlag

Genetic etiology of behavioral inhibition among 2-year-old children
LF Dilalla et al. INFANT BEHAVIOR AND DEVELOPMENT 1994; 17(4): 405-412
Inhibited behavior in 157, 24-month-old twin pairs was studied in a situation in which two
pairs of twins, unfamiliar with each other, played together in an unfamiliar room. An intraclass
correlation comparison between monozygotic (MZ) and dizygotic (DZ) twins showed that the
heritability for inhibited behavior, for the entire sample, was significantly different from zero:r  
= .82, r  = .47. The genetic influence on extreme inhibition was assessed using a relatively new
technique which employs a multiple-regression model to predict the co-twin's inhibition score
from the proband's score and the degree of genetic relationship (1.0 for MZ twins and 0.5 for
DZ twins). The partial regression of co-twin's score on relationship, an index of the extent to
which the deviant scores of probands are due to heritable influences, was large and statistically
significant. This result provides evidence favoring a genetic contribution to behavioral inhibition
in children.

Hypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls
GP Chrousos, FW Putnam et al. Journal of Clinical Endocrinology & Metabolism (1994), Vol
78, 249-255
Childhood sexual abuse is associated with an increased incidence of age- concurrent and adult
psychopathology. Little is known, however, about the biological manifestations and sequelae of
childhood sexual abuse. In this study, we characterized the hypothalamic-pituitary-adrenal axis
of a self-selected sample of sexually abused and control girls recruited from a prospective
longitudinal study. Plasma ACTH and total and free cortisol responses to ovine CRH (oCRH)
stimulation were measured in 13 sexually abused and 13 control girls, aged 7-15 yr.
Psychiatric profiles and 24-h urinary free cortisol (UFC) measures were also obtained.
Sexually abused girls had a greater incidence of suicidal ideation (chi 2 = 4.51; df = 1; P <
0.05), suicide attempts (chi 2 = 4.51; df = 1; P < 0.05), and dysthymia (chi 2 = 8.85; df = 1; P
< 0.01) than control girls. Sexually abused girls showed significantly lower basal (t = 2.1; df =
24; P < 0.05), and net oCRH stimulated (t = 2.2; df = 24; P < 0.05) ACTH levels and
significantly reduced total ACTH responses (t = 2.5; df = 24; P < 0.05) compared with control
subjects. Their total and free basal and oCRH-stimulated plasma cortisol levels and 24-h UFC
measures, however, were similar to those in controls. The attenuated plasma ACTH with
corresponding robust plasma cortisol responses to oCRH stimulation and normal 24-h UFC
measures in sexually abused girls suggest a dysregulatory disorder of the HPA axis in these
individuals. This may reflect pituitary hyporesponsiveness to oCRH. The ability of sexually
abused subjects to correct for the proposed pituitary hyporesponsiveness to CRH may be
related to their young age and the presence of intact glucocorticoid feedback regulatory

Author’s comment: this is one of papers in which George Chrousos puts forward his theory
on the genetic vulnerability to stress spectrum. There are many others that were published
since re-inforcing the same concept.

Corticosterone in the Range of Stress-Induced Levels Possesses Reinforcing Properties:
Implications for Sensation-Seeking Behaviors
PV Piazza, H Simon et al. Proceedings of the national academy of sciences 1993; Vol 90,
In both humans and animals certain individuals seek stimuli or situations that are considered
stressful and consequently avoided by others. A common feature of such situations is an
activation of the hypothalamo-pituitary-adrenal axis leading to secretion of glucocorticoids.
Since glucocorticoids have euphoric effects in some individuals and have been shown to
potentiate the reinforcing properties of drugs of abuse in animals, we hypothesized that
corticosterone secretion during stress-like situations may have reinforcing effects and that a
higher sensitivity to the reinforcing effects of glucocorticoids might be a biological basis of
sensation seeking. In this report we show that (i) corticosterone has reinforcing properties, as
evidenced by the development of intravenous self-administration, (ii) self-administration of
corticosterone is observed at plasma levels that are comparable to those induced by stress, and
(iii) there are individual differences in corticosterone self-administration, which are related to
individual reactivity to novelty and sensitivity to drugs of abuse, behavioral features akin to
certain traits of high-sensation seekers. These findings provide insight into the physiological
role of glucocorticoids and the biology of sensation seeking and may have clinical implications.


Beyond IQ: broad-based measurement of individual success potential or "emotional intelligence".
Mehrabian A. Genet Soc Gen Psychol Monogr. 2000 May;126(2):133-239.
Department of Psychology, University of California, Los Angeles
Individual-difference correlates of life success were studied using 302 participants aged 17-46
years (107 men, 195 women) and 31 individual-difference measures. Factor 1 (Relaxed
Temperament) included Trait Pleasure-Displeasure (+), Anxiety (-), Depression (-), Optimism
(+), Self-Esteem (+), Covert Index of Employee Reliability (+), and Functional Flexibility (-).
Positively loading scales on Factor 2 (Arousable Temperament) were Trait Arousability,
Emotional Empathy, Emotional Thinking, and Affiliative Tendency. Factor 3 (Disciplined Goal
Orientation) included Delay of Gratification (+), Impulsivity (-), Procrastination (-), Patience
(+), Integrity (+), Adaptive Coping (+), and Intelligence (+). Positively loading scales on
Factor 4 (Dominant Temperament) were Trait Dominance-Submissiveness, Social
Competence, Achieving Tendency, and Self-Actualization. Factors 1, 3, 4, and intelligence
exhibited positive relations with all peer-rated criterion measures of life success. Trait
Arousability, representing Factor 2, correlated negatively with relationship, physical, work, and
overall success. Physical attractiveness correlated positively with all success measures except
emotional success. When success measures were regressed against intelligence and personality
scales or factors, intelligence did not account for variance beyond that explained by personality.

AUTHOR’S COMMENT: trait arousability is one of the terms used scientifically to describe
sensitive people (those who are highly emotionally aroused during stress or highly reactive to
stress in general). This study concludes that screeners (high emotional arousability) have a
social and interpersonal disadvantage brought on by the emotional component being constantly
injected into their affairs. This and many other studies also show that habituation is the way to
minimize the impact of the emotional component in social interactions.

Relationships among three general approaches to personality description
Albert Mehrabian; The Journal of Psychology Sept 1995; 129(5):565-81
The present study was designed to investigate relationships among three basic models used in
research on personality description: Wiggins’s (1979) Circumplex, Goldberg’s (1992) Big-
Five, and Mehrabian’s (1978, 1980) PAD Temperament models. Wigginsts Nurturance and
Dominance scales were highly reliable and nearly independent, as were Mehrabian’s Trait
Pleasure, Trait Arousability, and Trait Dominance scales. The Big-Five scales exhibited lower
reliabilities and an average interscale correlation of .21 for the Opaque and .39 for the
Transparent scales. Regression and factor analyses showed that basic factors of pleasantness
(Goldberg’s Agreeableness, Wiggins’s Nurturance, and Mehrabian’s Trait Pleasure),
dominance (Wiggins’s Dominance and Mehrabian’s Trait Dominance), and arousability
(Mehrabian’s Trait Arousability) provided a sufficient and reasonably parsimonious description
of the variance in all the scales investigated.

AUTHOR’S COMMENT: this article is meant mostly for health professionals, since
mainstream medicine is obsessed with the “BIG 5” approach to personality description. The
PAD (pleasure-arousability-dominance) is the approach Dr Mehrabian uses. The arousability
component of this approach is the part we use in the text to describe screeners and non-

Individual differences in stimulus screening and arousability
Mehrabian A; J Pers. 1977 Jun; 45(2): 237-50
AUTHOR’S COMMENT: this is the original article for the model of screeners/non-screeners in
the context of emotional arousability spectrum.


HABITUATION & Dishabituation of the electrodermal orienting reflex in relation to
extraversion & neuroticism
Wigglesworth, MJ & Smith, BD (1976); Journal of research in personality 10(4); 437-445
Orienting reflex (OR) habituation and dishabituation may be influenced by individual difference
variables, including Eysenck's Extraversion (E) and Neuroticism (N) dimensions. Ninety
subjects formed nine groups based on the crossover of high, medium, and low E and N. Each
subject received, at each of two auditory stimulus intensities, two blocks of tone presentations.
The last standard stimulus trial was followed by a novel stimulus and four repetitions of the
standard stimulus. Using square root SCR, extraverts showed smaller initial response
amplitudes than introverts at the low intensity of stimulation, while the reverse was true at high
intensity. E and N were unrelated to SCR habituation rate. However, extraverts showed no
dishabituation, while introverts did dishabituate.

Extraversion & electrodermal activity; arousability & the inverted u;
SMITH, BD (1983); Personality & Individual Differences, Vol 4; p 411-420
Department of Psychology, University of Maryland, College Park, MD
The Eysenck hypothesis that extraverts are less aroused or more inhibited than introverts has
been subjected to a number of tests in the psychophysiological literature. Research to date
suggests the need to clearly differentiate between tests of overall group differences in arousal
or inhibition and studies of the differential reactions of the two groups to arousal
manipulations. Psychophysiological studies of overall arousal differences in our laboratories
and elsewhere have yielded somewhat inconsistent results for SCL, nonspecific response
frequency, trials-to-criterion habituation and initial response amplitude, though dishabituation
results are consistent with the expectation of higher amplitudes in introverts. Far more
consistent are findings testing the inverted-U hypothesis, which suggests that introverts reach
a point of optimal arousal at lower levels of stimulus input than do extraverts and hence should
show earlier asymptotes and decrements in arousal measures. Using stimulus intensity and
caffeine to manipulate arousal, we have found supportive results for SCL and several phasic
measures, including the initial, test, and dishabituation responses. Overall, findings suggest that
the two personality groups differ more clearly in arousability than in overall arousal level and
that this difference is most consistent when conditions induce a rapid breakdown of inhibition
and increase in arousal. Further research is needed to better understand the conditional
relationship of extraversion to arousability, and arousal-manipulation paradigms would appear
to be a fruitful initial approach to carrying out the needed research.

Extraversion and multiple levels of caffeine-induced arousal: effects on
overhabituation and dishabituation.
Smith BD, Wilson RJ, Jones BE. Psychophysiology 1983 Jan;20(1):29-34.
Psychophysiological tests of the Eysenck hypothesis that introverts are more arousal prone
than extraverts have yielded somewhat mixed results. In an attempt to clarify and extend
previous findings, the present study manipulated arousal level, using caffeine. Extreme groups
of 48 extraverts and 48 introverts were used, and each subject was randomly assigned to a
low, medium, or high dosage of caffeine or a placebo. Each subject heard a series of tones
until criterion electrodermal habituation occurred. This was followed by dishabituation,
overhabituation, and a further dishabituation procedure. Increasing caffeine dosages produced
a linear increment in tonic levels in extraverts, but had little effect on SCL in introverts. Higher
caffeine dosages also increased phasic response amplitudes in extraverts but decreased
amplitudes in introverts. Although somewhat complex, results were partially supportive of the
Eysenck hypothesis.

Sensation-seeking: electrodermal and behavioral effects of stimulus content and intensity.
Smith BD, Davidson RA, Perlstein W, Gonzalez F. Int J Psychophysiol. 1990 Sep; 9(2):179-88.
ABSTRACT: Although a number of studies support an arousal theory interpretation of
differential sensation-seeking behavior, the conditions under which arousal correlates of this
personality dimension are manifest is as yet unclear. Both theory and research suggest that
among the external factors affecting the differential arousal response are stimulus relevance
and stimulus intensity. The present study assessed the impact of these factors on both
psychophysiological and behavioral responses. Subjects were preselected to represent the
extremes of the sensation-seeking dimension, then exposed to auditory and visual presentations
of a series of sexual and aggressive stimuli of systematically varied intensity. High sensation
seekers gave larger amplitude SCRs to violent stimuli and larger initial responses to sexual
stimuli presented visually, while verbal response intensities showed an opposite pattern.
Overall, results provided support for an arousal theory interpretation of sensation-seeking, but
suggested that the probability and magnitude of group differences is a somewhat complex
function of stimulus intensity, stimulus modality, and perhaps other factors not yet assessed.

Advances in personality theory and research
Stelmack RM. J Psychiatry Neurosci. 1991 Sep;16(3):131-8.
School of Psychology, University of Ottawa, Ontario, Canada
ABSTRACT: This paper briefly describes important advances in personality research that have
been achieved during the past 20 years in the development of a fundamental personality
typology and in the determination of the heritability of personality traits. Research conducted at
the University of Ottawa that has contributed to the exploration of the biological bases of the
extraversion trait is summarized.

Neurocognitive components of the behavioral inhibition and activation systems: Implications
for theories of self-regulation
DM Amodio, SE Taylor et al. Psychophysiology 2008; 45(1): 11-19
Abstract: We examined the neurocognitive correlates of the Behavioral Inhibition and
Behavioral Activation Systems (BIS/BAS) in an effort to clarify ambiguities concerning
interpretations of BIS as reflecting inhibition versus avoidance. We hypothesized that self-
reported BIS should relate to neural mechanisms associated with conflict monitoring, whereas
self-reported BAS should be associated with neural correlates of approach motivation.
Consistent with these predictions, higher self-reported BIS was uniquely related to the N2
event-related potential on No-Go trials of a Go/No-Go task, linking BIS with conflict
monitoring and sensitivity to No-Go cues. Higher BAS was uniquely related to greater left-
sided baseline frontal cortical asymmetry associated with approach orientation. Implications for
theories of self-regulation involving conflict monitoring, cognitive control, and
approach/avoidance motivation are discussed.


Stress and Body Shape: Stress-Induced Cortisol Secretion Is Consistently Greater Among
Women with Central Fat
Bruce McEwen, Jeanette R. Ickovics et al. Psychosomatic Medicine 62:623–632 (2000)
Objective: Excessive central fat puts one at greater risk of disease. In animal studies, stress-
induced cortisol secretion has been shown to increase central fat. The objective of this study
was to assess whether women with central fat distribution (as indicated by a high waist-to-hip
ratio [ WHR ]), across a range of body mass indexes, display consistently heightened cortisol
reactivity to repeated laboratory stressors. Methods: Fifty nine healthy premenopausal women,
30 with a high WHR and 29 with a low WHR , were exposed to consecutive laboratory
sessions over 4 days (three stress sessions and one rest session). During these sessions,
cortisol and psychological responses were assessed. Results: Women with a high WHR
evaluated the laboratory challenges as more threatening, performed more poorly on them, and
reported more chronic stress. These women secreted significantly more cortisol during the
first stress session than women with a low WHR . Furthermore, lean women with a high WHR
lacked habituation to stress in that they continued to secrete significantly more cortisol in
response to now familiar challenges (days 2 and 3) than lean women with a low WHR .
Conclusions: Central fat distribution is related to greater psychological vulnerability to stress
and cortisol reactivity. This may be especially true among lean women, who did not habituate
to repeated stress. The current cross-sectional findings support the hypothesis that stress
induced cortisol secretion may contribute to central fat and demonstrate a link between
psychological stress and risk for disease. Key words: stress, cortisol, waist-to-hip ratio, body
mass index.

Shy-bold continuum in pumpkinseed sunfish (Lepomis gibbosus): an ecological study of a
psychological trait
Wilson, D. S., Biederman, L et al. Journal of Comparative Psychology 1993; 107: 250–60
The shy–bold continuum is recognized as a fundamental axis of behavioral variation in humans,
but 3 major issues have not been addressed. First, the taxonomic distribution of shyness and
boldness is unknown. Second, the ecological consequences of shyness and boldness have not
been studied in natural populations. Third, no one has tried to predict and test patterns of
shyness and boldness that might result from natural selection. We show that a shy–bold
continuum, which influences diet, predator risk, and parasite fauna, exists in juvenile
pumpkinseed sunfish (Lepomis gibbosus). Individual differences are relatively stable in nature
but seem to disappear when the fish are held in social and ecological isolation in the laboratory.
Thus, phenotypic stability may not reflect innate tendencies to be shy or bold but rather
environmental conditions that maintain differences between phenotypically plastic individuals.

Neuronal polymorphism among natural alleles of a cGMP-dependent kinase gene, foraging, in
Renger J, Sokolowski M et al. J Neurosci. 1999; 19(19): RC28 1-8
Natural variation in neuronal excitability and connectivity has not been extensively studied. In
Drosophila melanogaster, a naturally maintained genetic polymorphism at a cGMP-dependent
protein kinase (PKG) gene, foraging (for), is associated with alternative food search strategies
among the allelic variants Rover (for(R); higher PKG activity) and sitter (for(s); lower PKG
activity). We examined physiological and morphological variations in nervous systems of these
allelic variants isolated from natural populations. Whole-cell current clamping revealed distinct
excitability patterns, with spontaneous activities and excessive evoked firing in cultured sitter,
but not Rover, neurons. Voltage-clamp examination demonstrated reduced voltage-dependent K
(+) currents in sitter neurons. Focal recordings from synapses at the larval neuromuscular
junction demonstrated spontaneous activity and supernumerary discharges with increased
transmitter release after nerve stimulation. Immunolabeling showed more diffuse motor axon
terminal projections with increased ectopic nerve entry points in sitter larval muscles. The
differences between the two natural alleles was enhanced in laboratory-induced mutant alleles
of the for gene. The pervasive effects of the for-PKG on neuronal excitability, synaptic
transmission, and nerve connectivity illustrate the magnitude of neuronal variability in
Drosophila that can be attributed to a single gene. These findings establish the consequences in
cellular function for natural variation in an isoform of PKG and suggest a role for natural
selection in maintaining variation in neuronal properties.

Isotope analysis reveals foraging area dichotomy for atlantic leatherback turtles.
Caut S, Das K, Girondot M. et al. PLoS ONE. 2008 Mar 26; 3(3):e1845.
Laboratory for Oceanology, MARE Center, B6C Liège University, Belgique
BACKGROUND: The leatherback turtle (Dermochelys coriacea) has undergone a dramatic
decline over the last 25 years, and this is believed to be primarily the result of mortality
associated with fisheries bycatch followed by egg and nesting female harvest. Atlantic
leatherback turtles undertake long migrations across ocean basins from subtropical and tropical
nesting beaches to productive frontal areas. Migration between two nesting seasons can last 2
or 3 years, a time period termed the remigration interval (RI). Recent satellite transmitter data
revealed that Atlantic leatherbacks follow two major dispersion patterns after nesting season,
through the North Gulf Stream area or more eastward across the North Equatorial Current.
However, information on the whole RI is lacking, precluding the accurate identification of
feeding areas where conservation measures may need to be applied.
METHODOLOGY/PRINCIPAL FINDINGS: Using stable isotopes as dietary tracers we
determined the characteristics of feeding grounds of leatherback females nesting in French
Guiana. During migration, 3-year RI females differed from 2-year RI females in their isotope
values, implying differences in their choice of feeding habitats (offshore vs. more coastal) and
foraging latitude (North Atlantic vs. West African coasts, respectively). Egg-yolk and blood
isotope values are correlated in nesting females, indicating that egg analysis is a useful tool for
assessing isotope values in these turtles, including adults when not available.
CONCLUSIONS/SIGNIFICANCE: Our results complement previous data on turtle movements
during the first year following the nesting season, integrating the diet consumed during the year
before nesting. We suggest that the French Guiana leatherback population segregates into two
distinct isotopic groupings, and highlight the urgent need to determine the feeding habitats of
the turtle in the Atlantic in order to protect this species from incidental take by commercial
fisheries. Our results also emphasize the use of eggs, a less-invasive sampling material than
blood, to assess isotopic data and feeding habits for adult female leatherbacks.

Foraging modes of Mesozoic birds and non-avian theropods
Glen CL, Bennett MB Curr Biol. 2007 Nov 6; 17(21): R911-2.
The origin and early evolution of birds has been a major topic in evolutionary biology. In the
20th century, evolutionary scenarios posited either ground-based bird ancestors or tree-
dwelling ancestors. This has since been recognized as a false dichotomy [1]. We suggest that
part of the problem is the loose categorization of many extant bird species as either ground or
tree locomotors when considering hind-limb function [2-7]. In reality these are not mutually
exclusive alternatives. Many extant birds exhibit different degrees of ground- and tree-based
behaviors. We thus propose they can be better placed on a spectrum - rather than a dichotomy
- according to the extent of ground and/or tree foraging they exhibit. To test this system we
analyzed the toe claws of 249 species of Holocene birds, revealing that claw curvature
increases as tree foraging becomes more predominant. Improved claw morphometrics allow
more direct comparisons between extant and extinct birds in order to infer the behaviors of the
latter. In contrast to previous studies [2-6], we find that claw curvatures of Mesozoic birds
and closely related non-avian theropod dinosaurs, differ significantly from Holocene arboreal
birds and more closely resemble those of Holocene 'ground-foraging' birds.

Divergent stress responses and coping styles in psychogenetically selected Roman high-(RHA)
and low-(RLA) avoidance rats: behavioral, neuroendocrine and developmental aspects.
Steimer T, Driscoll P. Stress. 2003 Jun;6(2):87-100.
Abstract: The Swiss sublines of Roman high-(RHA/Verh) and low-(RLA/Verh) avoidance rats
have been genetically selected for good vs. poor performance in two-way active avoidance
since 1972. RLA/Verh rats show increased stress responses (e.g. freezing behaviour, ACTH,
corticosterone and prolactin secretion) and adopt a more passive (or reactive) coping style
when confronted with a novel environment. In the open field, elevated plus-maze, black/white
box test, and in a new light/dark open field test, RLA/Verh rats appear to be more anxious than
their RHA/Verh counterparts. Anxiety may result from their particular psychophysiological
profile, i.e. increased emotionality combined with a passive coping style. In contrast,
RHA/Verh rats are less responsive to stress, they show little anxiety in novel situations and
tend to be impulsive and novelty (sensation) seekers. Some behavioural differences are already
noticeable shortly after birth, but the full pattern appears to stabilize only after puberty. Gene-
environment interactions are critical in establishing this pattern. The data reviewed indicate that
the differences between RHA/Verh and RLA/Verh rats probably result from a complex
interaction among divergent anxiety/emotionality characteristics, differences in locomotor
activity and novelty/reward seeking, as well as active vs. passive coping styles. It is proposed
further that these divergent personality types are to be found not only in other selective
breeding programs but in the form of individual differences in most populations of rats used
for this type of research.

This group in Switzerland thought to find out whether there is any difference in sensitivity to
stress among rats. Well, as you might imagine, something so instinctively essential to the
survival of any species is likely to be found once you look for it. It is my contention that the
presence of groups who are highly sensitive as opposed to groups who are less sensitive
within the same species is a basic survival strategy likely to be found throughout the animal
kingdom regardless of level of intelligence attained by any particular species.



Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults
Entringer S, Kumsta R, Hellhammer DH, Wadhwa PD, Wüst S. Horm Behav. 2008 Nov 25
University of Trier, Germany; University of California, Irvine
Epidemiological studies have reported associations between measures of size and weight at
birth and disease risk in later life. Alteration in the regulation of the hypothalamic-pituitary-
adrenal (HPA) axis in response to prenatal stress has been proposed as one underlying
mechanism. The present study investigated in humans the association of prenatal psychosocial
stress exposure with subsequent HPA axis regulation in adult life, with a focus on measures of
response to challenge and feedback sensitivity. Healthy young adults whose mothers
experienced severe stress during their pregnancy in form of major negative life events (e.g.
death of someone close; prenatal stress (PS) group, n=31) and an age-matched comparison
group (CG, n=30) underwent the Trier Social Stress Test (TSST) and a 1 mug ACTH(1-24)
stimulation test. In addition, a diurnal cortisol profile was assessed. ACTH concentrations
following a standardized behavioural challenge paradigm (TSST) were marginally significantly
higher in PS subjects than in CG subjects (p=.06). Pre-TSST adrenocortical (cortisol) levels
were lower (p=.007), whereas the increase in cortisol in response to the TSST was higher (p=.
03) in PS subjects compared to CG subjects. Cortisol concentrations following a
pharmacological stimulation test simulating pituitary activity (ACTH (1-24) test) were
significantly lower in PS than in CG subjects (p=.006). No differences emerged between the
two groups in basal diurnal cortisol levels. This study provides first evidence in humans of an
association between prenatal psychosocial stress exposure and subsequent alterations in the
regulation of the HPA axis.

The selfish brain: competition for energy resources.
Fehm HL, Kern W, Peters A. Prog Brain Res. 2006; 153:129-40
Abstract: Although the brain constitutes only 2% of the body mass, its metabolism accounts
for 50% of total body glucose utilization. This delicate situation is aggravated by the fact that
the brain depends on glucose as energy substrate. Thus, the contour of a major problem
becomes evident: how can the brain maintain constant fluxes of large amounts of glucose to
itself in the presence of powerful competitors as fat and muscle tissue. Activity of cortical
neurons generates an "energy on demand" signal which eventually mediates the uptake of
glucose from brain capillaries. Because energy stores in the circulation (equivalent to ca. 5 g
glucose) are also limited, a second signal is required termed "energy on request"; this signal is
responsible for the activation of allocation processes. The term "allocation" refers to the
activation of the "behavior control column" by an input from the hippocampus-amygdala
system. As far as eating behavior is concerned the behavior control column consists of the
ventral medial hypothalamus (VMH) and periventricular nucleus (PVN). The PVN represents
the central nucleus of the brain's stress systems, the hypothalamus-pituitary-adrenal (HPA)
axis and the sympathetic nervous system (SNS). Activation of the sympatico-adrenal system
inhibits glucose uptake by peripheral tissues by inhibiting insulin release and inducing insulin
resistance and increases hepatic glucose production. With an inadequate "energy on request"
signal neuroglucopenia would be the consequence. A decrease in brain glucose can activate
glucose-sensitive neurons in the lateral hypothalamus (LH) with the release of orexigenic
peptides, which stimulate food intake. If the energy supply of the brain depends on activation
of the LH rather than on increased allocation to the brain, an increase in body weight is
evitable. An increase in fat mass will generate feedback signals as leptin and insulin, which
activate the arcuate nucleus. Activation of arcuate nucleus in turn will stimulate the activity of
the PVN in a way similar to the activation by the hippocampus-amygdala system. The activity
of PVN is influenced by the hippocampal outflow, which in turn is the consequence of a
balance of low-affinity and high-affinity glucocorticoid receptors. This set point can
permanently be displaced by extreme stress situations, by starvation, exercise, hormones,
drugs or by endocrine-disrupting chemicals. Disorders in the "energy on request" process will
influence the allocation of energy and in so doing alter the body mass of the organism. In this
"selfish brain theory" the neocortex and the limbic system play a central role in the
pathogenesis of diseases, such as anorexia nervosa, obesity and diabetes mellitus type II. From
these considerations it appears that the primary disturbance in obesity is a displacement of the
hippocampal set-point of the system. The resulting permanent activation of the feedback
system must result in a likewise permanent activation of the sympatico-adrenal system, which
induces insulin resistance, hypertension and the other components of the metabolic syndrome.
Available therapies for treatment of the metabolic syndrome (blockade of alpha- and beta-
adrenergic receptors, insulin and insulin secretagogues) interfere with mechanisms, which
must be considered compensatory. This explains why these therapies are disappointing in the
long run. New therapeutic strategies based on the "selfish brain theory" will be discussed.

Influence of Stress during Pregnancy on HPA Activity and Neonatal Behavior
DIRK H. HELLHAMMER et al. ANN NY ACAD SCI 2004; 1032: 228-230
Graduate School of Psychobiology, University of Trier, Germany
Prenatal maternal stress has been shown to impair birth outcome and behavioral functioning in
nonhuman primate offspring. Little is known about the effects of prenatal stress on behavioral
development in humans. We assessed the effect of self-reported prenatal stress on behavioral
characteristics of 81 newborns using the Neonatal Behavioral Assessment Scale (NBAS). We
suspected that high levels of perceived chronic stress during pregnancy may negatively affect
the brain development of the fetus, reflected in poorer behavioral maturity and higher
irritability. We found a poorer performance of newborns from high stressed mothers in the

Prenatal stress and risk for psychopathology: specific effects or induction of general
Huizink AC, Buitelaar JK et al. Psychol Bull. 2004 Jan;130(1):115-42;
University Medical Center Utrecht, Utrecht, Netherlands
This review focuses on prenatal stress as a risk factor for psychopathology. Evidence from
animal studies is summarized, and the relevance of prenatal stress models in animals for human
studies is discussed. In the offspring of prenatally stressed animals, overactivity and impaired
negative feedback regulation of the hypothalamic-pituitary-adrenal axis are consistent findings
and may reflect a pathophysiological mechanism involved in the development of
psychopathology. Reduced activity of the opioid GABA/benzodiazepine, serotonin, and
dopamine systems and increased activity of the sympathico-adrenal system have been found as
well. These alterations have been linked to a diverse spectrum of psychopathology. Therefore,
the evidence supports the view that exposure to prenatal stress may result in a general
susceptibility to psychopathology, rather than exerting a direct effect on a specific form of

Prenatal stress and long-term consequences: implications of glucocorticoid hormones.
Maccari S, Van Reeth O et al. Neurosci Biobehav Rev. 2003;27(1-2):119-27.
Université de Lille 1, FRANCE
We have shown that prenatal restraint stress (PNRS) induces higher levels of anxiety, greater
vulnerability to drugs, a phase advance in the circadian rhythm of locomotor activity and an
increase in the paradoxical sleep in adult rats. These behavioral effects result from permanent
modifications to the functioning of the brain, particularly in the feedback mechanisms of the
hypothalamic-pituitary-adrenal (HPA) axis: the secretion of corticosterone is prolonged after
stress and the number of the central glucocorticoid receptors is reduced. These abnormalities
are associated with modifications in the synthesis and/or release of certain neurotransmitters.
Dysfunction of the HPA axis is due, in part, to stress-induced maternal increase of
glucocorticoids, which influences fetal brain development. Some biological abnormalities in
depression can be related to those found in PNRS rats reinforcing the idea of the usefulness of
PNRS rats as an appropriate animal model to study new pharmacological approaches.

The neurobiology of stress in human pregnancy: implications for prematurity and development
of the fetal central nervous system.
Wadhwa PD, Sandman CA, Garite TJ. Prog Brain Res. 2001;133:131-42
University of California, Irvine
Adverse early experience, including prenatal maternal psychosocial stress, has the potential to
negatively influence developmental processes through both physiological and behavioral
mechanisms. This in turn may have adverse consequences for the mental and physical health,
well being and aging of the individual throughout the entire life-span. We have initiated a
program of research on humans to examine the consequences of maternal stress and related
factors in pregnancy on the length of gestation, fetal growth, and brain development. We have
also investigated the physiological mechanisms that are involved. In this chapter we outline the
theoretical rationale for this work and give an overview of our findings to date. These findings
support a significant and independent role for behavioral processes such as maternal prenatal
stress in the etiology of prematurity-related outcomes, and suggest that these effects are
mediated, in part, by the maternal-placental-fetal neuroendocrine axis; specifically by placental
corticotropin-releasing hormone. Using a fetal challenge paradigm as a novel method for
quantifying fetal neurologic maturity in utero, we have found that the maternal environment
exerts a significant influence on the fetal autonomic nervous system and on central nervous
system processes related to recognition, memory and habituation. Finally, our findings provide
preliminary evidence to support the notion that the influence of prenatal stress and maternal-
placental hormones on the developing fetus may persist after birth, as assessed by measures of
temperament and behavioral reactivity in the first 3 years of postnatal life. The implications of
these studies for life-span development and health are discussed.

The role of brothers and sisters in the gender development of preschool children
Rust J, Golombok S, Hines M, Johnston K, Golding J; ALSPAC Study Team; J Exp Child
Psychol. 2000 Dec; 77(4): 292-303.
Goldsmiths College, University of London, United Kingdom
The study examined whether the sex of older siblings influences the gender role development
of younger brothers and sisters of age 3 years. Data on the Pre-School Activities Inventory, a
measure of gender role behavior that discriminates within as well as between the sexes, were
obtained in a general population study for 527 girls and 582 boys with an older sister, 500 girls
and 561 boys with an older brother, and 1665 singleton girls and 1707 singleton boys. It was
found that boys with older brothers and girls with older sisters were more sex-typed than
same-sex singletons who, in turn, were more sex-typed than children with other-sex siblings.
Having an older brother was associated with more masculine and less feminine behavior in
both boys and girls, whereas boys with older sisters were more feminine but not less
masculine and girls with older sisters were less masculine but not more feminine.

Prenatal stress and gender role behavior in girls and boys: a longitudinal, population study.
Hines M, Johnston KJ, Golombok S, Rust J, Stevens M, Golding J; ALSPAC Study Team.
Avon Longitudinal Study of Parents and Children Horm Behav. 2002 Sep;42(2):126-34.
Department of Psychology, City University, London, United Kingdom.
Prenatal stress influences neural and behavioral sexual differentiation in rodents. Male offspring
of stressed pregnancies show reduced masculine-typical characteristics and increased feminine-
typical characteristics, whereas female offspring show the opposite pattern, reduced feminine-
typical and increased masculine-typical characteristics. These outcomes resemble those seen
following manipulations of gonadal hormones and are thought to occur because stress
influences these hormones during critical periods of development. Research on prenatal stress
and human sexual differentiation has produced inconsistent results, perhaps because studies
have used small samples and assessed prenatal stress retrospectively. We related maternal self-
reports of prenatal stress to childhood gender role behavior in a prospective, population study
of 13,998 pregnancies resulting in 14,138 offspring. Neither stress reported during the first 18
weeks of pregnancy nor stress reported from week 19 of pregnancy to week 8 postnatal
related to gender role behavior in male offspring at the age of 42 months. In female offspring,
maternal reports of stress during both periods showed only small correlations with masculine-
typical behavior. Although this relationship remained significant when other factors that related
to stress were controlled, these other factors made larger contributions to girls' gender role
behavior than did prenatal stress. In addition, in both boys and girls, older male or female
siblings, parental adherence to traditional sex roles, maternal use of tobacco or alcohol during
pregnancy, and maternal education all related significantly to gender role behavior. Our results
suggest that prenatal stress does not influence the development of gender role behavior in boys
and appears to have relatively little, if any, influence on gender role behavior in girls.

Author’s comment: the conclusion of this study does not fit the finding. What they found is
that the preferences carried over from the womb can be overridden by experience and
environmental influences. This does not preclude an underlying natural preference formed
during pregnancy through the mother’s experience and other hormonal and genetic factors.

Testosterone during pregnancy and gender role behavior of preschool children: a longitudinal,
population study.
Hines M, Golombok S, Rust J, Johnston KJ, Golding J; Avon Longitudinal Study of
Parents and Children Study Team Child Dev. 2002 Nov-Dec;73(6):1678-87.
Department of Psychology, City University, London, UK.
Levels of testosterone (T) and sex hormone-binding globulin (SHBG) were measured in blood
samples from pregnant women and related to gender role behavior in 342 male and 337 female
offspring at the age of 3.5 years. Gender role behavior was assessed using the Pre-School
Activities Inventory, a standardized measure on which a parent indicates the child's
involvement with sex-typical toys, games, and activities. Levels of T, but not SHBG, related
linearly to gender role behavior in preschool girls. Neither hormone related to gender role
behavior in boys. Other factors, including the presence of older brothers or sisters in the
home, parental adherence to traditional sex roles, the presence of a male partner in the home,
and maternal education, did not relate to gender role behavior in this sample and did not
account for the relation observed between T and behavior. Although other, unmeasured factors
may explain the relation, the results suggest that normal variability in T levels prenatally may
contribute to the development of individual differences in the gender role behavior of preschool

Reduced Infant Birth weight Consequent upon Maternal Exposure to Severe Life Events
AS Khashan, PN Baker, et al. Psychosomatic Medicine 2008; 70: 688-694
Objective: To investigate the association between maternal exposure to severe life events and
fetal growth (birth weight and small for gestational age). Stress has been associated with
adverse pregnancy outcome.
Methods: Mothers of 1.38 million singleton live births in Denmark between 1979 and 2002
were linked to information on their spouses, parents, siblings, and older children. Exposure
was defined as death or serious illness in a relative during pregnancy or in the 6 months before
Results: Death of a relative during pregnancy or in the 6 months before conception reduced
birth weight by 27 grams. There was a significant association between maternal exposure to
death of a relative and risk of a baby weighing below the 10th percentile and 5th percentile.
Conclusions: Mothers exposed to severe life events before conception or during pregnancy
have babies with significantly lower birth weight. If this association is causal, the potential
mechanisms of stress-related effects on birth weight include changes in lifestyle due to the
exposure and stress-related dysregulation of the hypothalamic-pituitary-adrenal axis during

Maternal depression and infant cortisol: influences of timing, comorbidity and treatment.
Walker EF, Newport JD et al. J Child Psychol Psychiatry 2008 May 19
Emory University, Atlanta, GA
Background: The current study examines the relationship between maternal depression and
infant cortisol concentrations. The potential roles of comorbid maternal anxiety disorders,
timing of maternal depression, and maternal treatment with psychotropic medications during
pregnancy are addressed. Methods: Women with 6-month-old infants (105 boys and 84 girls)
participated in a laboratory paradigm that included infant saliva collection at six points, noise
burst and arm restraint stressor tasks, and a diagnostic interview of the mother. Results:
Lifetime history of maternal depression was associated with increased baseline and mean
(average) infant cortisol levels. Comorbidity with anxiety disorder was related to infant cortisol
reactivity. Peripartum (prepartum and/or postpartum) maternal depression, rather than a pre-
pregnancy history of disorder, was associated with higher infant cortisol reactivity. Prenatal
and postnatal exposure to maternal disorder had similar effects, but prenatal maternal
psychotropic medication treatment appeared to attenuate infant cortisol increases associated
with prenatal maternal disorder exposure. Conclusions: These data suggest that exposure to
maternal depression and anxiety during pregnancy and the postpartum period may increase
infant salivary cortisol. This maternal depression-infant cortisol association is independent of
the effects of delivery complications, and appears to be modulated by prenatal maternal
psychotropic treatment.

The depressed mother as a source of stimulation for her infant
Livingood AB, Smith BD et al. J Clin Psychol. 1983 May;39(3):369-75.
Compared a group of 25 postpartum depressed mothers and 25 control mothers with respect
to the level and quality of stimulation they provided for their newborn infants during a feeding
session. Observer measures of maternal behavior included visual, auditory and kinesthetic
stimulation and levels of unconditional positive regard. Results did not indicate any differences
between the two groups in levels of stimulation. However, depressed mothers provided
significantly lower levels of unconditional positive regard and exhibited less continuity of
rocking behavior with their infants. A post hoc analysis that compared the extremes of the two
S groups (N = 22) revealed significant differences in gazing behavior, with more depressed
mothers gazing less at their infant's faces. Depressed mothers exhibited significantly lower
levels of marital adjustment and had more extensive postpartum concerns. Contrary to
expectations, no relationship was demonstrated between level of marital adjustment and
maternal behavior toward the infant.

Childhood behavioral inhibition and maternal symptoms of depression
Moehler E, Resch F. Psychopathology. 2007; 40(6):446-52
BACKGROUND: The significance of behavioral inhibition in the second year of life for the
development of social phobia in later childhood was the incentive to explore whether maternal
postnatal psychopathology is a predictor for behavioral inhibition in the offspring. METHOD:
101 mother-infant pairs were recruited from local obstetric units and examined for maternal
psychopathology by the Symptom Checklist and the Edinburgh Postnatal Depression Scale
several times during the first postnatal year. Child behavioral inhibition was assessed at 14
months in a laboratory procedure. RESULTS: Postpartum depression at 4 months measured by
the Edinburgh Postnatal Depression Scale was found to be strongly associated with toddlers'
fear score/behavioral inhibition at 14 months. Maternal depressive symptoms assessed by the
revised 90-item Symptom Checklist at 6 weeks , 4 and 14 months were found to be related to
child inhibition as well. CONCLUSIONS: Even maternal depression not reaching the level of
clinical diagnosis and treatment has an impact on child behavioral development. These data
should give rise to further studies on the origins of this relationship, which might be primarily
genetic or interactional.

Cardiff puerperal mood and hormone study; III. Postnatal depression at 5 to 6 weeks
postpartum, and its hormonal correlates across the peripartum period
Read G, Walker R et al. R. Br J Psychiatry 1996 Jun; 168(6):739-44.
Department of Psychiatry, University of Wales, Cardiff
BACKGROUND: We assessed associations of mood at 5-6 weeks postpartum with peripartum
saliva cortisol and progesterone profiles. METHOD: A prospective study involved 120
primiparous women free of major marital, socioeconomic and health problems, who collected
saliva twice daily from 2 weeks before delivery to day 35 postpartum. This allowed intensive
characterization of cortisol and progesterone profiles. At the conclusion of the study, mood
was assessed according to standard criteria. RESULTS: Seven women developed major
depression according to DSM-III-R criteria. No associations emerged between progesterone
and mood at 5 to 6 weeks. Lower levels of evening cortisol in the immediate peripartum
period, were associated with postnatal depression. CONCLUSION: The study provides no
support for the treatment strategy of progesterone augmentation following delivery, as a
prophylactic against postnatal depression. The HPA axis and its associations with postnatal
mood warrant further investigation.

Sympathoadrenal Stress Reactivity Is a Predictor of Future Blood Pressure. An 18-Year
Follow-Up Study.
Rostrup M et al. Hypertension. 2008 Jun 23
In the present study we hypothesized that arterial catecholamine concentrations during rest and
2 laboratory stress tests were independent predictors of blood pressure at an 18-year follow-
up. At entry, blood pressure, heart rate, and arterial plasma epinephrine and norepinephrine
concentrations were measured in 99 healthy men (age: 19.3+/-0.4 years, mean+/-SD) at rest,
during a mental arithmetic test, and during a cold pressor test. After 18.0+/-0.9 years of follow-
up, resting blood pressure was measured. The norepinephrine and epinephrine concentrations
during the mental arithmetic explained 12.7% of the variation of future systolic blood pressure
after adjusting for initial resting blood pressure, family history, body mass index, and systolic
blood pressure during the stress test in a multiple regression analysis (adjusted R(2)=0.651;
P<0.001). To conclude, the present study shows that sympathetic nervous activity during
mental arithmetic predicts future blood pressure, indicating a possible causal factor in the
development of essential hypertension independent of the initial blood pressure.


Diet and the epigenetic (re)programming of phenotypic differences in behavior
McGowan PO, Meaney MJ, Szyf M. Brain Res. 2008 Jul 29
Abstract: Phenotypic diversity is shaped by both genetic and epigenetic mechanisms that
program tissue specific patterns of gene expression. Cells, including neurons, undergo massive
epigenetic reprogramming during development through modifications to chromatin structure,
and by covalent modifications of the DNA through methylation. There is evidence that these
changes are sensitive to environmental influences such as maternal behavior and diet, leading to
sustained differences in phenotype. For example, natural variations in maternal behavior in the
rat that influence stress reactivity in offspring induce long-term changes in gene expression,
including in the glucocorticoid receptor, that are associated with altered histone acetylation,
DNA methylation, and NGFI-A transcription factor binding. These effects can be reversed by
early postnatal cross-fostering, and by pharmacological manipulations in adulthood, including
Trichostatin A (TSA) and l-methionine administration, that influence the epigenetic status of
critical loci in the brain. Because levels of methionine are influenced by diet, these effects
suggest that diet could contribute significantly to this behavioral plasticity. Recent data suggest
that similar mechanisms could influence human behavior and mental health. Epidemiological
data suggest indeed that dietary changes in methyl contents could affect DNA methylation and
gene expression programming. Nutritional restriction during gestation could affect epigenetic
programming in the brain. These findings provide evidence for a stable yet dynamic epigenome
capable of regulating phenotypic plasticity through epigenetic programming.

Author’s comments: this work is summarizing studies done in rats, so the applicability to
humans is fifty-fifty at best. However, this study introduces the concept of mechanisms by
which environmental factors influence mental and physical growth and development. The
epigenetic effects are the mechanisms by which the environment modulates the programming
of our DNA function.

Epigenetic Programming of Stress Responses through Variations in Maternal Care
Fish EW, Meaney MJ et al. Ann N Y Acad Sci. 2004; 1036: 167-80.
Douglas Hospital Research Centre, Montréal (Québec)
Early life experiences shape an individual's physical and mental health across the lifespan. Not
surprisingly, an upbringing that is associated with adversity can produce detrimental effects on
health. A central theme that arises from studies in human and nonhuman species is that the
effects of adversity are mediated by the interactions between a mother and her young. In this
review we describe some of the long-term effects of maternal care on the offspring and we
focus on the impact of naturally occurring variations in the behavior of female rats. Of
particular interest are mothers that engage in high or low amounts of licking/grooming (LG)
and arched-back nursing (ABN) of their pups, but do so within the normal range for this
species. Such variations in LG-ABN can alter the function of the hypothalamic-pituitary-
adrenal (HPA) axis, and cognitive and
emotional development by directly affecting the underlying neural mechanisms. At the heart of
these mechanisms is gene expression. By studying the hippocampal glucocorticoid receptor
gene, we have identified that maternal care regulates its expression by changing two processes:
the acetylation of histones H3-K9, and the methylation of the NGFI-A consensus sequence on
the exon 1(7) promoter. Sustained "maternal effects" appear elsewhere in biology, including
plants, insects, and lizards, and may have evolved to program advantages in the environments
that the offspring will likely face as adults. Given the importance of early life and parent-child
interactions to later behavior, prevention and intervention programs should target this critical
phase of development.

Maternal care and the development of stress responses
Francis DD, Meaney MJ. Curr Opin Neurobiol. 1999 Feb;9(1):128-34.
Developmental Neuroendocrinology Laboratory McGill University, Canada
Studies dating from the 1950s have documented the impact of early life events on the
development of behavioral and endocrine responses to stress. Recent findings suggest that
these effects are mediated through changes in mother-offspring interactions and have identified
central corticotropin-releasing factor systems as a critical target for the effects of variations in
maternal care.

Neurobiology of mother-infant interactions: experience and central nervous system plasticity
across development and generations.
Fleming AS, O'Day DH, Kraemer GW. Neurosci Biobehav Rev. 1999 May;23(5):673-85.
The optimal coordination between the new mammalian mother and her young involves a
sequence of behaviors on the part of each that ensures that the young will be adequately cared
for and show healthy physical, emotional, and social development. This coordination is
accomplished by each member of the relationship having the appropriate sensitivities and
responses to cues that characterize the other. Among many mammalian species, new mothers
are attracted to their infants' odors and some recognize them based on their odors; they also
respond to their infants' vocalizations, thermal properties, and touch qualities. Together these
cues ensure that the mother will nurse and protect the offspring and provide them with the
appropriate physical and stimulus environment in which to develop. The young, in turn, orient
to the mother and show a suckling pattern that reflects a sensitivity to the mothers odor,
touch, and temperature characteristics. This article explores the sensory, endocrine, and neural
mechanisms that underlie this early mother-young relationship, from the perspective of, first,
the mother and, then, the young, noting the parallels between them. It emphasizes the
importance of learning and plasticity in the formation and maintenance of the mother-young
relationship and mediation of these experience effects by the brain and its neurochemistry.
Finally, it discusses ways in which the infants' early experiences with their mothers (or the
absence of these experiences) may come to influence how they respond to their own infants
when they grow up, providing a psychobiological mechanism for the inter-generational
transmission of parenting styles and responsiveness.

Cortisol circadian rhythms and response to stress in children with autism
Corbett BA, Levine S. et al. Psychoneuroendocrinology 2006 Jan; 31(1): 59-68
Department of Psychiatry, University of California at Davis
BACKGROUND: Autism is a severe neurodevelopmental disorder characterized by impairment
in communication, social interaction, repetitive behaviors and difficulty adapting to novel
experiences. The Hypothalamic-Pituitary-Adrenocortical (HPA) system responds consistently
to perceived novel or unfamiliar situations and can serve as an important biomarker of the
response to a variety of different stimuli. Previous research has suggested that children with
autism may exhibit dysfunction of the HPA system, but it is not clear whether altered
neuroendrocrine regulation or altered responsiveness underlies the differences between children
with and without autism. In order to provide preliminary data concerning HPA regulation and
responsiveness, we compared circadian rhythms and response to a non-social, environmental
stressor in children with and without autism. METHODS: Circadian rhythms of cortisol were
estimated in children with (N=12) and without (N=10) autism via analysis of salivary samples
collected in the morning, afternoon and evening on 2 consecutive days. HPA responsiveness
was assessed by examining the time course of changes in salivary cortisol in response to a
mock MRI. RESULTS: Both groups showed expected circadian variation with higher cortisol
concentration in morning than in the evening samples. The children with autism, but not typical
children, showed a more variable circadian rhythm as well as statistically significant elevations
in cortisol following exposure to a novel, nonsocial stimulus. CONCLUSIONS: The results
suggest that children with autism process and respond idiosyncratically to novel and
threatening events resulting in an exaggerated cortisol response.

Author’s comment:
This is an advanced study given the current state of research about stress in autism in the
United States. Judgment and irrelevant conclusion crack notwithstanding, this is one of the
rare domestic articles that proves the link between stress and autism. However, there is
nothing idiosyncratic about autistic children’s response to unfamiliarity. It is however a
response characterized by sings of excessive stress and a greater difficulty habituating to new

Neurochemical correlates of autistic disorder: a review of the literature.
Lam KS, Arnold LE et al. Res Dev Disabil. 2006 May-Jun;27(3):254-89
Neurodevelopmental Disorders Research Center, University of North Carolina at Chapel Hill,
Review of neurochemical investigations in autistic disorder revealed that a wide array of
transmitter systems have been studied, including serotonin, dopamine, norepinephrine,
acetylcholine, oxytocin, endogenous opioids, cortisol, glutamate, and gamma-aminobutyric
acid (GABA). These studies have been complicated by the fact that autism is a very
heterogeneous disorder, which often presents with comorbid behavioral problems. In addition,
many of these studies employed very small samples and inappropriate control groups, making
it difficult to draw conclusions with confidence. Overall, serotonin appears to have the most
empirical evidence for a role in autism, but this requires further investigation and replication.
There is little support for the notion that a dysfunction of norepinephrine or the endogenous
opioids are related to autism. The role of dopaminergic functioning has not been compelling
thus far, though conflicting findings on central dopamine turnover require further study.
Promising new areas of study may include possible dysfunction of the cholinergic system,
oxytocin, and amino acid neurotransmitters. Implications for pharmacotherapy are briefly
discussed for each neurotransmitter system with brief research examples. Review of this work
emphasizes the need for future studies to control for subject variables, such as race, sex,
pubertal status, and distress associated with blood draws, which can affect measures of
neurochemical function. In addition, research in neurochemistry must continue to work in
concert with other subspecialties to form a more comprehensive and theory-based approach to
the neurobiological correlates of autistic disorder.

Unresponsiveness to psychosocial stress in a subgroup of autistic-like children, multiple
complex developmental disorder
Jansen LM, Van Engeland H et al. Psychoneuroendocrinology. 2000; 25(8): 753-64.
Rudolf Magnus Institute of Neurosciences, Utrecht, The Netherlands
In this study, we tried to replicate the finding of a diminished cortisol response to stress in
autistic-like patients in a more homogenous Multiple Complex Developmental Disorder
(MCDD) group. MCDD forms a distinct group within the autistic-like disorders, characterized
by impaired regulation of anxiety and affective state, impaired social behavior/sensitivity, and
thought disorder. A number of MCDD children develop schizophrenia in adult life. Responses
to a psychosocial stressor, consisting of speaking in public while recorded on video, were
measured in 10 MCDD children and 12 healthy control children. The public speaking test was
imbedded in a two-hour test session, and compared to a control test session. Hypothalamic-
pituitary-adrenal (HPA) responses were measured on salivary cortisol at about 20-minute
intervals. Heart rate was measured continuously. Delta AUC's were computed for both heart
rate (dAUCHR) and salivary cortisol (dAUCCORT), as a measure of response to the test.The
public speaking task resulted in significant responses in heart rate and salivary cortisol in
healthy control children, but not in MCDD children. dAUCHR was 3.28+/-2.37 in healthy
control children, but -0.09+/-1.73 in MCDD children (t=3.31, P<0.01). dAUCCORT was 3.22
+/-3.16 in healthy control children, but 0. 17+/-1.74 in MCDD children (t=2.72, P<0.05).The
impaired responses to psychosocial stress found in MCDD children may be the result of their
limited abilities to react adequately to their (social) environment. The same impairment in stress
processing has been found in schizophrenia, and might be a factor in the vulnerability of these
MCDD children to develop schizophrenia.
AUTHOR’S COMMENT: in keeping with the mainstream tradition of attempting to categorize
a continuum, they point a very important aspect of autism. Some sensitive children have less
resilient adrenals. With severe and repetitive stress, the adrenal functional capacity is
compromised and these kids can go into limited adrenal reserves and adrenal fatigue early on.

Plasma beta-endorphin, adrenocorticotropin hormone, and cortisol in autism
Tordjman S, Cohen DJ et al. J Child Psychol Psychiatry. 1997 Sep;38(6):705-15.
Universite de Paris-Sud, Paris, France.
Plasma levels of the hypothalamo-pituitary-adrenal axis hormones beta-endorphin (BE),
adrenocorticotropin hormone (ACTH), and cortisol were measured in autistic (N = 48),
mentally retarded/cognitively impaired (MR/CI, N = 16), and normal control (N = 26)
individuals. Comparison of log transformed data from the three groups revealed that levels of
BE and ACTH were significantly higher (p < .05) in the autistic individuals than in normal
controls. The higher means in the autistic group were due to significantly higher plasma levels
of BE and ACTH, indices of acute stress response, in the more severely affected individuals.
The data support the idea that individuals with severe autism have a heightened response to
acute stressors rather than chronic hyperarousal or elevated basal
stress response system functioning.
AUTHOR’S COMMENTS: this can be considered another classic. This study shows that
autistic children are highly reactive to stress, but that in the presence of a consistently loving
caring environment they are able to thrive.

The diurnal variation and response to dexamethasone suppression test of saliva cortisol level in
autistic children.
Hoshino Y, Kumashiro H et al. Jpn J Psychiatry Neurol. 1987 Jun; 41(2): 227-35.
In order to examine the function of hypothalamic-pituitary-adrenal axis (HPA-axis) in autistic
children, the diurnal rhythm of saliva cortisol and the response of cortisol to the DST was
investigated using saliva samples. 1) The plasma and saliva cortisol levels showed a positive
correlation in normal healthy adults. Moreover, the saliva cortisol level exhibited a similar
diurnal rhythm and DST response as did the plasma cortisol level. 2) The saliva cortisol level in
normal children showed a similar diurnal rhythm and DST response as that in normal healthy
adults. 3) Some children with infantile autism showed an abnormal diurnal rhythm or DST
response for saliva cortisol. Moreover, the latter abnormality was observed more frequently in
poorly developed cases than in highly developed cases. 4) These results suggest that the
negative feedback mechanism of the HPA-axis may be disturbed in autistic children, especially
the poorly developed cases, owing to a disorder in the regulation by serotonin metabolism.
AUTHOR’S COMMENTS: repetitive stress can lead to resistance in the stress system. In
short, when stress overwhelms us, our stress response, in a misguided effort to adapt,
gradually releases its brakes and reinforces itself in preparation for the next stressful episode.
This is typically done by increasing the stress hormones (cortisol) even in the absence of
immediate stress. This is a known problem in ageing, but it can happen early on provided
sufficient exposure to stress. Resistance to relaxation by the stress system was discovered
back in the eighties by one of pioneers of the modern science of stress, Robert sapolsky.

Effect of Social Familiarity on Salivary Cortisol and Self-Reports of Social Anxiety and Stress
in Children with High Functioning Autism Spectrum Disorders
Lopata C, Volker MA, Putnam SK, Thomeer ML, Nida RE. J Autism Dev Disord. 2008 May 16
This study examined the effect of social familiarity on salivary cortisol and social anxiety/stress
for a sample of children with high-functioning autism spectrum disorders. The relationship
between self-reported social anxiety/stress and salivary cortisol was also examined.
Participants interacted with a familiar peer on one occasion and an unfamiliar peer on another
occasion. Data were collected using salivary cortisol and a scale measuring subjective stress.
Results indicated a significant condition by order interaction for salivary cortisol levels, while
self-rated stress did not differ significantly across situations. A mild-moderate correlation was
found between self-reported distress and salivary cortisol within each condition. Examination
of self-rated distress vs. cortisol scatter plots suggested a more complex relationship than the
correlation coefficient could adequately convey.

Slower cortisol response during ACTH stimulation test in autistic children
Marinović-Curin J, Terzić J et al. Eur Child Adolesc Psychiatry. 2008 Feb; 17(1):39-43
Autism is a hereditary, pervasive neurodevelopmental disorder that starts early in life. The main
characteristics of the autism are impairment in social interactions, difficulties in adapting to
novel environmental situations and improper reaction to stress. Since the Hypothalamic-
Pituitary-Adrenocortical (HPA) axis plays a key role in the response to stress and because the
previous research found abnormalities in HPA system, we conducted a study to test several
elements of the HPA axis. Because autism is a heritable disorder, autistic subjects were studied
as well as their parents. Cortisol circadian rhythm, cortisol daily secretion and its suppression
response to dexamethasone had been measured from saliva or urine samples of the autistic
children and their parents. Cortisol secretion response after ACTH stimulation was done with
the autistic children only. The cortisol elevation after ACTH stimulation among the autistic
individuals was slower (P = 0.017) than in healthy controls. No differences were
found in salivary cortisol circadian rhythm or suppression response, as well as in cortisol daily
excretion. These data indicate that, compared to healthy subjects, autistic individuals have fine
differences in cortisol response to ACTH stimulation or possibly to other types of stress.
AUTHOR’S COMMENTS: It typically takes 15 minutes from the application of a stressor until
the adrenals begin secreting extra amounts of cortisol to help cope and overcome the strain. In
times of inflammation, for example, especially gastrointestinal inflammation chemicals
[defensins] are secreted which can delay or lower the adrenal reaction to stress. This may be a
highly significant area of interest in optimizing autistic children’s coping strategies through
broadening the attention to the whole body and including sources of inflammation in the search
for answers.

Sex differences in the relationship between cortisol levels and the Empathy and Systemizing
Quotients in humans.
Nakayama Y, Radford MH et al. Neuro Endocrinol Lett. 2007 Aug; 28(4):445-8.
OBJECTIVE: Little is known regarding the relationship between cortisol (a stress hormone)
levels and psychological cognitive styles. Baron-Cohen proposed two fundamental cognitive
styles, which are measured by the Empathy Quotient (EQ) and the Systemizng Quotient (SQ).
Previous studies have examined the influences of prenatal testosterone exposure on EQ and SQ
scores. This study aimed to examine the relationships between morning cortisol levels and EQ
and SQ scores, and the 'brain types' which were determined by two quotients in both sexes.
These relationships are potentially important in the developmental psychopathology of autism
and neuroeconomics of empathy. METHODS: We assessed morning cortisol levels with
LC/MS (liquid chromatography-mass spectrometry) and ESQ in healthy male and female
university students. CONCLUSIONS: Results indicate clear sex differences between brain
types: i.e. E-type males and S-type females (participants with atypical cognitive styles) have
significantly higher cortisol levels than S-type males and E-type females (participants with
typical cognitive styles). Implications for the role of sex in social adaptation of autistic patients
are discussed.

Could oxidative stress from psychosocial stress affect neurodevelopment in autism?
McGinnis WR. J Autism Dev Disord. 2007 May; 37(5):993-4

Differentiation between autism and multiple complex developmental disorder in response to
psychosocial stress.
Jansen LM, van Engeland H et al. Neuropsychopharmacology. 2003 Mar;28(3):582-90
Multiple Complex Developmental Disorder (MCDD) represents a distinct group within the
autistic spectrum based on symptomatology. Unlike autistic children, part of MCDD children
develop schizophrenia in adult life. Despite the differences, patients of both disorders are
mainly characterized by abnormal reactions to their social environment. At the biological level,
we showed in a previous study that MCDD children have a reduced cortisol response to
psychosocial stress. Given the fact that autistic children clinically show more social
impairments, it was hypothesized that they may have even further decreased cortisol responses
to psychosocial stress than MCDD patients. Therefore, 10 autistic children were compared to
10 MCDD children and 12 healthy control children in their response to a psychosocial stressor,
consisting of a public speaking task. In order to test whether any impairments in the biological
stress response are specific for psychosocial stress, the autistic children were compared with
11 MCDD children and 15 control children in their response to a physical stressor, consisting
of 10 min of bicycle exercise. Heart rate and salivary cortisol levels were used as indicators of
response to the stress tests. Autistic children showed a relatively elevated cortisol response to
psychosocial stress, in contrast to MCDD children who showed a reduced cortisol response.
No differences in heart rate or cortisol responses to the physical stress test were found. The
specific difference between autistic and MCDD children in their cortisol response to
psychosocial stress indicates that the disturbed reactions to the social environment observed in
these disorders may have different biological backgrounds.

Joint attention development in toddlers with autism
Naber FB, van Ijzendoorn MH, Dietz C et al. Eur Child Adolesc Psychiatry. 2007 Sep 11
Deficits in Joint Attention (JA) may be one of the earliest signs of Autism Spectrum Disorders
(ASD). In this longitudinal study we investigated several types of JA behaviors at the age of 24
and 42 months, and their development over time. Eleven children with ASD, 10 children with
other developmental disorders, and eight children without a developmental disorder
participated. It was found that children with ASD showed significantly less JA at the age of 24
months. At this age, the various types of JA (Basic Joint Attention, Associated Joint Attention,
Joint Visual Attention) were correlated with developmental level and number of autistic
characteristics. However, at the age of 42 months, these associations were absent. Although
children with ASD may show less JA at the age
of 24 months compared to other groups of children, by the age of 42 months they reach about
the same level of JA, except for joint visual attention. In fact, at both ages, children with ASD
differed consistently only on JVA from the other groups. JVA may be a core component of an
early screening device for ASD.

Brief report: can you see what is not there? low-level auditory-visual integration in autism
spectrum disorder.
van der Smagt MJ, van Engeland H, Kemner C. J Autism Dev Disord. 2007; 37(10): 2014-9
Patients diagnosed with Autism Spectrum Disorder, show impaired integration of information
across different senses. The processing-level from which this impairment originates, however,
remains unclear. We investigated low-level integration of auditory and visual stimuli in subjects
with Autism Spectrum Disorder. High-functioning adult subjects with Autism Spectrum
Disorder as well as age- and IQ-matched adults were tested using a task that evokes illusory
visual stimuli, by presenting sounds concurrently with visual flashes. In both groups the
number of sounds presented significantly affected the number of flashes perceived, yet there
was no difference between groups. This finding implicates that any problems arising from
integrating auditory and visual information must stem from higher processing stages in high-
functioning adults with Autism Spectrum Disorder.

Autism: neuropathology, alterations of the GABAergic system, and animal models.
Schmitz C, Steinbusch HW et al. Int Rev Neurobiol. 2005;71:1-26.
Department of Neuropsychology, Maastricht University, The Netherlands.
AUTHOR’S COMMENTS: Nice review and update on the literature for providers and
interested public.

A controlled study of formal thought disorder in children with autism and multiple complex
developmental disorders
van der Gaag RJ, Caplan R, van Engeland H, Loman F, Buitelaar JK. J Child Adolesc
Psychopharmacol. 2005 Jun;15(3):465-76.
University Medical Centre St. Radboud The Netherlands
Along with well-defined categories in classification systems (e.g., autistic disorders and
attention-deficit/hyperactivity disorder (ADHD)), practitioners are confronted with many
children showing mixed forms of developmental psychopathology. These clusters of
symptoms are on the borderlines of more defined categories. The late Donald Cohen proposed
heuristic criteria to study a group defined by impaired social sensitivity, impaired regulation of
affect, and thinking disorders under the name multiple complex developmental disorders
(MCDD). Although these children meet criteria for pervasive developmental disorder--not
otherwise specified (PDD-NOS), they have additional important clinical features, such as
thought disorder. After highlighting similarities and differences between MCDD and
comparable groups (e.g., multidimensionally impaired children), this paper presents the
findings of a study comparing formal thought disorder scores in children with MCDD to
children with autism spectrum diagnoses, such as autistic disorder (AD), and to children with
nonspectrum diagnoses, such as ADHD and anxiety disorders. METHODS: Videotaped speech
samples of four groups of high-functioning, latency-aged children with MCDD, AD, ADHD,
and anxiety disorders were compared to a control group of normal children using the Kiddie
Formal Thought Disorder Rating Scale (K-FTDS). RESULTS: High formal thought disorder
scores were found both in the AD and MCDD groups, low rates in the ADHD groups, and no
thought disorder in the anxiety disorder and normal control groups. The severity of formal
thought disorder was related to verbal IQ scores
within the AD and MCDD groups. CONCLUSION: High formal thought scores in children
with complex developmental disorders, such as AD and MCDD, appear to reflect impaired
communication skills rather than early signs of psychosis.

Increased gray-matter volume in medication-naive high-functioning children with autism
spectrum disorder
Palmen SJ, Hulshoff Pol HE, Kemner C, Schnack HG, Durston S, Lahuis BE, Kahn RS, Van
Engeland H. Psychol Med. 2005 Apr;35(4):561-70.
Department of Child and Adolescent Psychiatry, Utrecht, The Netherlands
BACKGROUND: To establish whether high-functioning children with autism spectrum
disorder (ASD) have enlarged brains in later childhood, and if so, whether this enlargement is
confined to the gray and/or to the white matter and whether it is global or more prominent in
specific brain regions. METHOD: Brain MRI scans were acquired from 21 medication-naive,
high-functioning children with ASD between 7 and 15 years of age and 21 comparison
subjects matched for gender, age, IQ, height, weight, handedness, and parental education, but
not pubertal status. RESULTS: Patients showed a significant increase of 6% in intracranium,
total brain, cerebral gray matter, cerebellum, and of more than 40% in lateral and third
ventricles compared to controls. The cortical gray-matter volume was evenly affected in all
lobes. After correction for brain volume, ventricular volumes remained significantly larger in
patients. CONCLUSIONS: High-functioning children with ASD showed a global increase in
gray-matter, but not white-matter and cerebellar volume, proportional to the increase in brain
volume, and a disproportional increase in ventricular volumes, still present after correction for
brain volume. Advanced pubertal development in the patients compared to the age-matched
controls may have contributed to the findings reported in the present study.

Neuropathological findings in autism
Palmen SJ, van Engeland H, Hof PR, Schmitz C. Brain. 2004 Dec;127(Pt 12):2572-83
Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands
Autism is currently viewed as a largely genetically determined neurodevelopmental disorder,
although its underlying biological causes remain to be established. In this review, we examine
the available neuropathological literature on autism and discuss the findings that have emerged.
Classic neuropathological observations are rather consistent with respect to the limbic system
(nine of 14 studied cases showed increased cell packing density and smaller neuronal size), the
cerebellum (21 of 29 studied cases showed a decreased number of Purkinje cells, and in all of
five cases that were examined for age-related morphological alterations, these changes were
found in cerebellar nuclei and inferior olive) and the cerebral cortex (>50% of the studied cases
showed features of cortical dysgenesis). However, all reported studies had to contend with the
problem of small sample sizes, the use of quantification techniques not free of bias and
assumptions, and high percentages of autistic subjects with comorbid mental retardation (at
least 70%) or epilepsy (at least 40%). Furthermore, data from the limbic system and on age-
related changes lack replication by independent groups. It is anticipated that future
neuropathological studies hold great promise, especially as new techniques such as design-
based stereology and gene expression are increasingly implemented and combined, larger
samples are analysed, and younger subjects free of comorbidities are investigated.

Review on structural neuroimaging findings in autism.
Palmen SJ, van Engeland H. J Neural Transm. 2004 Jul;111(7):903-29
Rudolf Magnus Institute of Neuroscience, The Netherlands.
Autism is now widely viewed as a neurodevelopmental disorder, although the underlying
biological causes remain to be established. In this review, we examine the literature in magnetic
resonance imaging (MRI) as applied to autism, discuss the findings that have emerged, and
give directions for potential future research. To date, structural MRI results are inconsistent,
partly due to the heterogeneity of the disorder itself, and partly due to the different composition
and the varied degree of matching of the studied groups. However, recent studies have begun
to elucidate the underlying neuroanatomical abnormalities and brain-behavior relationships in
autism, with the most consistent finding being increased brain volume in autism. Future large-
scale longitudinal structural imaging studies, starting at very young ages, investigating
homogeneous groups of patients and extensively matched control groups, and making use of
(combinations of) newer and more sophisticated techniques, hold a great promise to further
elucidate the enigma of autism.

Attachment in toddlers with autism and other developmental disorders
Naber FB, Swinkels SH, Buitelaar JK, Bakermans-Kranenburg MJ, van IJzendoorn MH, Dietz
C, van Daalen E, van Engeland H. J Autism Dev Disord. 2007 Jul;37(6):1123-38.
University of Leiden, The Netherlands
Attachment was assessed in toddlers with Autistic Disorder (n=20), Pervasive Developmental
Disorder (n=14), Mental Retardation (n=12), Language Development Disorder (n=16), and a
non-clinical comparison group (n=18), using the Strange Situation Procedure (SSP). Children
in the clinical groups were more often disorganized and less often securely attached. Severity
of autism was associated with more attachment insecurity, and lower developmental level
increased the chance for disorganized attachment. Attachment disorganization was related to
increased heart rate during the SSP. Controlling for basal cortisol and developmental level,
more autistic symptoms predicted lower cortisol responses to the SSP. The findings support
the importance of disorganized attachment for children with autism.

Play Behavior and Attachment in Toddlers with Autism.
Naber FB, Bakermans-Kranenburg MJ, van Ijzendoorn MH, Swinkels SH, Buitelaar JK, Dietz
C, van Daalen E, van Engeland H. J Autism Dev Disord. 2007 Sep 26
University of Leiden The Netherlands.
Play helps to develop social skills. Children with autism show deviances in their play behavior
that may be associated with delays in their social development. In this study, we investigated
manipulative, functional and symbolic play behavior of toddlers with and without autism (mean
age: 26.45, SD 5.63). The results showed that the quality of interaction between the child and
the caregiver was related to the development of play behavior. In particular, security of
attachment was related to better play behavior. When the developmental level of the child is
taken into account, the attachment relationship of the child with the caregiver at this young age
is a better predictor of the level of play behavior than the child's disorder.

Parental sensitivity and attachment in children with autism spectrum disorder: comparison with
children with mental retardation, with language delays, and with typical development.
van Ijzendoorn MH, Rutgers AH, Bakermans-Kranenburg MJ, Swinkels SH, van Daalen E,
Dietz C, Naber FB, Buitelaar JK, van Engeland H. Child Dev. 2007 Mar-Apr;78(2):597-608.
This study on sensitivity and attachment included 55 toddlers and their parents. Samples
included children with autism spectrum disorder (ASD), mental retardation, language delay,
and typical development. Children were diagnosed at 4 years of age. Two years before
diagnosis, attachment was assessed with the Strange Situation procedure, and parental
sensitivity and child involvement during free play were assessed with the Emotional Availability
Scale. Parents of children with ASD were equally sensitive as parents of children without
ASD, but their children showed more attachment disorganization and less child involvement.
More sensitive parents had more secure children, but only in the group without ASD. Less
severe autistic symptoms in the social domain predicted more attachment security. Autism
challenges the validity of attachment theory.

Attachment in toddlers with autism and other developmental disorders.
Naber FB, Swinkels SH, Buitelaar JK, Bakermans-Kranenburg MJ, van IJzendoorn MH, Dietz
C, van Daalen E, van Engeland H. J Autism Dev Disord. 2007 Jul;37(6):1123-38.
Department of Education and Child Studies, University of Leiden
Attachment was assessed in toddlers with Autistic Disorder (n=20), Pervasive Developmental
Disorder (n=14), Mental Retardation (n=12), Language Development Disorder (n=16), and a
non-clinical comparison group (n=18), using the Strange Situation Procedure (SSP). Children
in the clinical groups were more often disorganized and less often securely attached. Severity
of autism was associated with more attachment insecurity, and lower developmental level
increased the chance for disorganized attachment. Attachment disorganization was related to
increased heart rate during the SSP. Controlling for basal cortisol and developmental level,
more autistic symptoms predicted lower cortisol responses to the SSP. The findings support
the importance of disorganized attachment for children with autism.

The physiology and psychology of behavioral inhibition in children
Kagan J, Reznick JS, Snidman N. Child Dev. 1987 Dec;58(6):1459-73.
Longitudinal study of 2 cohorts of children selected in the second or third year of life to be
extremely cautious and shy (inhibited) or fearless and outgoing (uninhibited) to unfamiliar
events revealed preservation of these 2 behavioral qualities through the sixth year of life.
Additionally, more of the inhibited children showed signs of activation in 1 or more of the
physiological circuits that usually respond to novelty and challenge, namely, the hypothalamic-
pituitary-adrenal axis, the reticular activating system, and the sympathetic arm of the
autonomic nervous system. It is suggested that the threshold of responsivity in limbic and
hypothalamic structures to unfamiliarity and challenge is tonically lower for inhibited than for
uninhibited children.

Neurobiological bases of behavioral development in the first year.
Kagan J et al. Neuropediatrics 1997 Dec;28(6):296-306.
This review summarizes the temporal relations between selected psychological milestones in
the first year of the human infant and theoretically relevant developmental neurobiological
changes in the brain, supplemented where appropriate, with evidence from the non-human
primate. The disappearance of the palmar grasp reflex and the decrease in endogenous smiling
and spontaneous crying, which occur at 2-3 months, are correlated to emergent cortical
inhibition of brainstem circuits. In addition, the improved ability to recognize an event
experienced in the immediate past (recognition memory) is related to growth of the
hippocampus and adjacent structures at this age. The behavioral developments at 7-10 months
include an enhanced ability to retrieve stored representations of the past and to compare past
and present (working memory), along with the emergence of the universal fears of strangers
and separation from the caretaker. These milestones are correlated in time with maturational
changes in the prefrontal and rhinal cortices and hippocampal formation, the integration of the
limbic system and increased responsiveness of the hypothalamus-pituitary-adrenal axis.
Knowledge of age-dependent correlations of brain and behavioral maturation is a basis for the
investigation of causal relationships between brain development and behavior. A close
collaboration of pediatricians, psychologists and neuroscientists is, therefore, necessary.

Attachment security in infancy and early adulthood: a twenty-year longitudinal study.
Everett Waters et al. Child Dev. 2000 May-Jun; 71(3):684-9.
Sixty White middle-class infants were seen in the Ainsworth Strange Situation at 12 months of
age; 50 of these participants (21 males, 29 females) were re-contacted 20 years later and
interviewed by using the Berkeley Adult Attachment Interview (AAI). The interviewers were
blind to the participants' Strange Situation classifications. Overall, 72% of the infants received
the same secure versus insecure attachment classification in early adulthood, K = .44, p < .
001. As predicted by attachment theory, negative life events-defined as (1) loss of a parent, (2)
parental divorce, (3) life-threatening illness of parent or child (e.g., diabetes, cancer, heart
attack), (4) parental psychiatric disorder, and (5) physical or sexual abuse by a family member-
were an important factor in change. Forty-four percent (8 of 18) of the infants whose mothers
reported negative life events changed attachment classifications from infancy to early
adulthood. Only 22% (7 of 32) of the infants whose mothers reported no such events changed
classification, p < .05. These results support Bowlby's hypothesis that individual differences in
attachment security can be stable across significant portions of the lifespan and yet remain
open to revision in light of experience. The task now is to use a variety of research designs,
measurement strategies, and study intervals to clarify the mechanisms underlying stability and

Individual differences in infant-mother attachment at twelve and eighteen months: stability and
change in families under stress.
Vaughn B, Egeland B, Sroufe LA, Waters E. Child Dev. 1979 Dec; 50(4):971-5.
100 economically disadvantaged mothers and their infants were observed in the Ainsworth and
Wittig "strange situation" at 12 and 18 months. Infants were classified as secure, anxiously
attached/avoidant, or anxiously attached/resistant. In addition, mothers reported occurrence of
stressful events related to the stability of the caretaking environment during the 12--18 month
period by completing a 44-item checklist concerning work, finances, family, neighbors, health,
etc. 62 infants were assigned to the same attachment classification at both 12 and 18 months
(p less than .01). Despite this stability, significantly more infants changes classification than in
a recent study of stable middle-class families. With the present sample, anxious attachment
was associated with less stable caretaking environments than secure attachment; change from
secure to anxious attachment was associated with higher stressful-event scores than stable
secure attachment.

Author’s comment: Everett Waters is one of the most celebrated contemporary scientists for
his contributions to attachment theory. He follows in the footsteps of Mary Ainsworth the
Canadian pioneer who was the first to put forward this theory and test it. As one can see from
these really unique studies attachment type developed early in life follows the person into
adulthood and probably for the rest of their natural life. It is not impossible to shift from an
insecure to a secure attachment style. However, it takes plenty of suffering and mindfulness
for that to happen. It may sometimes take a major adverse life event for that to happen. In the
upcoming chapters we will take a jab at some tools an adult can use to move in the direction of
restoring a secure attachment.

Heritability of facial expressions’ references:

Hereditary family signature of facial expression
Gili Peleg, Eviatar Nevo et al PNAS October 24, 2006 vol. 103 no. 43 P 15921-15926
Abstract: Although facial expressions of emotion are universal, individual differences create a
facial expression “signature” for each person; but, is there a unique family facial expression
signature? Only a few family studies on the heredity of facial expressions have been
performed, none of which compared the gestalt of movements in various emotional states;
they compared only a few movements in one or two emotional states. No studies, to our
knowledge, have compared movements of congenitally blind subjects with their relatives to our
knowledge. Using two types of analyses, we show a correlation between movements of
congenitally blind subjects with those of their relatives in think-concentrate, sadness, anger,
disgust, joy, and surprise and provide evidence for a unique family facial expression signature.
In the analysis “in-out family test,” a particular movement was compared each time across
subjects. Results show that the frequency of occurrence of a movement of a congenitally blind
subject in his family is significantly higher than that outside of his family in think-concentrate,
sadness, and anger. In the analysis “the classification test,” in which congenitally blind subjects
were classified to their families according to the gestalt of movements, results show 80%
correct classification over the entire interview and 75% in anger. Analysis of the movements'
frequencies in anger revealed a correlation between the movements' frequencies of congenitally
blind individuals and those of their relatives. This study anticipates discovering genes that
influence facial expressions, understanding their evolutionary significance, and elucidating
repair mechanisms for syndromes lacking facial expression, such as autism.

The spontaneous expression of pride and shame: Evidence for biologically innate nonverbal
displays JL Tracy, D Matsumoto PNAS August 19, 2008 vol. 105 no. 33 P 11655-11660
Abstract: The present research examined whether the recognizable nonverbal expressions
associated with pride and shame may be biologically innate behavioral responses to success
and failure. Specifically, we tested whether sighted, blind, and congenitally blind individuals
across cultures spontaneously display pride and shame behaviors in response to the same
success and failure situations—victory and defeat at the Olympic or Paralympic Games.
Results showed that sighted, blind, and congenitally blind individuals from >30 nations
displayed the behaviors associated with the prototypical pride expression in response to
success. Sighted, blind, and congenitally blind individuals from most cultures also displayed
behaviors associated with shame in response to failure. However, culture moderated the shame
response among sighted athletes: it was less pronounced among individuals from highly
individualistic, self-expression-valuing cultures, primarily in North America and West Eurasia.
Given that congenitally blind individuals across cultures showed the shame response to failure,
findings overall are consistent with the suggestion that the behavioral expressions associated
with both shame and pride are likely to be innate, but the shame display may be intentionally
inhibited by some sighted individuals in accordance with cultural norms.


Early identification of autism: how early can we go?
Reznick JS et al. Semin Speech Lang. 2006 Aug;27(3):143-60.
Identification of young children at risk for Autism Spectrum Disorders (ASD) depends on
early behavioral symptomatology and yet conventional criteria provide little guidance for use
with infants and toddlers. Recent research, however, has demonstrated that there are patterns
of behavior below 2 years of age that distinguish children with autism from those who are
developing typically or those with other developmental disabilities. Skill areas with particular
promise for early identification include social communication, sensory regulation, and play.
This article previews current innovative methodologies, presents a synthesis of recent research
findings related to these three key areas, and provides clinicians with practical guidelines for
early identification of infants and toddlers at risk for ASD and other disorders.



General relations among drug use, alcohol use, and major indexes of psychopathology.
Mehrabian A. J Psychol. 2001 Jan; 135(1):71-86.
Relations among measures of trait anxiety, depression, panic, somatization, alcohol use, drug
use, and treatment for depression were investigated because, typically, studies (a) addressed
relations among subsets of only 2 or 3 of the measures and (b) dealt almost exclusively with
narrow samples of the population representing extremes on 1 or 2 of the measures. In this
study, relations among all 7 measures were assessed with participants representing a wide
range of scores on all the measures. The 369 participants (155 men, 214 women) were
sampled from the general population. Three replications of the same study consistently yielded
hypothesized positive intercorrelations among all 7 scales. Factor 1 (Anxiety-Depression)
included Trait Anxiety, Depression, and Panic scales. Factor 2 (Substance Abuse) included
Drug Use, Alcohol Use, Treatment for Depression, and Somatization scales. Factor 2
highlighted self-medication as a defining characteristic of somatizers and corroborated findings
showing that substance abuse is often a precursor to treatment for depression-like symptoms
that can be ameliorated with abstinence. Factors 1 and 2 were significantly intercorrelated (r = .
41, df = 367, p < .05), showing a 17% shared variance in two common groupings of
psychological dysfunction (anxiety-depression, substance abuse) in the general population.
Thus, depending on socioeconomic and demographic variables, a third common form of
dysfunction in the general population is represented by a combination of anxiety-depression
plus substance abuse.

Post-error adaptation in adults with high functioning autism.
Bogte H, Flamma B, van der Meere J, van Engeland H. Neuropsychologia. 2007 Apr 9;45(8):
Deficits in executive function (EF), i.e. function of the prefrontal cortex, may be central in the
etiology of autism. One of the various aspects of EF is error detection and adjusting behavior
after an error. In cognitive tests, adults normally slow down their responding on the next trial
after making an error, a compensatory mechanism geared toward improving performance on
subsequent trials, and a faculty critically associated with activity in the anterior cingulated
cortex (ACC). The current study evaluated post-error slowing in people with high functioning
autism (HFA) (n=36), taking symptom severity into account, compared to the performance of
a normal control group (n=32). Symptom severity in the HFA group was defined in terms of
level of adaptation: living independently
(outpatients; n=12) and living residentially (inpatients; n=24). Half the group of inpatients was
on medication; the results of their performance were analyzed separately. A computerized
version of a memory search task was used with two response probability conditions. The
subjects in the control group adjusted their reaction time (RT) substantially after an error,
while the group of participants with HFA appeared to be overall slow, with no significant
adjustment of RT after an error. This finding remained significant if the medication factor was
taken into account, and was independent of the degree of severity of the autistic disorder, as
defined by the dichotomy 'inpatient versus outpatient'. Possible causes and implications of the
finding are discussed.

Autonomic and neuroendocrine responses to a psychosocial stressor in adults with autistic
spectrum disorder.
Jansen LM, Gispen-de Wied CC, Wiegant VM, Westenberg HG, Lahuis BE, van Engeland H. J
Autism Dev Disord. 2006 Oct;36(7):891-9.
Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands.
Objective of the study was to replicate in adults our previous findings of decreased heart rate
and normal endocrine responses to stress in autistic children and to elucidate the discrepancy
between autonomic and endocrine stress responses by including epinephrine, norepinephrine,
oxytocin and vasopressin measurements. Ten autistic spectrum disorder (ASD) adults were
compared to 14 healthy controls in their response to a psychosocial stressor (public speaking).
ASD patients showed decreased heart rate, but normal cortisol responses, consistent with our
prior findings in children. No differences in norepinephrine, epinephrine, oxytocin or
vasopressin responses to stress were found. However, in contrast to previous findings in low
functioning autistic children, ASD adults showed increased basal oxytocin levels, which may
be related to developmental factors.

Lower cortisol and higher ACTH levels in individuals with autism.
Susnjara IM. Et al. J Autism Dev Disord. 2003 Aug;33(4):443-8.
Blood concentrations of pituitary hormones adrenocorticotropin (ACTH), prolactin, growth
hormone, and adrenal hormone-cortisol were measured in 36 autistic and 27 control
individuals. Individuals with autism had significantly lower serum concentrations of cortisol (p
< 10(-6)), and significantly higher concentrations of ACTH (p = 0.002) than control age- and
sex-matched subjects. Also, prolactin concentrations in autistic patients with epilepsy were
significantly higher when compared with normal subjects. The observed hormonal changes
may indicate dysfunction of the hypothalamo-pituitary-adrenal axis in individuals with autism.

Higher plasma ACTH levels in adults with Asperger syndrome.
Tani P, Porkka-Heiskanen T et al. J Psychosom Res. 2005 Jun;58(6):533-6.
OBJECTIVE: The aim of this preliminary study was to characterize the levels of plasma
adrenocorticotropic hormone (ACTH) and cortisol in adult patients with Asperger syndrome
(AS). METHODS: Twenty medication-free individuals with high-functioning AS were
recruited from a clinic specialized in autism spectrum disorders. Ten age-matched healthy
persons (hospital staff or students) with no neuropsychiatric disorders served as controls.
Blood samples for the assessment were collected at 8:00 a.m. RESULTS: The patients with AS
had significantly higher plasma-ACTH values than did the healthy controls. Plasma-cortisol
levels were similar in both groups. CONCLUSION: Increased plasma-ACTH levels are
associated with AS. Future studies are needed to clarify whether this finding is a biological
consequence of chronic anxiety and elevated stress, or a sign of facilitated response to an
acute novel stressor.

Lowered DHEA-S plasma levels in adult individuals with autistic disorder.
Strous RD, Mozes T et al. Eur Neuropsychopharmacol. 2005; 15(3):305-9.
Beer Yaakov Mental Health Center, Beer Yaakov, Israel.
The aim of this study was to determine for the first time neurosteroid levels,
dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) in particular, in a group of adult
patients with autistic disorder and compare these levels with normal healthy individuals. Levels
of DHEA, DHEA-S and cortisol were compared between 15 adult drug-free patients with
autistic disorder and 13 healthy controls. The Ritvo-Freeman Real-Life Rating Scale (RLRS)
and the Overt Aggression Scale (OAS) were assessed as a measure of symptom severity.
Significant lower DHEA-S levels were observed in the group with autistic disorder as
compared to controls (p <0.05). DHEA-S levels appear to be low in patients with autistic
disorder and, while speculative, may play a role in the etiopathophysiology of the disorder.

Cognitive flexibility in adults with high functioning autism
Bogte H, Flamma B, van der Meere J, van Engeland H. J Clin Exp Neuropsychol. 2007 Apr 11:
Department of Child and Adolescent Psychiatry, Adhesie GGz
The goal of the current study was to evaluate presetting, response inhibition, set shifting, and a
priori planning in autism: abilities that can be lumped together under the term cognitive
flexibility. Cognitive flexibility is an aspect of executive functioning, which in turn is mediated
by the prefrontal cortical lobes. A group of adults with high-functioning autism (HFA; n = 23)
were compared with a normal control group (n = 32), by using a computerized variant of the
Sternberg response bias paradigm. Contrary to the results of earlier studies, no deficit was
found in presetting, response inhibition, set shifting, and a priori planning in participants with
autism, even when the medication factor was taken into account. Methodological issues that
could be explanatory for this difference are discussed. An additional finding was, that
individuals with HFA (especially those on medication) were slow in reacting. Possible origins
and consequences of this slowness, also for cognitive flexibility, are discussed.

Brief report: circadian melatonin, thyroid-stimulating hormone, prolactin, and cortisol levels in
serum of young adults with autism.
Nir I, Meir D, Zilber N, Knobler H, Hadjez J, Lerner Y. J Autism Dev Disord. 1995 Dec;25(6):
Eitanim Psychiatric Hospital, Jerusalem, Israel.
An abnormal circadian pattern of melatonin was found in a group of young adults with an
extreme autism syndrome. Although not out of phase, the serum melatonin levels differed from
normal in amplitude and mesor. Marginal changes in diurnal rhythms of serum TSH and
possibly prolactin were also recorded. Subjects with seizures tended to have an abnormal
pattern of melatonin correlated with EEG changes. In others, a parallel was evidenced between
thyroid function and impairment in verbal communication. There appears to be a tendency for
various types of neuroendocrinological abnormalities in autistics, and melatonin, as well as
possibly TSH and perhaps prolactin, could serve as biochemical variables of the biological
parameters of the disease.

Recurrent brief depression revisited.
Pezawas L, Angst J, Kasper S. Int Rev Psychiatry. 2005 Feb;17(1):63-70.
Recurrent Brief Depressive Disorder (RBD) is a well-defined and prevalent mood disorder with
an increased risk of suicidal behavior and significant clinical impairment in the community and
general practice. Occurring at least monthly with depressive episodes lasting only a few days
defines recurrent Brief Depressive Disorder. The lifetime co-occurrence of both RBD and
Major Depressive Disorder (MDD), called Combined Depression (CD), substantially increases
the risk for attempted suicide, even more than that known for 'pure' MDD. The diagnostic
criteria for RBD found in the ICD-10 and DSM-IV are helpful in research and clinical routine
as well as several methodological issues, which make clinical diagnostic and drug response
evaluation of RBD very different from MDD. Formal differences in the course of RBD and
MDD require different designs for drug treatment studies. Denials of disorder, specific
methodological requirements, and highly selected patient samples have probably been
responsible for false negative results in double blind, placebo-controlled treatment studies.
Although several authors reported successful treatment of RBD with different compounds in
about 60 patients, it is still not possible to deduce a treatment algorithm for RBD to date.
Obviously future treatment studies without the limitations of previous studies are clearly
required for RBD. Results of ongoing studies will soon provide the first data on the biological
underpinnings of RBD.

The mood spectrum: improving the diagnosis of bipolar disorder.
Angst J, Cassano G Bipolar Disord 2005;7 Suppl 4:4-12.
Zurich University Psychiatric Hospital, Zurich, Switzerland.
Although the distinction between bipolar and unipolar disorders served our field well in the
early days of psychopharmacology, in clinical practice it is apparent that their phenotypes are
only partially described by current diagnostic classification systems. A substantial body of
evidence has accrued suggesting that clinical variability needs to be viewed in terms of a broad
conceptualization of mood disorders and their common threshold or subthreshold comorbidity.
The spectrum model provides a useful dimensional approach to psychopathology and is based
on the assumption that early-onset and enduring symptoms shape the adult personality and
establish a vulnerability to the subsequent development of Axis-I disorders. To obtain a clearer
understanding of the depressive phenotype, it is pivotal that we increase our detection of
hypomanic symptoms so that clinicians can better distinguish bipolar II disorder from unipolar
depression. Diagnostic criteria sensitive to hypomanic symptoms have been identified that
suggest bipolar II disorder is at least as prevalent as major depression. Moreover, the
comorbidities of these illnesses are very different and alcoholism in particular appears to be a
greater problem in bipolar II disorder than in unipolar depression. Structured clinical interviews
and patient self-report questionnaires have also successfully identified the presence of
hypomanic symptoms in patients with unipolar disorder and support the concept of a spectrum
of bipolar illness. In conclusion, the importance of subthreshold syndromes should not be
underestimated as failure to recognize bipolar spectrum disorder could delay treatment and
worsen prognosis.

Are hypomanics the happier normals?
Angst J et al. J Affect Disord. 2008 Apr 9
Zurich University Psychiatric Hospital, Switzerland
BACKGROUND: Not much is known about hypomanic states in subjects free of major and
minor depressive mood disorders. Our aim was to identify and characterise a group of such
"pure" hypomanics in relation to a normal control group. METHODS: Data were obtained from
the Swiss Zurich study, a stratified epidemiological sample of young adults from the general
population, followed from age 20 to 40. "Pure" hypomania was defined as a period of
increased activity and decreased need for sleep with consequences (e.g. legal trouble or
reactions by others). Minor and major mood disorders were excluded. RESULTS: Twenty-
three subjects were identified as pure hypomanics. They overlapped minimally with and were
clearly different from subjects with DSM-IV defined hypomanic episodes, most of whom had
a bipolar disorder. Pure hypomanics were characterised by physical and social overactivity,
elevated and irritable mood, as well as increases in extraversion, sexual interest, and risk-taking
behaviors. They had higher monthly incomes and were more often married than controls.
Subjective distress due to hypomanic symptoms was virtually absent. Quality of life and
treatment rates for mood and anxiety were not different from controls, although sleep
disturbances, substance abuse and binge eating were more frequent. LIMITATIONS: The
subsample identified was small. Due to the focus of the study on pathology, some positive
aspects of hypomania may have been missed. CONCLUSIONS: The existence of a group of
pure hypomanics presenting a mixed picture of clinically relevant and irrelevant characteristics
supports the concept of a continuum from normal to pathological mood states.

Melancholia and atypical depression in the Zurich study: epidemiology, clinical characteristics,
course, comorbidity and personality.
Angst J, Gamma A, Benazzi F, Ajdacic V, Rössler W. Acta Psychiatr Scand Suppl. 2007;(433):
Zurich University Psychiatric Hospital, Department of Psychiatry, Zurich,
OBJECTIVE: A comparison of psychiatric, psychological and somatic characteristics in
specified subgroups of major depressive episodes (MDE). METHOD: In a stratified
community sample of young adults investigated prospectively from age 20/21 to 40/41, we
defined four MDE subgroups: i) DSM-IV melancholia or atypical depression (the 'combined
group'), ii) pure melancholia, iii) pure atypical depression, and iv) unspecified MDE.
RESULTS: The cumulative incidence rates of the four groups were 4.1%, 7.1%, 3.5% and
8.2% respectively. Women were over-represented in the combined and atypically depressed
group. In 56 of 117 (47.9%) cases, melancholia was longitudinally associated with atypical
MDE (n = 84) (OR = 11.9). CONCLUSION: Melancholic MDE was more severe than atypical
MDE although the two groups shared many characteristics. The longitudinal overlap of
melancholia with atypical depression in almost half of all cases calls for comparative analyses
of combined, pure and unspecified MDE.

Recurrence of bipolar disorders and major depression; A life-long perspective
Angst J, Gamma A, Sellaro R, Lavori PW, Zhang H. Eur Arch Psychiatry Clin Neurosci. 2003
Zurich University Psychiatric Hospital, Switzerland
OBJECTIVE: It is not known whether the risk of recurrence declines with time in bipolar
disorders and in major depression. This study describes the life-long recurrence risk of bipolar
I, bipolar II and major depressive disorders. METHOD: 160 bipolar-I, 60 bipolar-II and 186
depressive patients hospitalised between 1959 and 1963 were followed up every five years
from 1965 to 1985. The course prior to the index hospitalisation was assessed in retrospect.
The recurrence risk was computed by the multiplicative intensity model (Aalen et al. 1980).
RESULTS: The cumulative intensity curves for the transition from states of remission to new
episodes remained linear over 30 to 40 years after onset, indicating a constant risk of
recurrence over the life-span up to the age of 70 or more. The recurrence risk of bipolar
disorders (0.40 episodes per year) was about twice that of depression (0.20 episodes per
year); BP-II disorders had only a slightly higher recurrence risk than BP-I disorders. There
were no significant gender differences in the course of either bipolar or depressive disorders.
CONCLUSION: If long-term trials confirm its efficacy, these results support lifelong
prophylactic treatment of severe types of mood disorders.


Mechanisms of Memory Suppression in Stress-related Psychiatric Disorders: A Functional
Magnetic Resonance Study
Nivedita Agarwal, Giuseppe Como, Giovanni Brondani,  Paolo Brambilla, Monica Baiano,
Massimo Bazzocchi et al
30TH, 2008; CODE: SSQ15-01
PURPOSE: functional Magnetic Resonance Imaging (fMRI) technique called BOLD (Blood-
Oxygen-Level-Dependent) detects signal intensity changes caused by increased paramagnetic
deoxygenated haemoglobin in activated brain structures. The prefrontal cortex (PFC) exercises
a cognitive control over memories processed by the hippocampus including traumatic
memories through a mechanism known as memory suppression. We hypothesized that this is
dysfunctional in patients with psychiatric disorders such as Major Depression (MD) and
Borderline Personality Disorder (BPD), suffering recurrent early sexual/physical abuse or
difficult relationship.
METHOD AND MATERIALS: 10 patients (5 with MD and 5 with BPD; mean age: 40.9±11.5
years; 3M/7F; all right-handed; 10 Caucasians) and 11 healthy controls (HC) (mean age: 34.2
±13.9 years; 3M/8F; 10 right-handed/1 left-handed; 10 Caucasians/1 Indian) underwent a
specific think/no-think test (suppression and retrieval phase; Anderson test) using a 1.5T MR
scanner. A qualitative cluster analysis, based on Talairach and Tourneaux parameters, was
performed by visually detecting the activation of PFC and hippocampus.
RESULTS: While PFC was bilaterally activated in both HC and patients during both the
suppression phase (SP) and the retrieval phase (RP), significantly reduced activation was
found among patients. A trend towards greater activation during the SP was seen in the
hippocampus of patients while HC showed greater activation during the RP.
CONCLUSION: These preliminary data suggest a dysfunctional cognitive memory suppression
mechanism primarily due to alteration in the PFC in patients with stress related disorders. Also,
altered memory retrieval process in patients would account for memory problems in patients.
fMRI-BOLD permits investigation of transient cognitive functions in small brain areas.
CLINICAL RELEVANCE/APPLICATION: These preliminary data suggest that the PFC-
hippocampus neural circuitry dysfunction may play a key role in supporting cognitive
symptoms of stress related psychiatric disorders



Hypothyroidism in children: diagnosis and treatment.
Setian NS. J Pediatr (Rio J). 2007 Nov;83(5 Suppl):S209-16
Faculdade de Medicina, Universidade de São Paulo (USP), Brazil
OBJECTIVE: To present relevant and updated information on the status of
Hypothyroidism in the pediatric population (newborn infants to adolescents); SOURCES:
Original and review articles and books containing relevant updated data. SUMMARY OF THE
FINDINGS: This review addressed data on the etiopathogeny of hypothyroidism and on the
importance of screening for congenital hypothyroidism to assure early diagnosis and treatment
of the newborn. We point out the difficulties experienced in the handling of subclinical
hypothyroidism; we also address the importance of diagnosing autoimmune Hashimoto's
thyroiditis, the high incidence of the disease among adolescents, mainly females, and the
occurrence of a severe neurological condition, Hashimoto's encephalopathy. We indicate
situations in which severe hypothyroidism may lead to puberty disorders (precocious or
delayed puberty) and describe the importance of transcription factors in thyroid
embryogenesis. Diagnostic and therapeutic criteria are also addressed. CONCLUSION:
Thyroid hormones are necessary for normal growth and development since fetal life.
Insufficient production or inadequate activity on the cellular or molecular level lead to
hypothyroidism. These hormones are necessary for the development of the brain in the fetus
and in the newborn infant. Neonatologists and pediatricians deal with child development issues
in their practice, and many of these issues start during intrauterine life. Currently, with neonatal
screening, neonatologists and pediatricians can prevent irreversible damage through early
treatment. They should also be alert for dysfunctions such as subclinical hypothyroidism and
Hashimoto's thyroiditis, which may provoke damage not only to growth, but also to the
neurological and psychological development of these children and adolescents.

The role of thyroid hormone in fetal neurodevelopment
Morreale de Escobar G. J Pediatr Endocrinol Metab. 2001;14 Suppl 6:1453-62.
Departamento de Endocrinología, Universidad Autónoma de Madrid, Spain
Thyroid hormones are necessary for normal brain development during fetal and postnatal life.
The stage at which the central nervous system becomes thyroid hormone sensitive, however,
has not been clearly defined. There is increasing evidence from epidemiological studies and
patient reports that these hormones are already needed for orderly development during the first
trimester, when the fetus is entirely dependent on the maternal transfer of thyroxine, the main
substrate for intracellular generation of the more active 3,5,3'-triiodothyronine for binding to
the nuclear hormone receptors. A decrease in maternal circulating thyroxine during the first
trimester, whether or not accompanied by increased circulating thyroid-stimulating hormone,
may well result in irreversible mental and psychomotor impairments. The very frequent cause
of this is an iodine intake insufficient to meet the requirements of the pregnant woman. It
appears urgent to ensure the use of iodine supplements from before or very early in pregnancy,
and to screen all women for hypothyroxinemia as early as possible. Maternal thyroxine
continues to be important for the exposure of fetal tissues to adequate amounts of this
hormone during the second and, possibly, the third trimesters. Premature birth, which
interrupts this transfer, results in neonatal hypothyroxinemia. This is more severe the earlier it
occurs during development, and is an important cause of the poorer mental and neuromotor
development of many preterm infants. The possibility of supplying them with thyroxine during
the neonatal period is being seriously tested.

Hypothyroidism and pregnancy: impact on mother and child health
Menif O, Omar S, Feki M, Kaabachi N. Ann Biol Clin (Paris). 2008 Jan-Feb;66(1):43-51.
Laboratoire de biochimie, Hôpital la Rabta de Tunis, Tunisie.
Pregnancy is associated with physiological changes in thyroid function that may result in
thyroid insufficiency, especially in presence of autoimmunity or iodine deficiency. Gestational
hypothyroidism has been associated with adverse health outcomes for both the mother and
child, including increased miscarriage risk and delayed neuropsychological development in
neonate and child. The severity of such complications mainly depends on the precocity and the
adequacy of L-thyroxin treatment. There is no consensus regarding systematic thyroid
function testing in pregnant women. But, the majority of authors are favorable for systematic
screening, especially in iodine deficient or marginally sufficient areas. However, when
systematic screening could not be performed for economic reasons, physicians should achieve
aggressive case finding for thyroid disease during pregnancy.

Thyroid hormones states and brain development interactions.
Ahmed OM, El-Gareib AW, El-Bakry AM, Abd El-Tawab SM, Ahmed RG. Int J Dev
Neurosci. 2008 Apr;26(2):147-209
Zoology Department, Faculty of Science, Beni Suef University, Egypt
The action of thyroid hormones (THs) in the brain is strictly regulated, since these hormones
play a crucial role in the development and physiological functioning of the central nervous
system (CNS). Disorders of the thyroid gland are among the most common endocrine
maladies. Therefore, the objective of this study was to identify in broad terms the interactions
between thyroid hormone states or actions and brain development. THs regulate the neuronal
cytoarchitecture, neuronal growth and synaptogenesis, and their receptors are widely
distributed in the CNS. Any deficiency or increase of them (hypo- or hyperthyroidism) during
these periods may result in an irreversible impairment, morphological and cytoarchitecture
abnormalities, disorganization, maldevelopment and physical retardation. This includes
abnormal neuronal proliferation, migration, decreased dendritic densities and dendritic
arborizations. This drastic effect may be responsible for the loss of neurons vital functions and
may lead, in turn, to the biochemical dysfunctions. This could explain the physiological and
behavioral changes observed in the animals or human during thyroid dysfunction. It can be
hypothesized that the sensitive to the thyroid hormones is not only remarked in the neonatal
period but also prior to birth, and THs change during the development may lead to the brain
damage if not corrected shortly after the birth. Thus, the hypothesis that neurodevelopmental
abnormalities might be related to the thyroid hormones is plausible. Taken together, the
alterations of neurotransmitters and disturbance in the GABA, adenosine and pro/antioxidant
systems in CNS due to the thyroid dysfunction may retard the neurogenesis and CNS growth
and the reverse is true. In general, THs disorder during early life may lead to distortions rather
than synchronized shifts in the relative development of several central transmitter systems that
leads to a multitude of irreversible morphological and biochemical abnormalities
(pathophysiology). Thus, further studies need to be done to emphasize this concept.

Reflections on mental retardation and congenital hypothyroidism: effects of
trace mineral deficiencies
Sidibé el H. Sante. 2007 Jan-Mar;17(1):41-50
Centre médical Marc Sankalé, BP 5062, Fann Dakar, Sénégal
While deficiencies of trace minerals and vitamins are rare in humans eating a variety of food,
they can occur in premature infants and those with disturbances in dietary behavior for
physical or psychological reasons and during parenteral or enteral nutrition. Some deficiencies
- such as iron and iodine - cause such serious specific disorders that they must be considered
separately. Congenital hypothyroidism induced by iodine deficiency is a major problem. Its
public health importance comes from the neurological complications that lead to the most
severe forms of endemic congenital hypothyroidism (cretinism). In areas without iodine
deficiency, the standard incidence of this disease in the West is 1/4,500 live births. In areas
with iodine deficiency, however, its incidence varies from 1 to
5%! It is nonetheless underestimated, because the screening methods revolutionized 20 years
ago are still not applied systematically. Additional factors include the thiocyanates in cassava,
the selenium deficiency resulting in selenium-dependent glutathione peroxidase deficiency, and
the natural goitrogens in some foods: milk, millet, walnuts, and bacterial and chemical water
pollutants. Adolescents and adults need 100 microg/day, children aged 1-10 years 60-100
microg, and babies under one year, 35-40 microg, but these daily requirements are not
necessarily met. This threat weighs on a billion people, 50-100 million in Europe, especially
pregnant women, fetuses, newborns, and young children whose cerebral development may be
negatively affected in the womb and in early life. According to some authors, subjects with
cretinism syndrome should be found in places where goiter prevalence exceeds 20%.
Evaluation of diffuse intellectual impairment in the population would require tools too specific
for most studies. Generations of children are the victims throughout wide swaths of
the African ecosystem in which it is endemic and associated with poor adaptation to the
environment. But studies of isolated places cannot be transposed to entire populations. Because
pregnancy in women with hypothyroidism is often thought to have a very negative prognosis,
the two cases we report merit attention. In one case, despite certainly insufficient thyroid
hormone replacement treatment, the child was born alive and healthy. In the second case,
where hypothyroidism followed a thyroidectomy in a woman with Graves disease, a
hydrocephalic child
was liveborn, without any replacement treatment. In her next pregnancy, she received optimal
hormonal treatment and delivered a healthy liveborn child. The disorders due to severe iodine
deficiency did not affect our two patients. In a series of 166 cases of congenital
hypothyroidism in newborns, only two cases had maternal antithyroid antibodies. Elsewhere, 9
women with hypothyroidism had 11 pregnancies, 9 normal children, 1 premature child (mother
had eclampsia), and 1 with Down syndrome and an Ostium primum defect (mother aged 41
years). Ontogenesis of the hypothalamo-pituitary-thyroid axis of the fetus still appears today to
develop independently of the mother in cases of hypothyroidism. An important role is played
by type III deiodinase, which is especially active in the placenta during pregnancy, probably
involving the T3 activity on nuclear and also mitochondrial receptors. The maturation of these
receptors is not well understood.

Thyroid hormones, learning and memory.
Rivas M, Naranjo JR. Genes Brain Behav. 2007 Jun;6 Suppl 1:40-4.
Dpto. Biología Molecular y Celular, Centro Nacional de Biotecnología, CSIC,
Madrid, Spain.
Thyroid hormones (THs), T3 and T4, have many physiological actions and are essential for
normal behavioral, intellectual and neurological development. THs have a broad spectrum of
effects on the developing brain and mediate important effects within the CNS throughout life.
Insufficient maternal iodine intake during gestation and TH deficiency during human
development are associated to pathological alterations such as cretinism and mental retardation.
In adulthood, thyroid dysfunction is related to neurological and behavioral abnormalities,
including memory impairment. Analysis of different experimental models suggests that most of
the effects on cognition as a result of thyroid dysfunction rely on hippocampal modifications.
Insufficiency of THs during development thus alters
hippocampal synaptic function and impairs behavioral performance of
hippocampal-dependent learning and memory tasks that persist in euthyroid adult animals. In
the present review, we summarize the current knowledge obtained by clinical observations and
experimental models that shows the importance of THs in learning and mnemonic processes.

Neonatal hyperthyroidism disrupts hippocampal LTP and spatial learning
C. Pavlides, B. S. McEwen et al. Experimental brain research 1991; vol 85(3): 559-564
Summary: Excess thyroid hormone at an early stage of development produces marked
neurochemical and morphological alterations in the rat hippocampal formation. In order to
better understand the functional significance of these changes, we tested adult rats treated
neonatally with triiodothyronine (T3), and their control litter mates, in a spatial learning task
and for the induction of longterm potentiation (LTP) in the dentate gyrus (DG) of the
hippocampal formation. The T3-treated rats were significantly impaired in their performance
on the spatial task in comparison to their matched controls. Similarly, the efficacy of LTP
induction was significantly attenuated in the T3-treated animals. Further, a significant
correlation was obtained between LTP induction and performance on the spatial learning task.
Thus, a brief neonatal excess of thyroid hormone produces impairments in spatial learning
along with decreases in LTP, long held as a model of learning and memory. This relationship
provides a unique opportunity to study associations between behavioral, physiological,
pharmacological and morphological processes intimately associated with the hippocampal

The Role of Thyroid Hormone on Testicular Development and Function
Wagner M, Magaginin S, Maia AL. J Endocrinol. 2008 Aug 26
Abstract: Thyroid hormone is a critical regulator of growth, development and metabolism in
virtually all tissues, and altered thyroid status affects many organs and systems. Although for
many years testis has been regarded as a thyroid hormone unresponsive organ, it is now
evident that thyroid hormone plays an important role in testicular development and function. A
considerable amount of data shows that thyroid hormone influences steroidogenesis as well as
spermatogenesis. The involvement of triiodothyronine (T3) in the control of Sertoli cell
proliferation and functional maturation is widely accepted, as well as its role in postnatal Leydig
cell differentiation and steroidogenesis. The presence of thyroid hormone receptors in testicular
cells throughout development and in adulthood implies that T3 may act directly on these cells
to bring about its effects. Several recent studies have employed different methodologies and
techniques in an attempt to understand the mechanisms underlying thyroid hormone effects on
testicular cells. The current review aims at presenting an updated picture of the recent
advances of our knowledge regarding the role of thyroid hormones in male gonadal function.

Behavior change after growth hormone treatment of children with short stature
Stabler B, Siegel PT, Clopper RR, Stoppani CE, Compton PG, Underwood LE. J Pediatr. 1998
University of North Carolina at Chapel Hill
OBJECTIVES: To measure the prevalence of behavioral and learning problems among children
with short stature and to assess the effect of growth hormone (GH) treatment on such
problems. STUDY DESIGN: A total of 195 children with short stature (age range 5 to 16
years, mean age 11.2 years) were tested for intelligence, academic achievement, social
competence, and behavior problems before beginning GH therapy and yearly during 3 years of
treatment. Children were classified as having growth hormone deficiency (GHD) when GH
responses to provocative stimuli were <10 ng/mL (n = 109) and as having idiopathic short
stature (ISS) when >10 ng/mL (n = 86). A normal-statured matched comparison group was
tested at the baseline only. RESULTS: Seventy-two children in the GHD group and 59 children
in the ISS group completed 3 years of GH therapy and psychometric testing. Mean IQs of the
children with short stature were near average. IQs and achievement scores did not change
with GH therapy. Child Behavior Checklist scores for total behavior problems were higher (P <
.001) in the children with short stature than in the normal-statured children. After 3 years of
GH therapy these scores were improved in patients with GHD (P < .001) and ISS (P < .003).
Also, there was improvement in the scores of children in the GHD group in the
internalizing subscales (withdrawn: P < .007; somatic complications, P < .001;
anxious/depressed, P < .001) and on the 3 components of the ungrouped subscales (attention,
social problems, and thought problems, each P = .001). Larger effects were observed in the
GHD group than in the ISS group. CONCLUSIONS: Many referred children with short stature
have problems in behavior, some of which ameliorate during treatment with GH.

Links between growth hormone deficiency, adaptation and social phobia
Stabler B, Clopper RR, Siegel PT, Nicholas LM, Silva SG, Tancer ME, Underwood LE. Horm
Res. 1996; 45(1-2):30-3
School of Medicine, University of North Carolina, Chapel Hill, USA.
Children referred for growth hormone (GH) treatment have increased school achievement
problems, lack appropriate social skills and show several forms of behavior problems. A
multicenter study in the United States has revealed that many GH-impaired children exhibit a
cluster of behavioral symptoms involving disorders of mood and attention. Anxiety,
depression, somatic complaints and attention deficits have been identified. These symptoms
decline in frequency over a period of 3 years, beginning shortly after GH replacement therapy
is started. Many of the patients who have received GH and had good growth responses show
lower than average quality of life in young adulthood after treatment is completed. GH-deficient
adults placed on GH therapy report improvement in psychological well-being and health status,
suggesting that GH might have a central neuroendocrine action. Among a group of adults who
were GH deficient as
children, we find a high incidence of social phobia, a psychiatric disorder
linked to GH secretion and usually accompanied by poor life quality. An ongoing study of non-
GH-deficient short individuals suggests that short stature is not the cause of this outcome. We
conclude that the origins of psychiatric comorbidities, such as social phobia and depression, in
GH deficient adults are likely to be neuroendocrine as well as psychosocial.

Academic achievement and psychological adjustment in short children. The National
Cooperative Growth Study.
Stabler B, Clopper RR, Siegel PT, Stoppani C, Compton PG, Underwood LE. J Dev Behav
Pediatr. 1994 Feb;15(1):1-6
Department of Psychiatry, University of North Carolina at Chapel Hill
Limited information is available on the educational and behavioral functioning of short children.
Through 27 participating medical centers, we administered a battery of psychologic tests to
166 children referred for growth hormone (GH) treatment (5 to 16 years) who were below the
third percentile for height (mean height = -2.7 SD). The sample consisted of 86 children with
isolated growth-hormone deficiency (GHD) and 80 children with idiopathic short stature (ISS).
Despite average intelligence, absence of significant family dysfunction, and advantaged social
background, a large number of children had academic underachievement. Both groups showed
significant discrepancy (p < .01) between IQ and achievement scores in reading (6%), spelling
(10%), and arithmetic (13%) and a higher-than-expected rate of behavior problems (GHD,
12%, p < .0001; ISS, 10%,
p < .0001). Behavior problems included elevated rates of internalizing behavior (e.g., anxiety,
somatic complaints) and externalizing behavior (e.g., impulsive, distractable, attention-seeking).
Social competence was reduced in school-related activities for GHD patients (6%, p < .03).
The high frequency of underachievement, behavior problems, and reduced social competency
in these children suggests that short stature itself may predispose them to some of their
difficulties. Alternately, parents of short, underachieving children may be more likely to seek
help. In addition, some problems may be caused by factors related to specific diagnoses.

Quality of life among formerly treated childhood-onset growth hormone-deficient adults: a
comparison with unaffected siblings.
Sandberg DE, MacGillivray MH, Clopper RR, Fung C, LeRoux L, Alliger DE. J Clin Endocrinol
Metab. 1998 Apr;83(4):1134-42
State University of New York at Buffalo and Children's Hospital of Buffalo
Several studies have investigated the quality of life (QOL) of GH-deficient (GHD) adults who,
as children, had been treated with GH. Variable findings are probably related to sample
heterogeneity and disparate research methodologies and designs, particularly the choice of
control or comparison groups. In addition to comparing a relatively large sample to
questionnaire norms, the present study is the first to compare the QOL adjustment of GHD
patients to that of same sex siblings. A total of 140 former patients (76% of those eligible;
mean age, 26 yr; n = 95 isolated GHD, n = 45 multiple pituitary hormone deficiencies; 117
males and 23 females) and 53 same sex siblings (84% participation), 18 yr and older,
participated in the telephone questionnaire survey. The majority of interviews with GHD
patients (78%) and siblings (87%) were conducted blind to the subject's
clinical status. Comparisons between GHD patients and norms for standardized questionnaires
indicated both better and worse functioning in several domains. In contrast, very limited
differences were detected between GHD cases and same sex siblings. Isolated GHD patients
were functioning better than those with multiple pituitary hormone deficiencies, but the effect
sizes of these differences in most areas were relatively small. Adult height and degree of
growth over the course of GH therapy were generally unrelated to QOL outcomes. Findings
from the present study underscore the importance of selecting unbiased control/comparison
groups in evaluating psychological outcomes among GHD adults.

Endocrinology of the stress response.
Charmandari E, Tsigos C, Chrousos G. Annu Rev Physiol. 2005;67:259-84.
Pediatric and Reproductive Endocrinology Branch, National Institutes of Health, Bethesda,
The stress response is subserved by the stress system, which is located both in the central
nervous system and the periphery. The principal effectors of the stress system include
corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived
peptides alpha-melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids; and
the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress
system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of
tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress
system may impair growth and development and may account for a number of endocrine,
metabolic, autoimmune, and psychiatric disorders. The development and severity of these
conditions primarily depend on the genetic vulnerability of the individual, the exposure to
adverse environmental factors, and the timing of the stressful events, given that prenatal life,
infancy, childhood, and adolescence are critical periods characterized by increased vulnerability
to stressors.

How do glucocorticoids [cortisol] influence stress responses? Integrating permissive,
suppressive, stimulatory, and preparative actions.
Sapolsky RM, Romero LM, Munck AU. Endocr Rev. 2000 Feb;21(1):55-89.
Department of Biological Sciences, Stanford University
The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that,
it remains controversial as to what purpose GCs serve at such times. One view, stretching
back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress
response, either via basal levels of GCs permitting other facets of the stress response to
emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response.
In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it
from being pathologically overactivated. In this review, we consider recent findings regarding
GC action and, based on them, generate criteria for determining whether a particular GC action
permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is
preparative for a subsequent stressor. We apply these GC actions to the realms of
cardiovascular function, fluid volume and hemorrhage, immunity and inflammation,
metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into
markedly different categories, depending on the physiological endpoint in question, with
evidence for mediating effects in some cases, and suppressive or preparative in others. We
then attempt to assimilate these heterogeneous GC actions into a physiological whole.

Stress system--organization, physiology and immunoregulation.
Elenkov IJ, Chrousos GP. Neuroimmunomodulation. 2006;13(5-6):257-67
Stress is defined as a state of threatened homeostasis. The principal effectors of the stress
system include corticotropin-releasing hormone, arginine vasopressin, the glucocorticoids, and
the catecholamines norepinephrine and epinephrine. Activation of the stress system leads to
adaptive behavioral and physical changes. The principal stress hormones glucocorticoids and
catecholamines affect major immune functions such as antigen presentation, leukocyte
proliferation and traffic, secretion of cytokines and antibodies, and selection of the T helper
(Th) 1 versus Th2 responses. A fully-fledged systemic inflammatory reaction results in
stimulation of the stress response, which in turn, through induction of a Th2 shift protects the
organism from systemic overshooting with Th1/pro-inflammatory cytokines. Stress is often
regarded as immunosuppressive, but recent evidence indicates that stress hormones influence
the immune response in a less monochromatic way--systemically they inhibit
Th1/pro-inflammatory responses and induce a Th2 shift, whereas in certain local responses
they promote pro-inflammatory cytokine production and activation of the corticotropin-
releasing hormone-mast cell-histamine axis. Through this mechanism a hyper- or hypoactive
stress system associated with abnormalities of the systemic anti-inflammatory feedback and/or
hyperactivity of the local pro-inflammatory factors may play a role in the pathogenesis of
chronic inflammation and immune-related diseases.

AUTHOR’S COMMENT: this is an authoritative review of the stress system and its influence
over the immune response. The traditional thinking used to be that stress suppresses the
immune system. It turns out to be more complicated than this. Immediate stress does not
weaken the immunity. In fact immediate stress leads the heavy artillery of the immune system
to leave its storage site in the blood stream and move to the tissues and take up defensive
positions. For many decades, people tested under stressful conditions were found to have
lower levels of the white blood cells, which represent the heavy artillery of the immune
system. Inevitably the conclusion was constantly made that stress must be weakening the
immune system. However, the truth is, these white blood cells, are mobilized out of the blood
to skin, muscle, liver and everywhere else where an injury or an invasion by a microbe or toxin
might happen. If you visit a National Guard base during a national emergency, you will
probably find very few people and equipment there. This does not mean that your state’s
national guard is depleted. It merely means that the National Guard has been mobilized to the
site of the threat or disaster. Long-term stress however, does dismantle the immune system
since otherwise it can eat our healthy tissues literally.

Stress and plasticity in the limbic system
Sapolsky RM. Neurochem Res. 2003 Nov;28(11):1735-42.
Department of Biological Sciences, Stanford University
The adult nervous system is not static, but instead can change, can be reshaped by experience.
Such plasticity has been demonstrated from the most reductive to the most integrated levels,
and understanding the bases of this plasticity is a major challenge. It is apparent that stress can
alter plasticity in the nervous system, particularly in the limbic system. This paper reviews that
subject, concentrating on: a) the ability of severe and/or prolonged stress to impair
hippocampal-dependent explicit learning and the plasticity that underlies it; b) the ability of mild
and transient stress to facilitate such plasticity; c) the ability of a range of stressors to enhance
implicit fear conditioning, and to enhance the amygdaloid plasticity that underlies it.

Organization and Integration of the Endocrine System
George P Chrousos, M.D. Sleep Med Clin. 2007 June; 2(2): 125–145
Cells communicate with each other through molecular messengers, the hormones. The simple
definition of a hormone as an intercellular messenger is much more inclusive than the original
one, which limited the hormones to substances produced by specialized multicellular organs—
the glands—that circulated in blood and acted on distant target organs. This simplification
allowed single cells to be considered glands or targets of hormones, or both, and eliminated
blood circulation as a prerequisite. The concept of endocrine function thus was expanded to
paracrine, autocrine, juxtacrine, and intracrine functions, whereas the classic endocrine
system, which included the traditional endocrine axes, was expanded to every organ and cell in
the body that produced and responded to hormones.
Other major conceptual changes have occurred in the past 2 decades. Many of the traditional
hormones that had defined sites of origin, roles, and target organs also were found to be
produced in nontraditional locations and to have apparently unrelated roles in nonconventional
target tissues. Also, as the molecular mechanisms of action of hormones were elucidated, it
became apparent that significant convergence between the actions of different hormones and
between the endocrine axes took place at the level of the target cells or tissues.
Life exists through maintenance of a complex dynamic equilibrium, or homeostasis, that is
constantly challenged by intrinsic or extrinsic adverse forces, or stressors. Thus, stress is
defined as a state of threatened homeostasis that is re-established by a complex repertoire of
physiologic and behavioral adaptive responses of the organism. Hormones have a crucial role in
the coordination of both basal and threatened homeostasis. One can clearly see the “wisdom”
of the endocrine system as it integrates its effects to readjust homeostasis and to improve the
chances of the self and species for survival; this paradigm is used to illustrate this integration.
The present overview focuses on the neuroendocrine infrastructure of the adaptive response to
stress and on its effects on the major endocrine axes in the body. Also discussed is the altered
regulation or dysregulation of the adaptive response in various physiologic and
pathophysiologic states, which may influence the growth and development of an individual and
define the vulnerability of this individual to endocrine, psychiatric, or immunologic disease.
This is a long awaited article about the organization of the endocrine system. All the old ideas
from the first half of the twentieth century have long become obsolete. Thinking of a hormone,
as being the product of one gland and targeting one site in the body could not be further from
the truth. Each hormone is produced in multiple sites throughout the body and acts on
countless target tissues including the production sites. The classic example is cortisol, which is
produced by the adrenals, and skin and other sites, and has valuable actions in every cell in the
body. Another example is DHEA. Recent research shows that the brain makes 10 folds more
DHEA than the rest of the body, including the adrenals, traditionally considered the main
source of DHEA. This opens the door wide for the future. We are learning that each individual
tissue has the ability to increase or decrease its exposure to hormones based on its own local
needs. This could take the concept of individualized medicine to a whole new level. This
abstract is singled out since it is written by the head of the pediatric endocrinology section of
the national institutes of health in Maryland.



MHC-correlated odor preferences in humans and the use of oral contraceptives
S. Craig Roberts, L. Morris Gosling, Vaughan Carter and Marion Petrie; Proceedings of the
Royal Society B: Biological Science. August 12, 2008
ABSTRACT: Previous studies in animals and humans show that genes in the major
histocompatibility complex (MHC) influence individual odors and that females often prefer
odor of MHC-dissimilar males, perhaps to increase offspring heterozygosity or reduce
inbreeding. Women using oral hormonal contraceptives have been reported to have the
opposite preference, raising the possibility that oral contraceptives alter female preference
towards MHC similarity, with possible fertility costs. Here we test directly whether
contraceptive pill use alters odor preferences using a longitudinal design in which women were
tested before and after initiating pill use; a control group of non-users were tested with a
comparable interval between test sessions. In contrast to some previous studies, there was no
significant difference in ratings between odors of MHC-dissimilar and MHC-similar men
among women during the follicular cycle phase. However, single women preferred odors of
MHC-similar men, while women in relationships preferred odors of MHC-dissimilar men, a
result consistent with studies in other species, suggesting that paired females may seek to
improve offspring quality through extra-pair partnerships. Across tests, we found a significant
preference shift towards MHC similarity associated with pill use, which was not evident in the
control group. If odor plays a role in human mate choice, our results suggest that
contraceptive pill use could disrupt disassortative mate preferences.

Author’s comment:
This study is not meant as a substance for gossip or jokes. You may use it that way though.
This is in fact pure science. These folks show that the birth control pill made up of synthetic
estrogen and progestin alters the interpretation of the sense of smell in women. In fact, this is
only the tip of the iceberg. Synthetic hormones may have untold adverse effects on the way
our brain works. The author is not a fanatic for or against birth control. I believe it is a
personal choice for every woman to make. However, I am serious about opposing giving
synthetic hormones to teenage girls for the purpose of “regulating the menstrual cycle”. The
reason for my opposition is the adverse and possibly permanent effects these powerful
chemicals can have on a growing brain.

Effects of neonatal dexamethasone treatment on the cardiovascular stress response of children
at school age
Karemaker R, Heijnen CJ et al. Pediatrics. 2008 Nov; 122(5): 978-87
OBJECTIVE: The goal was to investigate cardiovascular responses to a psychosocial stressor
in school-aged, formerly premature boys and girls who had been treated neonatally with
dexamethasone or hydrocortisone because of chronic lung disease.  
METHODS: We compared corticosteroid-treated, formerly preterm infants with formerly
preterm infants who had not been treated neonatally with corticosteroids (reference group).
Children performed the Trier Social Stress Test for Children, which include a public speaking
task and a mental arithmetic task. Blood pressure was recorded continuously before, during,
and after the stress test. Plasma norepinephrine levels were determined before the test, directly
after the stress task, and after recovery.
RESULTS: Overall, in response to stress, girls had significantly larger changes in systolic
blood pressure and mean arterial pressure and in stroke volume and cardiac output, compared
with boys. Boys exhibited larger total peripheral resistance responses, compared with girls.
The hydrocortisone group did not differ significantly from the reference group in any of the
outcome measures. However, dexamethasone-treated children had smaller stress-induced
increases in systolic and mean arterial blood pressure than did hydrocortisone-treated children.
In addition, the dexamethasone group showed smaller increases in stroke volume and blunted
norepinephrine responses to stress, compared with children in the reference group. Correction
for gender did not affect these results.
CONCLUSIONS: The differences in cardiovascular stress responses between girls and boys
are consistent with known gender differences in adult cardiovascular stress responses. Our
data demonstrate that neonatal treatment with dexamethasone has long-term consequences for
the cardiovascular and noradrenergic stress responses; at school age, the cardiovascular stress
response was blunted in dexamethasone-treated children. Hydrocortisone-treated children did
not differ from the reference group, which suggests that hydrocortisone might be a safe
alternative to dexamethasone for treating chronic lung disease of prematurity.

Activational Effects references:

Menstruation and accidents
DALTON K Br Med J. 1960 Nov 12; 2(5210): 1425-6.

Author’s comment: there is no available abstract for this study. However, this is a study that
shows increased proneness to accidents and injury in cycling women around the time of the
menstrual period.

Looking at images with human figures: comparison between autistic and normal children.
van der Geest JN, Kemner C, Camfferman G, Verbaten MN, van Engeland H. J Autism Dev
Disord. 2002 Apr;32(2):69-75.
Based on clinical observations of abnormal gaze behavior of autistic children, it has been
suggested that autistic children have a problem in processing social information. Several
studies on eye movements have indeed found indications that children with autism show
particularly abnormal gaze behavior in relation to social stimuli. However, the methodology
used in such investigations did not allow for precise gaze analysis. In the present study, the
looking behavior of autistic children toward cartoon-like scenes that included a human figure
was measured quantitatively using an infrared eye-tracking device. Fixation behavior of autistic
children was similar to that of their age- and IQ-matched normal peers. These results do not
support the notion that autistic children have a specific problem in processing socially loaded
visual stimuli. Also, there is no indication for an abnormality in gaze behavior in relation to
neutral objects. It is suggested that the often-reported abnormal use of gaze in everyday life is
not related to the nature of the visual stimuli but that other factors, like social interaction, may
play a decisive role.
AUTHOR’S COMMENT: I included this study to prove one point. Autistic children and adults
who have difficulty making eye contact do not suffer from any abnormality. They problem is
functional and dependent of the degree of stress at the time. This is why forcing them to make
eye contact may prove more stressful and lead to fear learning in that regard instead. Fear
learning makes it even more difficult to make eye contact later in life.

Ritual, habit, and perfectionism: the prevalence and development of compulsive-like behavior in
normal young children.
Evans DW, Leckman JF, Carter A, Reznick JS, Henshaw D, King RA, Pauls D. Child Dev.
1997 Feb;68(1):58-68.
Young children engage in a significant amount of ritualistic, repetitive, and compulsive-like
activity that appears to be part of their normal behavioral repertoire. Empirically, little is known
about the onset, prevalence, and developmental trajectory of these phenomena. A parent-report
questionnaire, the Childhood Routines Inventory (CRI), was developed to assess compulsive-
like behavior in young children, and was administered to 1,492 parents with children between
the ages of 8 and 72 months. The CRI has strong overall internal consistency and a distinct
two-factor structure. The frequency of compulsive-like behaviors changes with age: Two-, 3-,
and 4-year-olds engaged in more compulsive behavior than children younger than 1 year of age
and older than 4 years of age. Results are discussed from a developmental psychopathology
framework and for their implications for future research in this area.

Sleep restriction suppresses neurogenesis induced by hippocampus-dependent learning.
Hairston IS, Heller HC. J Neurophysiol. 2005 Dec; 94(6):4224-33
Psychology Department, University of California, Berkeley
Sleep deprivation impairs hippocampal-dependent learning, which, in turn, is associated with
increased survival of newborn cells in the hippocampus. We tested whether the deleterious
effects of sleep restriction on hippocampus-dependent memory were associated with reduced
cell survival in the hippocampus. We show that sleep restriction impaired hippocampus-
dependent learning and abolished learning-induced neurogenesis. Animals were trained in a
water maze on either a spatial learning (hippocampus-dependent) task or a non-spatial
(hippocampus-independent) task for 4 days. Sleep-restricted animals were kept awake for one-
half of their rest phase on each of the training days. Consistent with previous reports, animals
trained on the hippocampus-dependent task expressed increased survival of newborn cells in
comparison with animals trained on the hippocampus-independent task. This increase was
abolished by sleep restriction that caused overall reduced cell survival in all animals. Sleep
restriction also selectively impaired spatial learning while performance in the non-spatial task
was, surprisingly, improved. Further analysis showed that in both training groups fully rested
animals applied a spatial strategy irrespective of task requirements; this strategy interfered with
performance in the non-spatial task. Conversely, in sleep-restricted animals, this preferred
spatial strategy was eliminated, favoring the use of non-spatial information, and hence
improving performance in the non-spatial task. These findings suggest that sleep loss altered
behavioral strategies to those that do not depend on the hippocampus, concomitantly reversing
the neurogenic effects of hippocampus-dependent learning.

Sleep deprivation elevates plasma corticosterone levels in neonatal rats.
Hairston IS, Heller HC, Sapolsky RM. Neurosci Lett. 2001 Nov 23;315(1-2):29-32.
Neurosciences Program, Stanford University, CA
Plasma corticosterone (CORT) levels were measured after short periods of sleep deprivation in
rats at postnatal days 12, 16, 20, and 24. There was an age-dependent increase in basal CORT
levels and sleep deprivation significantly elevated CORT at all ages compared to non-sleep
deprived controls. The levels of CORT after sleep deprivation in P16, P20 and P24 animals
were similar, resulting in an age-dependent decrease of the magnitude of the response. Sleep
deprived P12 animals had lower levels of CORT. However, the observed response to sleep
deprivation suggests that sleep loss is a significant stressor at this age. These observations
suggest that younger animals are more sensitive to the effects of mild sleep deprivation than
older ones.

Intelligence quotient development and changes:
The development of cognitive and academic abilities: growth curves from an early childhood
educational experiment.
Campbell FA, Burchinal M, Ramey CT et al. Dev Psychol. 2001; 37(2): 231-42.
In the Abecedarian Project, a prospective randomized trial, the effects of early educational
intervention on patterns of cognitive and academic development among poor, minority children
were examined. Participants in the follow-up were 104 of the original 111 participants in the
study (98% African American). Early treatment was full-time, high-quality, educational
childcare from infancy to age 5. Cognitive test scores collected between the ages of 3 and 21
years and academic test scores from 8 to 21 years were analyzed. Treated children, on
average, attained higher scores on both cognitive and academic tests, with moderate to large
treatment effect sizes observed through age 21. Preschool cognitive gains accounted for a
substantial portion of treatment differences in the development of reading and math skills.
Intensive early childhood education can have long-lasting effects on cognitive and academic

Author’s comment: the life and work of Sharon and Craig Ramey provides some of the most
elegant evidence that the intelligent quotient in a dynamic parameter. Intelligence increases with
experience and learning. This couple studied a group of children since birth well into
adulthood. They taught the children early on and tested their IQ over the years. They found out
that the IQ increased with learning and that the gains persist to adulthood. More importantly,
the potential of the child to achieve success later in life increased also. Often the work of this
couple of scientists is used in society to over-schedule kids and cram 15 hours of various
activities into a child’s day. This, I contend, was never the intention of this research. The
intention was to teach kids methods of learning early on. They taught critical thinking and the
scientific method of exploration in order to raise kids who know how to pursue knowledge.
This cannot and should not be measured by hours or cramming of “educational” or other
activities. Education is measured through teaching children the tools needed to acquire the
knowledge of their choice and inclination. This is a complex topic but the idea in the case of
the sensitive child is to ask questions [by parent or child] and steer the child in the direction
where she can find the answers. She will gradually develop her own means of acquiring
knowledge and be set for life. Transferring information passively from parent to child or from
teacher to pupil actually makes the mind sluggish and impedes learning. This passive transfer
of information may work for insensitive kids who are not interested, nor capable, of dwelling
into the process of learning but can be destructive to the potential of a sensitive child.

Stress management section:
Sex, stress and the hippocampus: allostasis, allostatic load and the aging process
Bruce S. McEwen Neurobiology of Aging 23 (2002) 921–939
SUMMARY: The adaptive responses of the body that maintain homeostasis in response to
stressors can be called “allostasis”, meaning “achieving stability through change”. Mediators
produced by the immune system, autonomic nervous system (ANS) and hypothalamo–
pituitary–adrenal(HPA) axis produce allostasis. The brain also shows allostasis, involving the
activation of nerve cell activity and the release of neurotransmitters. When the individual is
challenged repeatedly or when the allostatic systems remain turned on when no longer needed,
the mediators of allostasis can produce a wear and tear on the body and brain that has been
termed “allostatic load”. Examples of allostatic load include the accumulation of abdominal fat,
the loss of bone minerals and the atrophy of nerve cells in the hippocampus. Studies of the
hippocampus as a target of stress and sex hormones have revealed a considerable degree of
structural plasticity and remodeling in the adult brain that differs between the sexes. Three
forms of hippocampal structural plasticity are affected by circulating hormones: (1) repeated
stress causes remodeling of dendrites in the CA3 region; (2) different modalities of stress
suppress neurogenesis of dentate gyrus granule neurons; (3) ovarian steroids regulate synapse
formation during the estrous cycle of female rats. All three forms of structural remodeling of
the hippocampus are mediated by hormones working in concert with excitatory amino acids
(EAA) and NMDA receptors. EAA and NMDA receptors are also involved in neuronal death
that is caused in pyramidal neurons by seizures, by ischemia and by severe and prolonged
psychosocial stress. The aging brain seems to be more vulnerable to such effects, although
there are considerable individual
differences in vulnerability that can be developmentally determined. Moreover, the brain retains
considerable resilience in the face of stress, and estrogens appear to play a role in this
resilience. “Resilience is an example of successful allostasis in which wear and tear is
minimized, and estrogens exemplify the type of agent that works against the allostatic load
associated with aging.” This review discusses the current status of work on underlying
mechanisms for protection and damage.


The lateralized processing of affect in emotionally labile extraverts and introverts: central and
autonomic effects.
Smith BD, Kline R, Lindgren K, Ferro M, Smith DA, Nespor A. Biol Psychol. 1995 Feb;39(2-
Department of Psychology, University of Maryland, College Park
ABSTRACT: The purpose of the present study was to better understand both the lateralized
hemispheric processing of emotion and the differential neural processing of arousal in
extraverts and introverts. We preselected right-handed male and female extraverts and
introverts who were high in emotional lability. Each subject was exposed to two positive and
two negative emotional stimuli under each of three counterbalanced conditions, including
affective, cognitive, and neutral, while EEG and electrodermal activity (EDA) were recorded.
Results showed that introverts are more aroused and that extraversion interacts with gender to
produce differentiated patterns of lateralized neural activity. In addition, affective conditions
produced higher levels of arousal than did cognitive or neutral conditions, particularly in the left
hemisphere and under negative as opposed to positive stimuli. Finally, the hemispherically
differentiated processing of positive and negative stimuli was affected by the contextual
conditions under which they were experienced.

Caffeine and novelty: effects on electrodermal activity and performance.
Davidson RA, Smith BD. Physiol Behav. 1991 Jun;49(6):1169-75.
National Institutes of Health, NINDS, Bethesda, MD 20892.
ABSTRACT: Caffeine has been shown to affect both physiological functioning and certain
aspects of performance. These effects are typically attributed to a simple increase in general
arousal. The present study was based on the theory that the effects of caffeine are actually
multidimensional. Specifically, we hypothesized that the drug raises arousal, acts to maintain
elevated arousal under conditions otherwise conductive to habituation, and enhances the impact
of situational and psychological sources of arousal. Subjects were given caffeine (300 mg) or
placebo and white noise or no noise and exposed to a series of pure tones and two Backwards
Recall Tasks, one novel, the other repetitive. Electrodermal activity (EDA) and task
performance were recorded. Caffeine increased arousal as measured by EDA. It also acted to
slow habituation during repetitive stimulation, thus maintaining heightened arousal. Finally, it
enhanced the effects of novel stimulation, which also independently raised arousal. These
results support a multidimensional theory of caffeine effects and provide some understanding
of the popularity of caffeine as a psychotropic agent.

Overhabituation and dishabituation responses as a function of stimulus intensity and amount of
overhabituation training
Smith BD, Council J. Psychophysiology 1978 Nov;15(6):517-21.
Several important issues regarding overhabituation and its effects have been raised. Of
particular interest are the effects of amount of overhabituation on responses during
overhabituation, the existence of important individual differences in response frequency and
amplitude during overhabituation, and the effect of varied amounts of overhabituation training
and of stimulus intensity on test and dishabituation response amplitudes. In the present study,
each of 108 subjects was randomly assigned to one of three overhabituation exposure
conditions (60, 120, or 180 trials) and one of two auditory stimulus intensities (60 or 85 dB).
After reaching a phasic electrodermal habituation criterion, each subject received the
appropriate number of overhabituation presentations of the standard stimulus (SS), followed by
a test stimulus and an additional SS (the dishabituation stimulus). Results showed significantly
higher frequencies and amplitudes of electrodermal responses to tonal stimuli with increasing
numbers of overhabituation trials, but no significant changes over trial blocks. Individual
differences were found. Subjects in a group defined by numerous overhabituation responses
showed slower habituation, larger responses and higher frequencies of nonspecific responses
during overhabituation, and larger test responses. Finally, the amplitude of test responses
increased with increasing length of overhabituation and with increased intensity.

Effects of pollution on human growth and development: an introduction.
Ravenscroft J. et al. J Physiol Anthropol. 2006 Jan;25(1):103-12.
Pollution is a worldwide problem and its potential to influence the physiology of human
populations is great. Studies of human growth and development in relation to pollution have
increased in number and quality since the mid-twentieth century. Many studies have found that
some pollutants have detrimental effects on human growth, particularly prenatal growth. The
heavy metal, lead, is commonly found in human populations and is related to smaller size at
birth and studies have reported decrements that range up to about 200 grams. Noise stress
from transportation sources also is related to reduced prenatal growth with somewhat smaller
decrements reported. Studies of humans exposed to polychlorinated biphenyls, one of the
persistent organic pollutants, have reduced size at birth, advanced sexual maturation and altered
hormone levels related to thyroid regulation. Thus different pollutants exert effects through
different physiological pathways. However, some studies have not observed these effects,
which indicates that the situation is complex and requires further study with better study
designs. Determining the effects of pollutants on human physiology and growth is difficult as it
requires fairly large numbers of subjects who are not purposely exposed but for whom
exposure can be measured. These effects of pollutants and the mechanisms of effect require
further study to understand and, it is hoped, to blunt or block any detrimental effects on
human health and well-being.

Fluoride and Apoptosis: Trading Dental Caries for Cellular Death?
Joseph Mercola British Medical Journal July 20, 2001[rapid response section to: BMJ 2001;
322: 1536-1538]
“When apoptosis or "programmed cell death" was first identified as a cellular function in 1972,
water fluoridation in the United States had already been around for over two decades. Several
years ago, fluoride (F) was found to induce apoptosis, joining a list of other apoptosis inducing
substances, such as radiation, mercury and anti-cancer drugs. The mechanism of action is
likely through activation of the enzyme caspase-3…”



Evaluation of autism Spectrum Disorders Using Magnetoencephalography
Timothy Roberts, J. Edgar, Deborah Zarnow, Susan Levy
30TH, 2008; CODE: VP11-03
PURPOSE: To evaluate the role of magnetoencephalography (MEG) n the evaluation of
patients with autism spectrum disorders (ASD) to determine if the spectral, temporal and
spatial resolution of this modality offers insights into abnormalities of auditory and language
METHOD & MATERIALS: 30 subjects (6-15yrs) with diagnoses of ASD (with or without
concomitant language impairment) and age-matched typically-developing subjects underwent
MEG studies using a 275-channel biomagnetometer. Auditory stimuli were presented to the
subjects without task demands. Stimuli included tones of differing frequencies, tone pairs in
rapid succession (inter-stimulus-interval 150ms), “oddball” paradigms of streams of tones or
vowels (with a 15% “oddball” occurrence – e.g. an /u/ in a stream of /a/’s) and stimuli
spanning an acoustic continuum between percepts of the vowels /u/ and /a/. MEG data was
collected over the whole head and analyzed in terms of its spatial source (using a beamforming
algorithm), temporal characteristics (using ms resolution) and spectral power fluctuations
(focusing on alpha, beta and gamma bands).
RESULTS: MEG recording was feasible in 80% of subjects. Main findings include localization
to superior temporal gyrus (in both ASD and TD), diminished range of evoked response
latencies in children with AUTISM as stimulus frequency was varied from 100-1000Hz) –
typically developing children exhibit an M100 latency range of ~40ms for such differing
stimuli; this was muted to ~20ms in ASD. For rapidly presented stimuli, evoked response
amplitudes to the second tone were reduced in children with ASD; detection of the oddball
token in a stream of stimuli was delayed (~50ms) in children with ASD. Abnormal patterns of
gamma oscillation (predominantly lower intensity) were observed in superior temporal gyrus of
children with ASD.
CONCLUSION: The spectral and temporal sensitivities of MEG in addition to its source
localizing capabilities offer intriguing insights into the neural dysfunction of auditory processing
systems in children with ASD. These observations may underpin the subsequent language and
communication impairment which are phenotypic characteristics of these disorders.
CLINICAL RELEVANCE/APPLICATION: Spectral and temporal resolution capabilities of
MEG offer a novel approach to neuropsychiatric disorders such As autism spectrum disorders,
with functional rather than structural lesions.


The evolution of human mating: trade-offs and strategic pluralism.
Gangestad SW, Simpson JA. Behav Brain Sci. 2000; 23(4):573-87; discussion 587-644.
During human evolutionary history, there were "trade-offs" between expending time and
energy on child-rearing and mating, so both men and women evolved conditional mating
strategies guided by cues signaling the circumstances. Many short-term matings might be
successful for some men; others might try to find and keep a single mate, investing their effort
in rearing her offspring. Recent evidence suggests that men with features signaling genetic
benefits to offspring should be preferred by women as short-term mates, but there are trade-
offs between a mate's genetic fitness and his willingness to help in child-rearing. It is these
circumstances and the cues that signal them that underlie the variation in short- and long-term
mating strategies between and within the sexes.


Changes in sexual function in middle-aged and older men: longitudinal data from the
Massachusetts Male Aging Study.
McKinlay JB. Et al. J Am Geriatr Soc. 2004 Sep;52(9):1502-9.

This longitudinal study was conducted to describe within-individual change in sexual function
over a 9-year period and to determine whether the amount of change differs by age group in
1085 adult men 40 – 70 years of age. Within-person change (follow-up minus baseline) in the
following sexual function variables was examined: sexual intercourse, erection frequency,
sexual desire, ejaculation with masturbation, satisfaction with sex, and difficulty with orgasm.
Analyses showed significant decline over the 9-year period in all tested domains of sexual
function except frequency of ejaculation with masturbation, which showed no change between
baseline and follow-up. Moreover, decline in sexual function parameters becomes more
pronounced with increasing age.

Sexual problems in healthy and depressed persons
Angst J. Int Clin Psychopharmacol. 1998 Jul;13 Suppl 6:S1-4.

In the ongoing Zurich Cohort Study, 591 males and females from the general population of
Zurich were interviewed five times over the 15-year period between the ages of 20 and 35
years. Changes in libido without associated emotional problems or sexual dysfunction are
relatively common. Libido therefore appears to be the core problem with which other sexual
problems overlap. Overall, sexual problems of some type were found in 26% of normal
subjects, 45% of non-treated depressed patients and 63% of treated depressed patients. This
increase in sexual problems in treated depressed patients is mainly due to an increase in sexual
dysfunction and emotional problems; the level of libido appears not to be affected by treatment.
There was no difference in the prevalence of sexual problems of any kind between patients
treated with medication and those treated only with psychotherapy.

Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid
Carani C, et al. J Clin Endocrinol Metab. 2005 Dec;90(12):6472-9

Thyroid hormones have a significant effect on human behavior. The objective of this study
was to evaluate the prevalence of sexual dysfunctions in patients with hyper- and
hypothyroidism and their
resolution after normalization of thyroid hormone levels. We conducted a multicenter
prospective study at endocrinology and andrology clinics in university hospitals. The study
included 48 adult men, 34 with hyperthyroidism and 14 with hypothyroidism. Subjects were
screened for hypoactive sexual desire (HSD), erectile dysfunction (ED), premature ejaculation
(PE), and delayed ejaculation (DE) on presentation and 8-16 wk after recovery from the
thyroid hormone disorder. In hyperthyroid men, premature ejaculation was the only relevant
problem with an incidence of 50% whereas in hypothyroid men, the prevalence of Delayed
Ejaculation was 64.3%. After thyroid hormone normalization in hyperthyroid subjects, PE
prevalence fell from 50 to 15%, whereas DE was improved in half of the treated hypothyroid
men. Despite the associated changes in sex hormone levels, the high prevalence of ejaculatory
disorders and their prompt reversibility suggest a direct involvement of thyroid hormones in the
physiology of ejaculation.

Sex steroids and sexual desire mechanism [expands on estrogen role in male sexual behavior]
Carani C et al. J Endocrinol Invest. 2003; 26 (3 Suppl): 29-36

Sexual behavior is mainly controlled by cognitive functions in men, though hormones,
particularly sex steroids, may modulate some aspects of male sexuality. This review focuses
on the role of both estrogens and androgens on male sexual desire, starting from both animal
and human studies. Estrogens could play a role in human male sexual activity, similarly to what
happens in animals, but even though physiological levels of estrogens could be probably
required for a completely normal male sexual behavior, testosterone remains the major
determinant of human male sexual behavior.

Conscious processing of sexual information: mechanisms of appraisal.
Laan E. et al. Arch Sex Behav. 2004 Aug; 33(4): 369-80

To elucidate some of the activational mechanisms of sexual response, this study investigated
the effects of conscious appraisal of sexual and neutral stimuli on a categorization task and on
ratings of sexual arousal. Conscious appraisal is dependent on memory, regulatory, and
attentional processes, interacting with one another. It is proposed that regulation is activated by
attention, furnished by
representations from implicit and explicit memory. Participants (26 men and 25 women) were
asked to respond to "target" stimuli that were preceded by sexual or neutral priming stimuli. In
a cognitive task, participants had to group randomly presented targets as quickly as possible
into sexual and nonsexual categories. Categorization of sexual targets was delayed when they
were preceded by sexual primes compared to neutral primes. This was interpreted as an
inhibitory process No gender difference was found. In a subsequent affective task, participants
provided an assessment of sexual arousal, followed by an evaluation of the target. This task
was hypothesized to result in differential access to memory. Gender differences were most
prominent in the evaluation aspect of this task. It was concluded that cognitive processing of
sexual information is similar for both genders, but that gender differences are present in
affective processing of sexual information.

“KINSEY” the movie 2004:
Wonderful, fascinating and heart-warming account of the changes in attitudes toward sexuality
in the twentieth century personalized through the life and achievements of doctor Alfred
Kinsey. Dr Kinsey single-handedly changed the public attitudes to sexuality through his
publications that helped propel the science of sexuality into the 21st century through
uncovering the “communally unsanctioned” aspects of sexuality. Liam Neeson and the creative
supporting cast give so much credibility to the production.

Journal of Clinical Endocrinology & Metabolism, Vol 57, 557-562, Copyright © 1983 by
Endocrine Society
The nature of androgen action on male sexuality: a combined laboratory- self-report study on
hypogonadal men
M Kwan, WJ Greenleaf, J Mann, L Crapo and JM Davidson
Sexual function and the effects thereon of testosterone enanthate were studied in six
hypogonadal men with the objective of delineating the specific components of male sexuality
affected by androgen. To obtain a detailed picture of these components, prospective self-report
data (from daily logs) of sexual activity and feelings, recordings of all night penile tumescence,
and laboratory psychophysiological data were assessed. Double blind placebo experiments with
cross-over design were used to compare the effects of placebo and 200- and 400-mg doses of
testosterone enanthate. Erectile responses to erotic film and fantasy were not lower in the
hypogonadal patients than in normal men and, in fact, were higher on some parameters,
especially prolongation of detumescence time after exposure to film or fantasy. Three subjects
who kept consistent daily logs had increased frequencies of sexual acts and feelings, orgasms,
and spontaneous erections after testosterone administration. Nocturnal penile tumescence and
spontaneous daytime erections were reduced in untreated hypogonadal men and were
significantly increased after testosterone treatment, but the laboratory-tested erectile responses
to film and fantasy were not affected by testosterone. These data and previous findings lead to
the conclusion that the major androgen action on male sexuality involves libido factors (i.e.
sexual motivation/interest). Though stimulus-bound erections elicited in the laboratory were not
reduced in hypogonadal men, spontaneous (sleep or waking) erections were clearly
testosterone dependent.

Personality Predictors of Longevity: Activity, Emotional Stability, and Conscientiousness
A Terracciano, PT Costa et al. Psychosomatic Medicine 2008; 70:621-627
Objective: To examine the association between personality traits and longevity.
Methods: Using the Guilford-Zimmerman Temperament Survey, personality traits were
assessed in 2359 participants (38% women; age = 17 to 98 years, mean = 50 years) from the
Baltimore Longitudinal Study of Aging, starting in 1958. Over the duration of the study, 943
(40%) participants died, on average 18 years after their personality assessment. The
association of each trait with longevity was examined by Cox regression controlling for
demographic variables.
Results: In preliminary analyses among the deceased, those who scored 1 standard deviation
(SD) above the mean on General Activity (a facet of Extraversion), Emotional Stability (low
Neuroticism), or Conscientiousness lived on average 2 to 3 years longer than those scoring 1
SD below the mean. Survival analyses on the full sample confirmed the association of General
Activity, Emotional Stability, and Conscientiousness with lower risk of death, such that every
1-SD increase was related to about 13%, 15%, and 27% risk reduction, respectively. The
association of personality traits with longevity was largely independent from the influence of
smoking and obesity. Personality predictors of longevity did not differ by sex, except for
Ascendance (a facet of Extraversion). Emotional Stability was a significant predictor when the
analyses were limited to deaths due to cardiovascular disease, with comparable effect sizes for
General Activity and Conscientiousness.
Conclusions: In a large sample of generally healthy individuals followed for almost five
decades, longevity was associated with being conscientious, emotionally stable, and active.

Atypical sleep architecture and the autism phenotype.
Limoges E, Mottron L, Bolduc C, Berthiaume C, Godbout R. Brain. 2005 May;128(Pt 5):1049-
A growing body of evidence indicates that people with autism frequently experience sleep
disorders and exhibit atypical sleep architecture. In order to establish whether sleep disorders
truly belong to the autism spectrum disorder (ASD) phenotype, we conducted a subjective and
objective study of sleep in a group of high-functioning adults with ASD but without sleep
complaints, psychiatric disorders or neurological comorbidity. We compared the subjective
data of 27 ASD participants with those of 78 healthy controls matched for chronological age
and gender. Subjective measures of sleep in the clinical group were compatible with insomnia
and/or a tolerable phase advance of the sleep-wake cycle. Subjective data were confirmed by
objective laboratory sleep recordings in a subset of 16 patients and 16 controls. Persons with
autism presented with a longer sleep latency (P < 0.04), more frequent nocturnal awakenings
(P < 0.03), lower sleep efficiency (P < 0.03), increased duration of stage 1 sleep (P <
0.02), decreased non-REM sleep (stages 2 + 3 + 4, P < 0.04) and slow-wave sleep (stages 3 +
4, P < 0.05), fewer stage 2 EEG sleep spindles (P < 0.004), and a lower number of rapid eye
movements during REM sleep (P < 0.006) than did control participants. On clinical scales, the
scores of persons with ASD on the Beck Depression Inventory were similar to those of
persons without, but their trait anxiety scores on the Spielberger Anxiety Scale were higher (P
< 0.02). The state anxiety scores of the Spielberger scale and cortisol levels were the same in
the two groups. Objective total sleep time correlated negatively with the Social (-0.52, P <
0.05) and Communication (-0.54, P < 0.02) scales of the Autism Diagnostic Interview-
Revised. The sleep of clinical subgroups (10 with
high-functioning autism, six with Asperger syndrome) did not differ, except for the presence
of fewer EEG sleep spindles in the Asperger syndrome subgroup (P <0.05). In conclusion,
these findings indicate that atypicalities of sleep constitute a salient feature of the adult ASD
phenotype and this should be further investigated in younger patients. Moreover, the results are
consistent with an atypical organization of neural networks subserving the macro- and
microstructure of sleep in ASD. We are furthering this research with quantified analysis of
sleep EEG.

Basta M, Chrousos GP, Vela-Bueno A, Vgontzas AN. Sleep Med Clin. 2007 Jun;2(2):279-291.
Sleep Research and Treatment Center, Penn State College of Medicine, Hershey, PA
Synopsis: In insomnia, which is a very common sleep disorder, objective sleep measures, EEG
activity, physiologic findings, HPA axis activity and inflammation markers suggest that it is not
a state of sleep loss, but a disorder of hyperarousal present both during the night and the
daytime. Several psychological and physiological factors contribute to the onset and
perpetuation of insomnia, such as anxious-ruminative personality traits, stressful events, age-
related sleep homeostasis weakening mechanisms, menopause and biologic – genetic diathesis
of CNS hyperarousal. The therapeutic approach in insomnia should be multidimensional
reducing the overall emotional and physiologic hyperarousal and its underlying factors present
throughout the 24-h sleep/wake period.

Neurochemical regulation of sleep.
Steiger A. J Psychiatr Res. 2007 Oct;41(7):537-52
Max Planck Institute of Psychiatry, Kraepelinstrasse, Germany
This review summarizes recent developments in the field of sleep regulation, particularly in the
role of hormones, and of synthetic GABA(A) receptor agonists. Certain hormones play a
specific role in sleep regulation. A reciprocal interaction of the neuropeptides growth hormone
(GH)-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) plays a key role
in sleep regulation. At least in males GHRH is a common stimulus of non-rapid-eye-movement
sleep (NREMS) and GH and inhibits the hypothalamo-pituitary adrenocortical (HPA)
hormones, whereas CRH exerts opposite effects. Furthermore CRH may enhance rapid-eye-
movement sleep (REMS). Changes in the GHRH:CRH ratio in favor of CRH appear to
contribute to sleep EEG and endocrine changes during depression and normal ageing. In
women, however, CRH-like effects of GHRH were found. Besides CRH somatostatin impairs
sleep, whereas ghrelin, galanin and neuropeptide Y promote sleep. Vasoactive intestinal
polypeptide appears to be involved in the temporal organization of human sleep. Beside of
peptides, steroids participate in sleep regulation. Cortisol appears to promote REMS. Various
neuroactive steroids exert specific effects on sleep. The beneficial effect of estrogen
replacement therapy in menopausal women suggests a role of estrogen in sleep regulation. The
GABA(A) receptor or GABAergic neurons are involved in the action of many of these
hormones. Recently synthetic GABA(A) agonists, particularly gaboxadol and the GABA
reuptake inhibitor tiagabine were shown to differ distinctly in their action from allosteric
modulators of the GABA(A) receptor like benzodiazepines as they promote slow-wave sleep,
decrease wakefulness and do not affect REMS.

Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic
hippocampal system.
Born J, Fehm HL. Exp Clin Endocrinol Diabetes. 1998;106(3):153-63.
Clinical Neuroendocrinology, University of Lübeck, Germany
This review focuses on experiments in humans examining the regulation of the hypothalamo-
pituitary-adrenal (HPA) system during nocturnal sleep. The HPA system is a most important
mediator of the organism's response to stress. The early phase of nocturnal sleep dominated by
extended epochs of slow wave sleep (SWS), is the only time of day in which secretory activity
of this axis is subject to a pronounced and persistent inhibition resulting in minimum
concentrations of ACTH and cortisol. During late sleep predominated by rapid eye movement
(REM) sleep. HPA secretory activity reaches a diurnal maximum. Comparison of the response
to administration of exogenous secretagogues of ACTH in men during sleep and nocturnal
wakefulness indicated that early sleep, and in particular SWS, is associated with an inhibition
of pituitary-adrenocortical responsiveness, which is presumably due to hypothalamic secretion
of an as yet unknown release inhibiting factor of ACTH. Pituitary-adrenocortical
responsiveness during early sleep was disinhibited after canrenoate which is a selective blocker
of mineralocorticoid receptors (MR) located primarily in limbic-hippocampal structures.
Hippocampal neuronal networks are known to integrate corticosteroid feedback via both, the
MR and the classical glucocorticoid receptor (GR). Prevailing MR related activity in this
network seems to act as a trigger for the inhibition of the HPA system. During early sleep, the
same hippocampal network appears to be concurrently involved in the formation of declarative
memory. Activation of GR after administration of dexamethasone completely blocked the
formation of declarative memory during early sleep, indicating that the inhibition of HPA
secretory activity is a necessary prerequisite for this memory process. Dysfunction of the
described neuro-endocrine mode of regulation during early sleep is present in patients with
Cushing's disease, in patients with severe depression and in aged humans. All of these groups
show insufficient inhibition of HPA secretory activity particular prominent during early sleep,
and reduced SWS in concert with impairments of declarative memory function. First clinical
trials suggest that this trias of symptoms may benefit from intranasal treatment with
neuropeptides like vasopressin and growth hormone releasing hormone.


Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine
Heim C, Reeves WC et al. Arch Gen Psychiatry. 2009 Jan; 66(1):72-80.
CONTEXT: Childhood trauma appears to be a potent risk factor for chronic fatigue syndrome
(CFS). Evidence from developmental neuroscience suggests that early experience programs
the development of regulatory systems that are implicated in the pathophysiology of CFS,
including the hypothalamic-pituitary-adrenal axis. However, the contribution of childhood
trauma to neuroendocrine dysfunction in CFS remains obscure. OBJECTIVES: To replicate
findings on the relationship between childhood trauma and risk for CFS and to evaluate the
association between childhood trauma and neuroendocrine dysfunction in CFS. Design,
Setting, and PARTICIPANTS: A case-control study of 113 persons with CFS and 124 well
control subjects identified from a general population sample of 19 381 adult residents of
Georgia. MAIN OUTCOME MEASURES: Self-reported childhood trauma (sexual, physical,
and emotional abuse; emotional and physical neglect), psychopathology (depression, anxiety,
and posttraumatic stress disorder), and salivary cortisol response to awakening. RESULTS:
Individuals with CFS reported significantly higher levels of childhood trauma and
psychopathological symptoms than control subjects. Exposure to childhood trauma was
associated with a 6-fold increased risk of CFS. Sexual abuse, emotional abuse, and emotional
neglect were most effective in discriminating CFS cases from controls. There was a graded
relationship between exposure level and CFS risk. The risk of CFS conveyed by childhood
trauma further increased with the presence of posttraumatic stress disorder symptoms. Only
individuals with CFS and with childhood trauma exposure, but not individuals with CFS
without exposure, exhibited decreased salivary cortisol concentrations after awakening
compared with control subjects. CONCLUSIONS: Our results confirm childhood trauma as an
important risk factor of CFS. In addition, neuroendocrine dysfunction, a hallmark feature of
CFS, appears to be associated with childhood trauma. This possibly reflects a biological
correlate of vulnerability due to early developmental insults. Our findings are critical to inform
pathophysiological research and to devise targets for the prevention of CFS.

Depression section:

Hypothalamic-pituitary-adrenal (HPA) axis function in 3-month old infants with prenatal
selective serotonin reuptake inhibitor (SSRI) antidepressant exposure
Oberlander TF, Weinberg J. et al. Early Hum Dev. 2008 Jul 17
BACKGROUND: Prenatal exposure to stress and selective serotonin reuptake inhibitors
(SSRIs) alter hypothalamic-pituitary-adrenal (HPA) stress reactivity in offspring, however, the
effects of combined exposure to HPA activity in human infants is unknown. OBJECTIVE: To
examine HPA basal levels and stress responsiveness in 3-month olds with prenatal exposure to
SSRIs. METHODS: Salivary cortisol levels in infants of SSRI treated mothers (n=31, mean
exposure 230.2+/-72.2 days) were compared with non-SSRI exposed (n=45) infants in
response to a challenge (infant-controlled habituation task) and under basal conditions in the
late afternoon/early evening. Mode of feeding, to account for possible postnatal drug exposure
via breast milk, as well as measures of pre and postnatal maternal mood, were included as
covariates. RESULTS: The cortisol reactivity slope (CRS) was significantly lower among non-
SSRI exposed infants compared with non-SSRI exposed infants. Early evening basal cortisol
levels were lower in SSRI exposed infants than in non-SSRI exposed infants, controlling for
maternal mood and mode of feeding. CONCLUSIONS: Prenatal SSRI exposure increased HPA
stress response patterns while reducing early evening basal cortisol levels. These findings
suggest an early "programming" effect of antenatal maternal mood, prenatal SSRI exposure
and postnatal maternal care giving on the HPA system.

The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future
research and new drug developments in depression.
Maes M, Maj M et al. Metab Brain Dis. 2008 Dec 16
SUMMARY: Despite extensive research, the current theories on serotonergic dysfunctions and
cortisol hypersecretion do not provide sufficient explanations for the nature of depression.
Rational treatments aimed at causal factors of depression are not available yet. With the
currently available antidepressant drugs, which mainly target serotonin, less than two thirds of
depressed patients achieve remission. There is now evidence that inflammatory and
neurodegenerative (I&ND) processes play an important role in depression and that enhanced
neurodegeneration in depression may-at least partly-be caused by inflammatory processes.
Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites-and
neurodegenerative biomarkers have been established in patients with depression and these
findings are corroborated by animal models of depression. A number of vulnerability factors
may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase
activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an
increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g.
psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or
conditions, such as the postpartum period, may trigger depression via inflammatory processes.
Most if not all antidepressants have specific anti-inflammatory effects, while restoration of
decreased neurogenesis, which may be induced by inflammatory processes, may be related to
the therapeutic efficacy of antidepressant treatments. Future research to disentangle the
complex etiology of depression calls for: 1) discovering new I&ND biomarkers, both at the
level of gene expression and the phenotype; and elucidating the underlying molecular I&ND
pathways causing depression; and 2) identifying new therapeutic targets in the I&ND
pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or
substances that could augment the efficacy of antidepressants; and predict therapeutic
response by genetic I&ND profiles.

The psychobiology of trait shame in young women: extending the social self preservation
Miller GE et al. Health Psychol. 2008 Sep; 27(5):523-32.

OBJECTIVE: The social self preservation theory (SSPT) proposes that social evaluative threat
evokes the emotion of shame, which then shapes a coordinated psychobiological response.
While this is supported in acute stress studies, there is no data on chronic experiences of
shame. DESIGN: We investigated the association of trait shame with activity of the
hypothalamic-pituitary-adrenal (HPA) axis, of the sympathetic nervous system (SNS), and
regulation of inflammation in n = 56 young women. MAIN OUTCOME MEASURES: Daily
profiles of salivary cortisol and alpha-amylase were assessed as indices of HPA axis and SNS
activity, respectively. Inflammatory regulation was assessed by lipopolysaccharide-stimulated
production and glucocorticoid inhibition of interleukin-6 in vitro. RESULTS: Trait shame was
associated with SNS (r = .49; p = .001), but not HPA activity (r = .14; ns). Shame was
associated with inflammatory activity (r = .35; p = .006) and glucocorticoid sensitivity (r =
-0.43; p = .001). Relationships were not mediated by HPA and SNS activity. CONCLUSIONS:
Results support SSPT predictions with respect to chronic shame experience and inflammation.
Results further suggest the importance of SNS activation related to shame, and the possibility
that HPA activation may be limited acute experiences of shame.


Cortisol Production Rate in Posttraumatic Stress Disorder
J. David Kinzie et al. The Journal of Clinical Endocrinology & Metabolism 2006; Vol. 91, No. 9
P 3486-3489
Several authors have reported the unsuspected finding of low cortisol levels (urinary, salivary,
and serum) in patients with posttraumatic stress disorder (PTSD). Symptoms result from
experiencing a severe traumatic event. Symptoms include increased sensitivity to stress,
increased startle responses, severe anxiety, hypervigilance, increased autonomic response, and
increased recollection of past stress as flashbacks and nightmares. These signs and symptoms
suggest that PTSD could be associated with increased circulating cortisol levels. It is
surprising that many reports show that cortisol levels are, in fact, low rather than high. It is
noted, however, that elevated urinary cortisol has been reported in combat-related PTSD and in
abuse-related PTSD.
Our objective was to assess concentrations of cortisol and its predominant metabolites, cortisol
production rate (CPR), and glucocorticoid receptor (GR) binding characteristics in PTSD
compared with normal subjects.
Matched PTSD patients and control subjects had CPR determined by a stable isotope dilution
technique after infusion of marked cortisol. Serum, salivary and urinary cortisol, and its
metabolites were measured.
Patients and Participants:
Ten patients with PTSD were matched by age and gender with 10 controls. All subjects were
tested during a 40-h admission in an inpatient clinical research center.
No statistical difference was found in mean level or circadian pattern of cortisol secretion
using serum or salivary immunoassay detection methods. Although in the normal range,
urinary cortisol by immunoassay showed statistically lower values over a 24-h period in PTSD
patients compared with controls. CPR was not statistically different between these groups.  
The data indicate that PTSD in the chronic and unprovoked state is not characterized by an
acute biological stress response.

Author’s comment:
You can see from this typical mainstream study the confusion that some of the smartest
scientists on earth go through. They are trying to categorize a diverse group of individuals who
have had a wide variety of trauma in the past into an absolute category of low, normal or high
cortisol. Often this does not work and leads to further intensification of confusion.
Unfortunately, it often leads to precious years lost before patients can get real help. Absent
from these studies is the functional perspective over a life cycle. Allowing for the possibility
that a PTSD patient may go through multiple phases all characterized by increased sensitivity
to stress and yet each characterized by a different physiologic response. In fact, it is my
experience that past trauma can increase the response to stress in the future, and usually does
lead to high adrenal cortisol output. However, the increased cortisol output will last only as
long as the adrenal reserves can hold up. At some point, the adrenal reserve becomes limited
and eventually exhausted. That usually leads to decreased cortisol output regardless of the
prevailing stress. Besides, most people with past trauma can have an average cortisol output on
a relatively typical and non-stressful day.

We first learned as a modern society about PTSD and the dysfunction that comes with it over
a half century ago. The dysfunction can alter every aspect o one’s life including the ability to
hold a job, to form a lasting relationship and to have a social life or even a peaceful day. Sadly,
today, 50 years later we are still bugged down with knit picking the infinite number of tiny
details without stepping back to gain some perspective of the problem as a whole and trying to
reconstruct a lifetime diary of PTSD in order to provide badly needed educated help for these
tormented souls. The accumulation of individual facts, no matter how great they maybe usually
falls short of having a meaningful impact on society unless and until the facts can fit into a
unifying theory. Aimless accumulation of disjointed facts, not based on an integrated
theoretical approach keeps science running in circles and deprives patients of the care they
need and deserve. If the Boeing Company limited its knowledge of airplanes to the mechanical
properties of engines, then they would be building airplanes that regularly fall from the sky.
The Boeing Company in fact possesses a unifying theory of flight that allows them to choose
only the appropriate mechanical and electronic equipment. The variety of equipment utilized in
building airplanes is only included in as much as they comply with or are explained by the
integrated theory of flight.

Post-traumatic Stress Disorder in children and adolescents: from Sigmund Freud's "trauma" to
psychopathology and the (Dys)metabolic syndrome.
Pervanidou P, Chrousos GP. Horm Metab Res. 2007 Jun;39(6):413-9.
Post-traumatic Stress Disorder (PTSD) is an anxiety syndrome that develops after exposure to
traumatic life events. Symptoms include re-experience of the initial trauma, avoidance of
stimuli associated with the trauma and symptoms of excessive arousal. Neuroendocrine studies
in adults with PTSD have demonstrated that basal cerebrospinal fluid (CSF) CRH levels are
elevated and urinary cortisol levels are variable--low in the majority of cases--whereas other
studies demonstrate no differences in urinary and plasma cortisol concentrations. Urinary
catecholamine excretion is higher in PTSD patients than those of control subjects and other
psychiatric disorders. Children may differ from adults in their psychologic and physiologic
responses to severe stressors. Also, exposure to stress during critical periods of development
may have irreversible effects on behavioral maturation and may affect specific vulnerable brain
areas, altering CNS development. Similar to findings in adult studies, PTSD in children is
characterized by increased sympathetic nervous system (SNS) activity, as indicated by
elevated norepinephrine levels in the periphery. High cortisol levels in urine or saliva have been
reported in most studies of childhood PTSD, while prospective longitudinal studies concerning
the natural history of neuroendocrine changes in pediatric PTSD after an acute stressor are
limited. The identification of neurobiologic changes in response to early adverse experiences is
of major importance for the prognosis, prevention, management, and treatment of children and
adolescents at risk for or suffering from PTSD.

Subtle neurologic compromise as a vulnerability factor for combat-related posttraumatic stress
disorder: results of a twin study.
Gurvits TV, Pitman RK. et al. Arch Gen Psychiatry. 2006; 63(5): 571-6
CONTEXT: Previous studies have demonstrated subtle neurologic dysfunction in chronic
posttraumatic stress disorder (PTSD) manifest as increased neurologic soft signs (NSSs). The
origin of this dysfunction is undetermined. OBJECTIVE: To resolve competing origins of
increased NSSs in PTSD, namely, preexisting vulnerability factor vs acquired PTSD sign.
DESIGN: Case-control study of identical twins. SETTING: A Veterans Affairs and academic
medical center (ambulatory). PARTICIPANTS: A convenience sample of male Vietnam veteran
twins with (n = 25) and without (n = 24) PTSD and their combat-unexposed identical
(monozygotic) co-twins. INTERVENTIONS: Neurologic examination for 45 NSSs. MAIN
OUTCOME MEASURE: Average scores for 45 NSSs, each scored on an ordinal scale from 0
to 3, masked to diagnosis and combat exposure status. RESULTS: There was a significant
between-pair main effect of PTSD diagnosis (as determined in the combat-exposed twin) on
average NSS score in the absence of a significant combat exposure main effect or diagnosis x
exposure interaction. Combat veterans with PTSD had significantly higher NSS scores than
combat veterans without PTSD. The "high-risk," unexposed co-twins of the former also had
significantly higher NSS scores than the "low-risk," unexposed co-twins of the latter. This
result could not be explained by age, number of potentially traumatic lifetime noncombat
events, alcoholism, or the presence of a comorbid affective or anxiety disorder. The average
NSS score in unexposed co-twins was not significantly associated with combat severity in
combat-exposed twins. CONCLUSIONS: These results replicate previous findings of increased
NSSs in Vietnam combat veterans with PTSD. Furthermore, results from their combat-
unexposed identical co-twins support the conclusion that subtle neurologic dysfunction in
PTSD is not acquired along with the trauma or PTSD but rather represents an antecedent
familial vulnerability factor for developing chronic PTSD on exposure to a traumatic event.

Author’s comment:
This is only one of many published studies this distinguished group of scientists led by Dr
Roger Pitman is working on. They are focusing on twin studies to separate problems seen in
PTSD into two categories; those problems that develop as a consequence of the trauma from
those problems that were present before the trauma and were preparing the person to become
a PTSD patient. They found indisputable evidence on genetic vulnerability to stress and
associated physical and functional peculiarities in the brain of people likely to develop PTSD
when exposed to extremely stressful situations. They are finding a smaller hippocampus,
which is usually associated with excessive stress. They are also finding changes in the
prefrontal cortex and other judgment and decision-making centers in the brain. All this is taking
us in one direction, further substantiating the evidence that sensitive people are sensitive by
birth and that they require to be recognized as a minority in society that transcends any tangible
characteristics into the intangible personality and biologic differences from the insensitive

Just in case, you go looking and think I am telling you half the story, the same group tried to
elicit higher cortisol responses in a PTSD group who had been surviving victims of terrorism
in Israel. The study did not yield any differences from non-PTSD victims. Anyone who knows
anything about the geography of this part of the world knows that Israelis (and especially
sensitive Israelis) have a baseline elevation in stress, nervousness and fear living in the middle
of a hostile neighborhood. Probably the patients in this study had already used up much of their
adrenal reserve surviving everyday life prior to the traumatic act they suffered. That is usually
why one cannot find the excessive cortisol response.  


Psychological triggers and hyperventilation symptoms in asthma
Ritz T, Steptoe A et al. Ann Allergy Asthma Immunol 2008; 100(5):426-32
Department of Psychology, Southern Methodist University, Dallas, Texas
BACKGROUND: Anecdotal accounts have identified hyperventilation as one route through
which psychological factors can trigger bronchoconstriction. However, little is known about
the empirical association between psychological and other trigger factors and hyperventilation
in asthma exacerbations. OBJECTIVE: To study the cross-sectional association between
perceived triggers and hyperventilation symptoms in 1 British and 1 German sample of patients
with asthma who were recruited from the community and from primary care clinics.
METHOD: Patients completed relevant language versions of the Asthma Trigger Inventory and
the Asthma Symptom Checklist. RESULTS: After controlling for demographics and asthma
severity, perceived asthma triggers measured by subscales of the Asthma Trigger Inventory
explained 12.5% to 37.3% of the variance in Asthma Symptom Checklist hyperventilation-
hypocapnia symptoms. Psychological triggers accounted for 10.6% to 26.7% of the variance
alone and 4.3% to 11.0% of the variance over and above other trigger factors. In contrast,
perceived animal and pollen allergen triggers did not contribute unique variance to the
hyperventilation symptom report. Psychological triggers did not explain variance in classic
airway obstruction symptoms, thus arguing against a general bias toward inflated symptom
reports in patients with psychologically induced asthma. CONCLUSION: Differences in
perceived asthma triggers are substantially associated with hyperventilation symptoms, and
patients with more frequent psychological triggers also tend to report that they experience
more hyperventilation symptoms during their asthma symptom episodes.

Seasonal affective disorder: an overview.
Magnusson A, Boivin D. Chronobiol Int. 2003 Mar;20(2):189-207.
Seasonal Affective Disorder (SAD) is a condition of regularly occurring depressions in winter
with a remission the following spring or summer. In addition to depressed mood, the patients
tend to experience increased appetite and an increased duration of sleep during the winter. SAD
is a relatively common condition, affecting 1-3% of adults in temperate climates, and it is more
prevalent in women. The pathological mechanisms underlying SAD are incompletely
understood. Certain neurotransmitters have been implicated; a dysfunction in the serotonin
system in particular has been demonstrated by a variety of approaches. The role of circadian
rhythms in SAD needs to be clarified. The phase-delay hypothesis holds that SAD patients'
circadian rhythms are delayed relative to the sleep/wake or rest/activity cycle. This hypothesis
predicts that the symptoms of SAD will improve if the circadian rhythms can be phase-
advanced. There is some experimental support for this. SAD can be treated successfully with
light therapy. In classical light therapy, the SAD sufferer sits in front of a light box, exposed to
2000-10,000 lux for 30-120 min daily during the winter. Other forms of light treatments,
pharmacotherapy, and other therapies are currently being tested for SAD.

Author’s comment: a very reserved review of seasonal affective disorder, almost to the degree
of “waiting for godot” mentality. However, it is scientific and informative for those interested.
The part that the article could have gone into is that one of theories behind seasonal affective
problems is that the prolonged absence of sunlight leads many sensitive people to forget –
subconsciously of course – the relationship with the dark and light cycles. It is temporary
forgetfulness related to the absence of stimulus. This is a common problem with the sensitive
mind in that the absence of at least occasional stimulation erodes recollection of the stimulus.
However, the absence of stimulus does not lead to complete disappearance of the memory.
That memory is still there but it requires the occasional prompting for the appropriate retrieval.

Seasonal-like growth and regression of the avian song control system: neural and behavioral
plasticity in adult male Gambel's white-crowned sparrows.
Meitzen J, Thompson CK. Gen Comp Endocrinol. 2008 Jul; 157(3):259-65
Abstract: Birdsong is regulated by a series of discrete brain nuclei known as the song control
system. In seasonally-breeding male songbirds, seasonal changes in steroid sex hormones
regulate the structure and electrophysiology of song control system neurons, resulting in
dramatic changes in singing behavior. Male songbirds can be brought into the laboratory,
where circulating levels of steroid hormone and photoperiod can be abruptly manipulated,
providing controlled conditions under which rapid "seasonal-like" changes in behavior and
morphology can be carefully studied. In this mini-review, we discuss the steroidal and cellular
mechanisms underlying seasonal-like growth and regression of the song control system in
adult male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii), and its
impact on song behavior. Specifically, we discuss recent advances concerning: (1) the role of
androgen and estrogen receptors in inducing seasonal-like growth of the song control system;
(2) how photoperiod modulates the time course of testosterone-induced growth of the song
control system; (3) how bilateral intracerebral infusion of androgen and estrogen receptor
antagonists near the song control nucleus HVC prevents seasonal-like increases in song
stereotypy but not song rate; and (4) the steroidal and cellular mechanisms that mediate rapid
regression of the song control system. Throughout this mini-review we compare data collected
from white-crowned sparrows to that from other songbird species. We conclude by outlining
avenues of future research.

Author’s Comment:
In sparrows residing here in the northwest, the male learns to sing his mating song early in life
during development. This is associated with growth of certain areas of the sparrow’s brain to
allow for forming a permanent memory of the song necessary for procreation. However, each
year, during the non-breeding season (fall & winter) stop singing. They can still make other
sounds but not the typical courtship song. Some sad scientists with too much funding on their
hands, have found out that during the fall and winter shorter dimmer days cue in the sparrow
to dismantle the neural structures responsible for singing. Then each year, during spring
season, when days are longer and brighter that same brain area develops again and the sparrow
starts singing again. No one really knows if what is true for birds turns out to be true for
humans. However, there seems to be a model in nature for birds ‘forgetting’ essential
functions during the winter season only to remember them again come spring. Over the years I
have come to know several people living in the Seattle area who struggled with seasonal
affective problems. Many of them decided to move south to California or Arizona in an attempt
to reclaim the six months they seem to lose each year. Many of these folks report that on
moving to a more sunny area, the problem does not completely disappear. However, they
report much better functionality, clarity of mind and memory improvements. They also report
less intense feelings of melancholy and less sleeping problems. Could it be that some
individuals living in the northern states and Canada literally ‘forget’ their daily biological
rhythms during fall and winter with resulting sadness and confusion? Are there brain regions in
humans that undergo seasonal modeling of shrinkage and growth depending on ubiquity of
sunlight? Is this more common in sensitive people than in less sensitive ones? Can anything be
done about it?


Low cortisol and a flattening of expected daytime rhythm: potential indices of risk in human
Gunnar MR, Vazquez DM. Dev Psychopathol. 2001 Summer;13(3):515-38.
Since the work of Hans Selye, stress has been associated with increased activity of the limbic-
hypothalamic-pituitary-adrenocortical (LHPA) axis. Recently, a number of studies in adults
have shown that this neuroendocrine axis may be hyporesponsive in a number of stress-related
states. Termed hypocortisolism, the paradoxical suppression of the LHPA axis under
conditions of trauma and prolonged stress presently challenges basic concepts in stress
research. Adverse conditions that produce elevated cortisol levels early in life are hypothesized
to contribute to the development of hypocortisolism in adulthood. However, as reviewed in this
paper, hypocortisolism also may be a common phenomenon early in human childhood.
Although preliminary at this point, the ubiquity of these findings is striking. We argue that
developmental studies are needed that help explicate the origins of low cortisol and to
determine whether the development of hypocortisolism is, in fact, preceded by periods of
frequent or chronic activation of the LHPA axis. We also argue that developmental researchers
who incorporate measures of salivary cortisol into their studies of at-risk populations need to
be aware of the hypocortisolism phenomenon. Lower than expected cortisol values should not
necessarily be relegated to the file drawer because they contradict the central dogma that stress
must be associated with elevations in cortisol. Lastly, we note that evidence of low cortisol
under adverse early life conditions in humans adds to the importance of understanding the
implications of hypocortisolism for health and development.

Stress at three-month immunization: Parents' and infants' salivary cortisol response in relation
to the use of pacifier and oral glucose.
Morelius E, Theodorsson E, nelson N Eur J Pain. 2008 May 15
Department of Molecular and Clinical Medicine, Linkoping University, Sweden
The aims of the present study were to investigate (1) whether the salivary cortisol response
could be dampened during a routine three-month immunization if the infant received sweet-
tasting solution in combination with a pacifier and (2) stress experienced by parents during
immunization of the infant. Ninety-eight infants were included into one of four intervention
groups: 'glucose and pacifier', 'water and pacifier', 'glucose', or 'water'. Saliva was collected
before and 30min after the immunization. Infants' crying-time and parents' self-reported stress
(VAS) were measured before and after immunization. Infants in the 'pacifier and glucose'
group had a significantly smaller change in salivary cortisol than infants in the other groups (F
(3,72)=3.1, p<0.05). In the 'glucose and pacifier' group the median salivary cortisol levels
decreased 33% after the immunization. In the 'water and pacifier', 'glucose', and 'water' group
median cortisol increased with 50%, 42%, and 8%, respectively. No significant differences in
crying-time were observed between the intervention groups. If the infant cried before the
immunization, the crying-time during the immunization was longer (p<0.01) and cortisol
increased more (p<0.05). Median cortisol levels for parents decreased after the immunization
(p<0.01). Median VAS increased 50% (p<0.0001) after immunization. First time parents rated
higher stress on VAS before immunization (p<0.01). Parents' change in cortisol and VAS were
significantly related to infants' crying time. In conclusion, the combination of oral glucose and
pacifier dampen infants' salivary cortisol in response to the three-month immunization.

Salivary cortisol and cardiovascular activity during stress in oppositional-defiant disorder boys
and normal controls
van Goozen SH, van Engeland H et al. Biol Psychiatry. 1998 Apr 1;43(7):531-9.
BACKGROUND: Arousal-regulating mechanisms are important in explaining individual
differences in antisocial behavior. METHODS: Alterations in salivary cortisol concentration and
cardiovascular activity were studied in 21 boys with oppositional defiant disorder (ODD) and
31 normal controls (NC) during a 2-hour stressful procedure involving frustration and
provocation. RESULTS: Baseline levels of heart rate (HR) were significantly lower in the ODD
group, but their HR levels were higher during provocation and frustration. Cortisol levels in the
ODD group were overall lower than those of the NC group, and the effect of stress seemed to
be minimal and similar for both groups; however, individual differences were large. Since
anxiety plays an important mediating role in cortisol response, subjects were divided into one
of four groups based on the intensity of their externalizing behavior and anxiousness. Cortisol
increase due to stress exposure was strongest in highly externalizing and highly anxious
subjects; cortisol decrease was strongest in those subjects who were high in externalizing
behavior and low in anxiousness. CONCLUSIONS: The results of the study support an
important role for hypothalamic-pituitary-adrenal axis sympathetic autonomic functioning in
persistent antisocial behavior in young boys.

Nurse evaluation of hyperactivity in anorexia nervosa: a comparative study.
van Elburg AA, Hoek HW, Kas MJ, van Engeland H. Eur Eat Disord Rev. 2007 Nov;15(6):425-
Department of Child and Adolescent Psychiatry, Utrecht, The Netherlands
Up to 80% of patients with anorexia nervosa (AN) manifest elevated levels of physical activity
or hyperactivity. A variety of methods have been used to evaluate activity levels, mostly
questionnaires but also expensive and invasive methods such as actometry or other
measurements of energy expenditure. Nurse observations have heretofore not been tested for
validity and reliability. In this study, 18 patients with AN under treatment in a specialized eating
disorder centre simultaneously rated their own physical activity levels, used an actometer, and
were observed for physical activity by trained nurses. We found that nurse ratings of activity
correlated significantly with the average actometer activity score (r = 0.61, p < 0.01). Patients
could not rate their own activity levels accurately. Nurse observation of activity levels of AN
patients during treatment is a reliable and useful monitoring tool.

Salivary testosterone and aggression, delinquency, and social dominance in a population-based
longitudinal study of adolescent males.
van Bokhoven I, van Goozen SH, van Engeland H, Schaal B, Arseneault L, Séguin JR, Assaad
JM, Nagin DS, Vitaro F, Tremblay RE. Horm Behav. 2006 Jun;50(1):118-25. Epub 2006 Apr
Testosterone (T) has been found to have a stimulating effect on aggressive
behavior in a wide range of vertebrate species. There is also some evidence of a positive
relationship in humans, albeit less consistently. In the present study we investigated the
relationship between T and aggression, dominance and delinquency over time, covering a
period from early adolescence to adulthood. From a large population-based sample (n = 1.161)
a subgroup of 96 boys was selected whose behavior had been assessed repeatedly by different
informants from age 12 to 21 years, and who had provided multiple T samples over these
years of assessment. On the whole, a decrease in aggressive and delinquent behavior was
observed in a period in which T rises dramatically. Boys who developed a criminal
record, had higher T levels at age 16. In addition, positive associations were
observed between T and proactive and reactive aggression and self-reported delinquent
behavior. Over the pubertal years different forms of aggressive and delinquent behavior were
positively related to T, which may indicate that specific positive links are dependent on the
social setting in which this relationship is assessed.

AUTHOR’S COMMENT: there is a good faith, yet misguided effort to explore the role of
excess “male” sex hormones in autism. In fact, most of the convincing evidence in the
literature points to increased testosterone in kids with ADH personality fueling aggressive and
disruptive behavior. There is no room in this book for a more detailed description of the role of
sex hormones in childhood and puberty. It takes plenty away from the core focus of the text in
this first edition. However, Dr Bruce McEwen of Rockefeller University is an author worth
mentioning in this field. He has written volumes on the developmental effects of sex hormones.
Hopefully, if I live to finish a second edition of this book, the topic of sex hormones and other
relevant but more peripheral topics will be expanded upon.

Prenatal androgenization affects gender-related behavior but not gender identity in 5-12-year-
old girls with congenital adrenal hyperplasia.
Meyer-Bahlburg HF, Obeid JS et al. Arch Sex Behav. 2004 Apr;33(2):97-104.
Department of Psychiatry, Columbia University, New York
Gender assignment of children with intersexuality and related conditions has recently become
highly controversial. On the basis of extensive animal research and a few human case reports,
some authors have proposed the putative masculinization of the brain by prenatal hormones-
indicated by the degree of genital masculinization-as the decisive criterion of gender assignment
and have derived the recommendation that 46,XX newborns with congenital adrenal
hyperplasia (CAH) and full genital masculinization should be assigned to the male gender. The
purpose of this study was to test in CAH girls of middle childhood the assumption that prenatal
androgens determine the development of gender identity. Fifteen girls with CAH (range of
genital Prader stage, 2-4/5), 30 control girls, and 16 control boys (age range, 5-12 years)
underwent 2 gender-play observation sessions, and a gender identity interview yielding scales
of gender confusion/dysphoria. About half a year earlier, mothers had completed 2
questionnaires concerning their children's gender-related behavior. The results showed that, as
expected, CAH girls scored more masculine than control girls on all scales measuring gender-
related behavior, with robust effect sizes. By contrast, neither conventionally significant
differences nor trends were found on the 3 scales of the gender identity interview. We
conclude that prenatal
androgenization of 46,XX fetuses leads to marked masculinization of later gender-related
behavior, but the absence of any increased gender-identity confusion/dysphoria does not
indicate a direct determination of gender identity by prenatal androgens and does not, therefore,
support a male gender assignment at birth of the most markedly masculinized girls.

This is the official version so far of the medical establishment about one of the possible genetic
reasons for homosexuality in girls.

Physiological and psychological stress responses in adults with attention-deficit/hyperactivity
disorder (ADHD)
Lackschewitz H, Hüther G, Kröner-Herwig B. Psychoneuroendocrinology. 2008 Jun; 33(5):
Georg-August University of Göttingen, Germany
According to self-report and unsystematic observational data adult patients with attention-
deficit/hyperactivity disorder suffer from increased vulnerability to daily life stressors. The
present study examined psychological and physiological stress responses in adult ADHD
subjects in comparison to healthy controls under laboratory conditions. Thirty-six subjects (18
patients with DSM-IV ADHD diagnosis, 18 sex- and age-matched healthy controls) underwent
the Trier Social Stress Test, a standardized psychosocial stress protocol which contains a
stress anticipation phase and a stress phase with a free speech assignment and subsequent
performance of a mental arithmetic. Physiological stress measures were salivary cortisol as an
indicator of the HPA axis, heart rate (HR), and time- and frequency-domain heart rate
variability (HRV) parameters. Subjective stress experience was measured via self-report
repeatedly throughout the experimental session. In line with previous theoretical and empirical
work in the field of childhood ADHD, it was hypothesized that the ADHD and control group
would exhibit comparable baseline levels in all dependent variables. For ADHD subjects, we
expected attenuated responses of the physiological parameters during anticipation and presence
of the standardized stressor, but elevated subjective stress ratings. Hypotheses were confirmed
for the baseline condition. Consistent with our assumptions in regard to the psychological
stress response, the ADHD group experienced significantly greater subjective stress. The
results for the physiological variables were mixed. While ADHD subjects revealed an attenuated
HR during the stress phase, no significant group differences were found for the other
parameters, although a trend was observed for both the low frequency/high frequency
(LF/HF) ratio of the HRV power spectral analysis and salivary cortisol (the latter possibly
indicating generally lower cortisol levels in ADHD subjects). In summary, the present findings
are the first to demonstrate a significant alteration of a specific physiological stress measure
(HR) and, more clearly, of psychological aspects of the stress response in adults suffering
from ADHD. In regard to the physiological stress response, it is recommended that future
studies employ larger sample sizes and a more comprehensive range of physiological stress
parameters. Additionally, the issue of transferability of laboratory results to real life stressors
needs to be addressed.

This is one of the rare studies detailing the response to stress in adults with the ADH
personality. As expected, the study results do not depart significantly from findings
documented in children. The HP-adrenal response is attenuated leaving the rest of the stress
response in the hands of the sympathetic system. Adrenaline is the main player here as it is in
children with the same personality.

XIV- APPENDIX                                                                                                       

A-        Salivary hormone testing


This section will take issue with the various available forms of hormone testing. Relying on a
personalized perspective, I shall discuss briefly the historic evolution of laboratory testing
paradigms. We shall discover, in a simplified manner, the rationale and historic origins of blood
testing, and its application to hormones. We will proceed to explore the natural dynamics of
sex and stress hormones in the human body with emphasis on hormone transportation and
tissue delivery. The illustration of physiologic hormone behavior shall lead us to differentiate
between serum (reservoir) total and free fraction testing on one hand and salivary (tissue
delivery) testing on the other hand. This will culminate in conclusions on the superiority of
saliva testing as the preferred medium for hormone assessment. I will start with a brief
technical introduction for health care providers and then move directly to a more plain English
description for lay people. If you are not interested in the medical jargon behind the topic skip
the first three pages to SALIVARY TESTING FOR THE LAY PERSON.
Brief Introduction for health care providers:

The interest in saliva as a medium that mirrors systemic physiologic / pathophysiologic
changes dates back to the nineteen fifties. Several critical discoveries in the last 30 years have
led to a worldwide increase in clinical usage of saliva in health and disease. So far, saliva is
used for a wide range of diagnostic and research purposes (See table 1). As we stand the
literature contains over ten thousand peer reviewed journal articles addressing salivary
diagnostic uses.

Saliva sampling provides a stress-free environment for laboratory analysis. Using a noninvasive
method, patients are able to collect saliva samples in the comfort of their homes or workplace.
Patients avoid the anxiety and distress of venipuncture reducing the need for technicians and
other trained personnel. Saliva specimens, for most hormones have a prolonged stability at
room temperature exceeding both blood and urine thus allowing shipping long distances.

With saliva, real life assessment of hormone levels becomes a reality. This is especially
beneficial in endocrine dynamic testing including Hypothalamic-Pituitary-Adrenal (HPA) axis
testing for stress response assessment, depression and other psychologic problems to name a
few; and female hormones where longitudinal studies using multiple sampling is merited for
infertility, luteal phase deficits, preterm labor, menopause etc…. Thus, saliva testing provides
an economical and effective way for testing in face of an ever-growing healthcare cost.
Salivary testing of steroid hormones is one promising area for saliva use.

Table 1-Possible Saliva Uses:
- Stress Hormone Assessment (cortisol, DHEA, 17-hydroxyprogesterone)
- Sex Hormone assessment (estradiol, progesterone, testosterone)
- Menopause and andropause studies (conventional sex hormones in addition to estrone, estriol,
androstenedione, dihydrotestosterone)
- Functional infertility, pre-menstrual syndrome and polycystic ovaries
- Thyroid Hormone Assessment (thyroxine, triiodothyronine, thyroid stimulating hormone)
- Pharmacologic (therapeutic) drug monitoring
- Toxicology assays
- Immunologic parameters
- Antibodies for infectious and autoimmune disease diagnosis (SIgA, IgG, IgM)
- Psychologic assessments
- Metabolic evaluations (insulin)
- Food intolerances
- Oral diseases
- Obstetric diagnosis (preterm labor)

Saliva testing of steroid hormones is an economical, stress-free, noninvasive, sensitive and
specific method that mirrors plasma free and tissue-delivery fractions. Steroid hormones have
very short half lives. To exert their endocrine effects on remote organs, unconjugated steroids
have to circulate in an aqueous medium [blood/serum compartment]. Steroid hormones are
transported in blood largely bound to water-soluble proteins (specific binding globulins and non-
specific albumin and prealbumin) to prolong their half life in circulation. The relative lipid-
solubility of each hormone allows on average 1-7% only of the total hormone concentration to
circulate freely (unbound to proteins; serum free-fraction compartment). This fraction is
potentially related to the biologically active portion of the hormone. A portion of the serum free
fraction may diffuse from the serum compartment to the extracellular (interstitial fluid)
compartment. In the extracellular matrix, the steroid hormones undergo further modifications
due to binding to albumin and other proteins, breaking down by enzymes, and other
physicochemical forces in the extracellular space. The eventual concentration of steroid
hormone that will diffuse into the intracellular spaces to carry the biological effect of the
hormone [tissue-delivery compartment] is the difference between the serum free fraction and
the level of extracellular modification.

The idea of using saliva as a medium to measure hormone tissue-delivery fractions started with
the detection of steroid hormones in salivary secretions, followed by confirmation of their
systemic source. Later, it was established that the mode of entry of unconjugated steroids into
saliva is mostly through intracellular diffusion, a mechanism shared by all salivary glands and
most non-CNS organs and tissues. There are exceptions to the diffusion system. For example
thyroid hormones may be transported to cells through active transport.

The kinetics of salivary flow of steroids repeatedly showed independence from the rate of
saliva secretion. This is true in resting and stimulated conditions to oral fluid and individual
salivary glands’ secretions. Regardless of the rate of flow of saliva, hormone concentration
generally remains unaltered. Saliva faithfully reflects the Free-Fraction derivative (tissue-
delivery or biologically active fraction) of unconjugated Steroid hormones.



I can vividly remember that first time when, as a medical student, I was anxiously observing
an attending physician reading a blue-on-white striped lab report of a hormone test! The doctor
looking through his glasses stared at us and said: “I can’t make anything out; let us go talk to
the patient”. Remember, this only happens in teaching hospitals, the talking to the patient

I will come back to that story but first I have a serious chronicle to tell you about. Years ago,
many more in fact than I care to admit, as a young, ambitious and pure medical student, I
arrived one day at work to learn that the emergency room is getting ready to transfer a stroke
patient to our ward. I went down to examine the patient and found her to be slurry, her face
looked awkward but she was generally awake which is a very good sign. Normally as a
medical student you are lucky to see one conscious patient under your care in a day’s work.
The patient was brought up to the floor, and immediately began deteriorating. Her situation was
worsening by the minute. On reviewing the chart I noticed patient was put on a blood thinner
while in the emergency room. I called the attending neurologist to alert him that the patient may
be actively bleeding in her brain and that I recommend withholding the blood thinning
medication she is on since it would only worsen the bleeding. The neurologist refused and
assured me that giving blood-thinning medicine to stroke patients was the “standard of care”.

I went back disappointed, guilty and afraid for opposing an attending physician naturally senior
to me. I went straight to the patient’s room to find her nearly unconscious. I immediately
decided to take her to the radiology department for an emergency CT scan for her brain which
is the fastest way you could tell if there is any bleeding. I knew I needed someone to help but
there was no one around and no cart available. The patient’s husband and I wheeled the bed
out the door to the elevator. As we arrived at radiology I noticed it was going to be a long wait.
At that time, CT scans were a big money maker to hospitals with long waiting lists. The scan
technician was hesitant at first, but he was alarmed when I told him the patient’s life was in his
hands; since he was not a doctor, he took the matter seriously. We were finally able to get the
patient on the imaging table.

So, here I was waiting in a side room with the technician, observing the computer-generated
images as they emerged on the screen. After two cuts only, all the technician could see was
blood covering the whole area of the brain imaged so far. We called the neurologist to tell him;
and boy, he was furious, not because his patient is bleeding to death, but because I dared defy
him and order an expensive procedure without authorization. He shouted profusely at me
saying that I overstepped my boundaries by deciding to take the patient to imaging without his
consent. It took a while to calm him down, but eventually he understood the seriousness of the
situation and told me to withhold the blood thinner and make sure to tell the family… after the
patient dies that is. He said he’ll be back at the hospital soon, but that if the patient dies in the
interim to make sure I told the family there was nothing we could have done differently!

Indeed the neurologist could not make it on time, the patient died in a few hours and I had to
leave her room and face a husband and two teenage kids waiting anxiously. The whole world
shrunk in front of my eyes. I wished I could disappear at that moment. I wished I did not
come to work that day, or may be that economics would have been a better suiting major for
me. Many things passed through my mind as I was opening the door getting ready to tell the
family “there was nothing we could have done differently”. I was visibly disturbed, angry,
embarrassed, sad and distraught. Standing in front of the family, I did not know where to
begin, I stood silent with my head facing the floor, until the husband said, “My wife was a
good woman, and a sacrificing mother; she earned a lot of goodwill in her life, she deserved
better”. I did not utter a word. I went home that night shocked and hopeless. I went home
thinking, there must be some other way; there must be a better way.

I faced the stubbornness of a neurologist who refused to stop heparin (blood thinner) on a
stroke patient until the patient bled to death. The only reason the neurologist wanted to stick to
the thinner is because it complied with the standards of practice in healthcare. Basically, these
standards are the work of a group of self-appointed authorities trying to simplify unusually
complex and many times ambiguous material. These “experts” are entrusted in steering the
medical profession in the “ethically correct” direction by consensus especially when it comes
to managing critical patients. They are usually a group of older people completely entrenched
and shackled in the history of medicine, being asked to make decisions about how to handle
the future of medicine. They usually make decisions that are more economically driven than
medically driven.

These experts usually arrive at their recommendations based on consensus given the best
“available” evidence. Available evidence means exactly that, the evidence at their disposal, it
does not have to be conclusive or inclusive evidence it just has to be available to them or to the
expert with the loudest voice or most dominant or aggressive personality and then this member
will successfully impose his opinion and will over the other committee members, and through
them over all physicians and over you and your health. Now nobody questions the quality of
the evidence these expert committees use because we are obsessed with uniformity, and
minimizing legal liabilities.

Unfortunately, these self-appointed experts not only decide what an individual physician does in
an emergency, but they control everything starting with the definition of health and disease, the
importance and priority of a particular disease or human complaint, the procedures and lab
tests used to diagnose the problem and of course the treatments (pharmaceuticals that is)
appropriate to treat the condition. They are legislators without any mandate; unelected
representatives you might say who decide what your doctor tells you or ignores to tell you.
They impose the views of their world on your world and future.

Where am I going with this you might ask? Unfortunately, I can go with this to each and every
area of medicine today. I could go to each and every sentence any physician has ever told you
through your life. After all, if you are an avid researcher you can predict what your doctor is
going to tell you by visiting the national guideline clearinghouse or NGC (http://www.guideline.
gov/), which lists all policy updates in the medical profession concerned with identification,
diagnosis and treatment of medical conditions. I am not suggesting you replace your doctor by
a website; I am just making a point of where the medical profession gets its “pearls of
wisdom”. I will limit myself in this section to concepts and methods used to determine which
hormone lab tests a person gets when she visits a doctor’s office as opposed to what she is
supposed to be getting.

I will come back to hormones and hormone tests extensively later in the course of the section,
but for now you want to ask why I sound so critical of the medical establishment and the
unified recommendations the medical profession is so brilliant at disseminating. Well, there is
nothing wrong with uniformity… if it works for you. There is nothing wrong with visiting 10
different doctors in ten different states, asking them all the same question and invariably getting
an identical answer. There is nothing wrong with that if the answer works for you.

If you have reached this paragraph, then perhaps you are not satisfied with the “standards of
care”; or you simply agree with me that uniformity is an easy way to rule a society but not
necessarily the best way. You might agree with me that the conservative narrow western
medicine attitude might be missing something. Oh! Missing something; losing direction; not as
inclusive in understanding a topic; these are words that could have landed me an execution in
the medieval ages. Believe it or not they still do, the establishment just has gotten smarter over
time; now they do it virtually instead of physically through isolation, belittling, and credibility

Let us go back now to the opening story, to that young, ambitious, pure, 23 years old me, let
us go back to that first time when I was anxiously observing an attending physician reading a
blue-on-white striped lab report of a hormone test! Going along hoping to learn something and
impressed by this doctor’s courage in ignoring the lab results we went to see the patient. On
the way, I leaned on an older member of the crew, “why is he ignoring the report,” I asked.
She smiled and answered, “You are truly new here, aren’t you! Many times these tests don’t
reveal much”. Doctors have gotten used to ordering blood hormone tests, but many times not
necessarily “actually using” them. Utter confusion I tell you and that lasted with me for a very
long time and still embodies many doctors who order “routine” blood work for hormones.

Anyway as I went along with a different physician each time, trying to learn something I
invariably learned one thing, that endocrinology (the science of hormones and hormone
disorders) is dead as a profession. “Go for gastroenterology” remarked my son-of-a-rich-
daddy-porcha-driving-materialistic colleague. “You can spend a few years scoping people
(tubes inserted to visualize a person’s stomach or intestines), and then off to a luxurious
retirement on a lofty yacht you go”. So why was endocrinology dead; “poor endocrinologists,
they might as well learn fortune-telling; they really sit there looking at a bunch of problems that
all look alike (symptomatically), and it is not like they have an easy way to differentiate and
distinguish amongst the possibilities” added my more-down-to-earth friend. “They really get
very little use out of the lab tests (blood tests) and their treatment options (once they decide
what to treat for!) are extremely limited”.

So what was my down-to-earth-realist friend saying is simple; blood work for hormones does
not work most of the times and hormone treatments are limited yet puzzling. I will be touching
very little on hormone treatments but I will take issue all along with hormone tests.

So, historically, when faced with patient complaints that sound hormonally related, doctors ask
for a hormone test that is invariably a blood test. They order selectively a blood test because
they have been doing it ever since laboratories existed. For the better part of the twentieth
century lab work meant to physicians (and patients) blood testing. Blood is a wonderful
medium that can carry nutrients and an unbelievably large number of substances to individual
organs and tissues and hauls away the waste material these tissues generate. Well, it only
sounds obvious that by taking a glimpse into a patient’s vein we can learn a lot about the
internal workings of her body. If you were a patient back then, you did not want a blood test.
Anybody who has ever had a blood test knows the trauma of a blood draw, especially if your
“doctor” is a third year medical student who has no idea what he is doing!

So, this wonderful medium, blood, which can give us plenty of information about the body’s
internal balances and imbalances, was adopted as the medical profession’s darling early on. I
have thought of going out and researching the first person ever to design a blood test but I was
afraid of getting caught with the rest of them back in history.

The fact remains blood testing has saved lives, countless lives over many years that it became
virtually unthinkable to question the wisdom of its use for any purpose. Kind of like a president
who goes to war and wins, and she (or he) can do no wrong after that. Was it Henry ford
who once said “ you can have your car in any color, as long it is in black” or something to that
effect; invariably over the years the utility of blood testing proved invaluable in many fields of
medicine that replacing it for any one purpose would face insurmountable resistance.

I don’t need to tell you about “conventional wisdom” and conservative ideals that refuse to
change regardless of the facts but I will anyway. At the turn of twentieth century physicists
across the world were convinced that every law of physics has been discovered and that all
they have to do is teach and propagate these laws between then and eternity; as soon as they
congratulated themselves on a job well done, along comes Albert Einstein to prove them all
wrong and revamp the whole science of physics, dethroning Lord Isaac Newton. Believe me I
am no Einstein, as is evident by now from this text, but then again, my role here is the
messenger of good news not the creator of such.

So, western conservative patriarchs have taken over in medicine, and they have collectively
decided that blood testing is the answer to diagnosing all of your ailments including hormone-
related illnesses; with only one problem, blood testing does not work when it comes to


Well, yes I will be saying that but not before I convince you using evidence that is
overwhelming and impossible to ignore. It is a little gross, a little politically incorrect and a little
impolite to ask perfectly gentle people to spit in a tube, but I am willing to take my chances. A
word of warning before we go on, we will get a little technical for the next few pages but I
will try to make it as plain as possible and explain every term.     

Like most physicians would agree, as a medical student nobody taught me about saliva as a
diagnostic medium; nobody even mentioned the possibility of saliva use for medical purposes
for obvious reasons. Anything that is not mentioned to you as a student is not supposed to be
important, but how come it is; how come it is actually superior to all the things you have been
taught. Our journey shall begin with the essence of hormones, their structure, the way they
look in other words.

[sketch of cholesterol and main steroid hormones]
All sex and stress hormones are based in structure on cholesterol, that dreaded name
everybody is trying to get rid of at any price. Cholesterol, we shall learn is not all bad, the body
has good uses for it, and I don’t mean the ‘good cholesterol, HDL’, I mean cholesterol itself
and its use as a backbone of all sex hormones, in addition to being a powerful anti-oxidant.
Cholesterol as is, does not function as a hormone (or at least not that we know of), but it can
be distributed in various tissues across the body and used to make hormones. By looking at the
structure of any sex hormone you can immediately see the similarity to cholesterol in shape
and form with minor variations here and there. What you can’t see but want to know, is two
common properties that cholesterol and the different hormones share, first they are very short
lived and second they do not dissolve.

Most sex and stress hormones live no longer than 20 to 90 minutes from the time they are
manufactured to the time they naturally disintegrate. This is a big hindrance for a substance
that has to travel distances to exert its effect. These hormones are usually produced in sites in
the body which are not necessarily their only site of action. In other words, a hormone
produced in the fat say, may have some effects locally in the fat itself, but many other effects
in the brain or bones etc… the short life of hormones would make these distant actions
virtually impossible. This is the first reason why the body has to find a way to prolong the life
of these hormones to get them safe and intact at their distant activity destinations.  

The second property of hormones is that they don’t dissolve. You could take a pure
preparation of any sex hormone and dip it in water, heat it, shake it, stir it, or do whatever
pleases you with it, and it still would not dissolve. It still would settle as the powder it is at the
bottom of the container. Solubility in water is an important feature of any substance that needs
to move along in our body; after all the human body is 60 – 65% water and so is our blood.
You can immediately see the problem, you have on your hands a bunch of hormones made at
point A (the adrenal glands for example) and wanting to exert their effect somewhere else, say
point B (brain for example) which is physically distant from A. To reach point B, this hormone
has to travel from point A through the blood stream to get to its destination. To do this the
hormone in question has to find a way to travel alongside other blood elements but since it is
not soluble in a watery environment, it simply cannot swim unimpeded in blood. In addition,
the hormone has to also find a way to get to point B while it has some life left in it.

A steroid hormone would immediately precipitate at blood vessel junctions and cross-roads and
would fill up the physical spaces in the heart and lungs no different than the same hormone
would behave in a water-filled container. Anyone who has gotten grease or fatty material on
their hands and attempted to clean them with cold, warm or hot water will know what I mean.
No amount of water will wash the grease off but once you apply a little soap it all goes away
since the detergent in soap is specifically designed to dissolve fats (among other things).

You have a hormone continuously manufactured in the adrenal glands, which the bones need
but it can’t get there because it lacks a method of transportation. Fortunately this does not
happen exactly that way in real life. Our body has figured out a way to overcome this problem.

So after you used the soap to get the grease off your hands, water was sufficient to wash the
soap off right. This is because the soap detergent has one end that dissolves fat and another
which dissolves in water. This way it can host the fat at one end and flow with the water
using its other end. The body does practically the same (obviously the soap makers learned
from the body but the analogy works both ways). The body uses a mandatory bussing system
no different than the school bussing system. This bussing system has two properties; it has a
face capable of hosting the water-insoluble hormone and another face that is sufficiently water-
soluble to swim through the blood.

The main function of the bussing system is to ensure equitable distribution of hormones
throughout the body. The bussing system ensures the hormone is distributed equally to all
tissues regardless of the amount of blood coming through to this particular tissue. This is a
very important feature of hormone transport, since hormones are carry signals of change
equally important to every cell in the body.

Now let us examine this bussing system a little more in-depth. It is made of bulky proteins that
can afford to have multiple faces designed to host hormones and other substances. These
carrier proteins are manufactured mostly in the liver and roam through the blood stream to get
custody of orphaned hormones for transportation. These proteins get protective custody of the
hormones until they get to the place they need to go to. It sure sounds simple so far but it is
not really that simple.

Back to dissolving those sex or stress hormones in water; actually if you analyze the water
after attempting to dissolve a hormone in it, you will find that 95-99% of the amount of
hormone settled at the bottom while the water now carries the difference – roughly 1 – 5%
depending on the hormone in question. The same practically happens in our blood stream. The
carrier proteins carry 95 – 99% of the amount of the hormone in question and the difference,
the other 1 – 5% is capable of swimming freely in the blood stream. This is partitioning.

Depending on the degree of water-insolubility of the hormone the distribution will favor
partitioning the total amount of the hormone into two pools, one attached and carried by the
proteins and one independent freely roaming in the circulation.

So, partitioning ensures adequate distribution of the hormone in question to two separate pools
in the blood. The sum of the two pools makes up the “total” amount of the hormone in blood.
And this is only the first dent in uniformity, much more to come, I promise and it is all derived
from the un-tempered with workings of the human body.

Invariably the two pools that make up the total amount of the hormone present in blood are
disproportionately distributed between the binding or carrier proteins (the bus carrying the bulk
of the hormone) and the much smaller pool or portion or fraction freely traveling through the
blood. The disproportionality is mandated by the extent of water-insolubility of the hormone in
question. For example, cortisol (the major stress hormone) is a little more water soluble than
estradiol (major estrogen in cycling women) where the bulk of cortisol attached or bound to
the carrier proteins (bound fraction) amounts to 93 - 95% of the total amount of cortisol in
blood, while the bulk of estradiol bound to the binding proteins is around 98%. Is it that this
wonderful female identifying hormone (estradiol) is a little more held back than the survival
hormone cortisol which needs to be more generously accessible everywhere in the body? Who
knows, I guess I am going out on a limb here to make the relationship but this is the kind of
jumping to conclusion from very limited and inconclusive data that the medical profession is so
brilliant at.

You do the math from here, if the bulk of cortisol bound to carrier proteins amounts to about
95% of the total cortisol then the difference, the unbound portion must amount to about 5%
give or take 1%. In the case of estradiol the majority bound fraction amounts to 98%, and the
minority 2% remains in the free or unbound fraction. This is an example where the whole
game is about that minority free fraction of hormone. The traditional attitude would go like
this, “I wanna see it all, what is this 2 or 5% you’re telling me about, I wanna see the whole
100%”; more is better mind you, well not in this case. This is your first compartment, the
blood compartment.

In this case, the 95% majority bound fraction of cortisol is by definition attached to bulky
proteins physically incapable of leaving the blood and are destined to remain in the blood. There
is nothing to it; the size of the binding proteins is so big making it prohibitive for them to cross
out of the blood stream into tissues. This is very important to realize since it implies that 95%
of the cortisol in your blood is un-usable; it never leaves the blood so your brain and bones and
heart never gets in touch with and never uses it. This majority is sacrificed in favor of keeping
a dynamic system operating.  

There is no way these carrier proteins are going to make it out of the blood, they are just there
to keep an equilibrium in blood necessary to deliver the free unbound fraction of cortisol to
organs and tissues. This reminds me of a refugee who has made it to this country. This guy
was displaced from his hometown and had to live in a refugee camp for years before he ended
up here. He is practically illiterate, so his job in camp was to guard at night against invaders
and looters. One night a friend of his gave him a hard time about his boring, unproductive job.
The guard basically had to just sit there and watch night after night. Most nights he ended up
watching himself against falling asleep. The next morning, early in the day, our refugee-guard
woke up his condescending friend and asked him to go watch a young woman getting ready to
take the bus out of camp on her way to the local medical college. The guard told his friend:
“Look at her, I am guarding here at night so this young woman can go to college the next day,
become a doctor and come back and treat me in my illnesses later”.

Now if you go to this guardsman and ask him about personal, communal or societal stress
management he would not have a word to say about it. If you ask this man about altruism and
about social capital, he would shrivel into his humble self and tell you that he was not familiar
with the subjects; but in reality he is. He knew that his altruism at camp was bound to create
goodwill in this young aspiring woman and that in turn would reflect itself in an ever-growing
social capital in his community. I am not going to tell you about the mystery person who used
to fit my drinking bills at the local bar years ago.

These binding proteins function as carriers of hormones essentially maintaining a delicate
balance and equilibrium between the bound and unbound fractions of the hormone to ensure
smooth sailing of the water-insoluble hormone in blood, in the first compartment (blood
compartment). For blood to deliver nutrients, hormones and a host of other substances to
tissues all over, it has to gradually flow in smaller and smaller vessels in order to reach the vast
yet delicate areas of the body it needs to reach. Basically, the blood vessels are a whole-seller
that is designed to carry material in bulk, but not to distribute it retail; in order to transform the
operation from wholesale to retail, it has to open stores in individual towns for effective retail
business. The wholesale centers (large blood vessels) keep bifurcating and getting smaller the
closer they get to tissues. This bifurcation process keeps duplicating itself down to very few
convenience stores on every block in a city. These convenience stores are called capillaries.

The capillary is a tiny blood vessel that can efficiently deliver substances to individual tissues at
a micro scale. While a large blood vessel has a wall made of muscle, literally, the capillary is so
tiny its wall is made of a one-cell-thick layer called the endothelial lining in reference to the
name of the one cell thick called endothelial cell. These endothelial cells form a continuum that
lines all capillaries all over the body reaching each and every tissue, and effectively forming a
non-discriminating distribution network that delivers an enormous number of substances,
including hormones to each and every cell and tissue. These endothelial cells are not much
bigger than the binding protein so you can conclude that the bound fraction of cortisol will
bounce against the endothelial wall but will not traverse it. The protein bound fraction of
cortisol will pass through the capillary maintaining its ever-boring job of keeping a healthy
equilibrium between it and the unbound fraction. This unbound fraction of cortisol, the 5% of
the total is made of freely circulating cortisol molecules sufficiently small to cross through the
endothelial wall to the other side, to the tissues. But how does this happen,

Finally that hormonal stubbornness pays off. Finally, we can make a good use of this staunch
refusal of hormones to dissolve in water. Well, this is about the smartest system you may ever
encounter, the human body that is. If you have ever used a hose to clean dirt off your drive
way, you can appreciate how water under pressure can sweep any solid object away with it.
How come the same does not happen in our body, how come the blood under the pumping
pressure of the heart does not wash out tissues with it? Obviously it does not. One of the
reasons the blood pressure does not washout tissues form their original locations is that tissues
and in particular cells build around themselves a wall called the cell membrane. The function of
the cell membrane is to create a separation between the internal and external environments of
the cell (in this case the external environment of the cell is the fluid bathing the tissue).
Remember more than 60% of the body and the blood also is water. For the cell to shield itself
from getting washed away under the hose [blood pressure], one of its defense mechanisms is
to form a water-insoluble wall around it. This is the cell membrane and it is fatty in nature. The
cell membrane simply does not dissolve in water.

So, a fatty water-insoluble material called the cell membrane surrounds all cells in the body.
This is true for your bone cell, your brain cell, your endothelial cell, and every other cell there
is. Now as you can probably remember, water-insoluble is a hormone’s middle name. Water-
insoluble is what hormones are all about. This cell membrane is a hormonal heaven. Hormones
march through cell membranes like a fish swims in the sea. Hormonal passage through cell
membranes could not be more facilitated.

Where are we at this stage?

I guess we have just gotten cortisol within a stone throw of its destination. We have brought it
from its originating point all the way to the capillary traversing the target tissue to the other
side of the capillary wall. What is there on that other side of the capillary wall; well the target
tissue. However, there is one more complication before the hormone actually gets there. Once
the hormone travels out of the capillary to the other side it is immediately faced with another
relatively hostile environment. Once the hormone travels through the comfort of the endothelial
cell membrane it is destined to end that part of its journey in the extracellular fluid or interstitial

Double taxation:

Personally I prefer the word interstitial over extracellular, despite the fact that it sounds a little
cryptic. Interstitial fluid is the fluid bathing the cells, the fluid in between and among cells in
one tissue. Extracellular means practically the same thing but blood is also extracellular (outside
the cells) but not in between the cells. We are now in the second compartment, the interstitial
compartment, the fluidy compartment present in every tissue in the body and acts as a
communication medium among cells of the same tissue. You know what fluidy implies, it
implies water-soluble environment and thus hostile environment to hormone passage. From
here on you might as well flip a few pages back where we were describing what the hormone
has to do to travel through blood. The same virtually applies here.

The hormone crosses the capillary wall only to be faced with another hostile environment in
the interstitial fluid. It is trying to swim through the interstitial fluid to reach the individual cell
but must find a way across. The body actually uses a very similar mechanism to let the
hormone through. Again here too, there are binding proteins that play the same boring role of
maintaining an equilibrium that allows some of but not the entire hormone amount that has
crossed beyond the capillary to arrive at the individual cell boundaries. Some of these binding
proteins are identical to those in blood (like albumin for example) and others carry different
names but still fulfill the same purpose of making the interstitial fluid environment less hostile
and more conducive to deliver some of this poor and by now battered hormone to its final
destination, the cell(s) that constitute the target tissue.

Again this 5% of cortisol available in blood to cross through, that we called free fraction, has
to be partitioned and fractionated and some sizable portion of it is sacrificed again in order for
that final fraction of 5% to make it to the target tissue. Here the science is still not as developed
and differentiated. We know for a fact that this process happens because we know that the
interstitial fluid is water-soluble and that to get the hormone through it has to partition, and we
can find the proteins that aid in making the partitioning possible abundantly in the interstitial
fluid. You have to remember that what we’re working with is not the 100% of the hormone
anymore. We are working with the 5% free fraction that we called potentially usable, but not
fully usable. It is not fully usable because some of it will be lost to creating and maintaining
equilibrium in the interstitial fluid (the second compartment).

Finally, a portion of this 5% free fraction of cortisol makes it to its destination, the target
tissue. Finally we can say after all this tortuous journey that cortisol has made it to the
boundaries of the individual cells that constitute the target tissue, but there are no problems
here. Target tissue cells are lined by a fatty cell membrane and all sex and stress hormones go
through fatty membranes with virtually no resistance.

This is not the end of the road for the hormone but we have at least delivered it to its final
destination, to the third compartment, the actual compartment that has use for the hormone,
the cellular compartment. I believe we have learned so far that most of the amount of the
hormone produced is lost to logistics along the road. Let us take cortisol for example, we
already lost 95% to the binding proteins in blood, and are left with only 5% potentially usable
cortisol to work with. This potentially usable free fraction crosses from the blood
compartment to the interstitial fluid compartment only to lose again some of that 5% to the
binding proteins present in the interstitial fluid compartment, the second compartment. Mind
you a sizable portion of this 5% is lost to the interstitial fluid (up to 70 – 80% of that unbound
fraction). It is very similar to double taxation of dividends for those of you who familiar with
the corporate world.

The amount of hormone that will actually make it to the cellular compartment, the third
compartment is only a small portion of the 5% free fraction from the blood compartment. This
fraction of 5% is the only amount of hormone that matters. It is the only amount of hormone
that reaches your cells and that can exert any biological activity at the cellular level. It is the
tissue delivery fraction otherwise called the biologically active fraction. That fraction of 5% is
all the cell has at its disposal and all the cell is affected by. This fraction of 5% is all the cell
has to work with and boy does it do miracles with it!


Let us go back to the daring doctor who wants to do something as archaic as talking to the
patient because the blood hormone test or as they professionally call it serum test was not as
revealing as he had hoped. I made notice into one occasion but in reality every physician who
has ever asked for serum hormone tests on a patient can probably validate my so far
contention; but building on the previous pages is about to be an inevitable reality to be reckoned

Routine, traditional or by now historic serum hormone tests refer to the total amount of a
hormone in blood. By going back to the blood compartment you can see what is meant by total
hormone concentration. It is the sum of the two pools, the 100%, of which only 5% or less is
potentially usable. The majority share, the 95% does not leave the blood and is not usable in
tissues. Testing this 100% total is testing the blood compartment which as you probably can
tell by now does not share much with the third compartment (the tissue compartment) if
anything at all.

The total amount of a hormone in blood is equivalent to the reservoir amount. It is very similar
to the water reservoirs somewhere on a hill close to your town or city. The third compartment
or cellular compartment is the tap at your own home that pours water necessary to wash
hands, drink, bathe… Now you are a model citizen living in a town of 3,000 people. You
follow the town news. It is springtime and everybody knows the rain this year has not been as
adequate as it had been in recent years. You go to the mayor’s office to ask about water
availability for the summer season. The mayor’s office pulls out a blue-on-white striped
document showing you the levels of water in the town reservoir and they review them with
you and compare them to historic averages of town water usage. By a simple comparison, you
look at the available water in the reservoirs and you compare it to the town needs over years
past and you go home satisfied that there is plenty of water for everybody, even if it does not
rain for the next three years.

Your happiness unfortunately lasts only until your doorsteps. You enter your house, happy and
content with what you’ve heard from the mayor’s office. You decide to take a shower to
celebrate the plenty of water available to you. You open your tap and not as much as a single
drop of water comes out. Go bathe at the mayor’s office if you want to. There is no water at
your tap.

The example above is a dramatization of how elusive it is to test the total amount of a hormone
in blood and come to make conclusions about the amount of a hormone in bones or muscles or
heart or brain or any other tissue. By looking at the total hormone concentration is serum, the
first compartment; you could jump to the wrong conclusion roughly in two thirds of the time
if not more. In plain English, the total hormone concentration in serum relates to your cellular
hormone concentration in less than 35% of the times. In more than 65% of the times it can be
totally misleading.

To give credit where credit is due, some physicians and medical professionals have realized
this phenomenon and began looking for a solution. Out of a lot of work came the relatively
newer idea of trying to test the free fraction instead of the total. Some went all the way to
abandon total hormone concentration in favor of free fraction concentrations as in the cases of
thyroid hormones and testosterone. Now you can find mainstream laboratories testing free
fraction of thyroxin (T4) and testosterone in serum. This is not nearly as bad as go bathe
yourself in the documents kept at the mayor’s office kind of scenario but it is still less than
adequate. The reason is that you are still in the first compartment; you are still testing blood
and assuming it represents tissue.

The free fraction is at least related to your tissue concentration but it is not identical or as
faithful in revealing your tissue hormones. Remember between the free fraction in serum and
the cellular compartment, there stands another space, the second compartment, the interstitial
fluid which further modifies the hormone concentration beyond the free fraction and the end
result is many times proportional to the free fraction, but not consistently or predictably. The
serum free fraction test remains an estimate at best and not an actual assessment of tissue

You could settle for the free fraction test in serum and hope that the second compartment does
not alter the hormone availability to your cells in any way or shape or you could try and get a
direct test for your tissue levels.

Spit, literally, that is all you have to do; well let the saliva drip from the side of your lip to a
small collection container.

We have established so far that all hormone blood tests (total and free fraction) only tell you
what is in blood and NOT what is actually in this third compartment, the cellular compartment,
which includes all tissues in your body from the brain to the toes. Now if only there was a
way to look beyond blood into this vital third compartment without actually taking out a sample
of your brain out for hormone examination. Fortunately there is!  

It is your salivary glands; did I just say saliva, that dreaded, socially despicable fluid that comes
out of our mouth only when we want to be impolite to people around us. Sounds unlikely, but
it is not.

Your salivary glands follow the same identical rules and mechanisms that every other tissue in
your body follows to receive hormones. The salivary glands follow exactly the same way your
bones and muscles and heart use to get hormones in. The only difference is, after the heart
takes in a hormone it uses it locally. The salivary glands are secretory by nature, meaning
anything that comes their way from blood is passed along to saliva. So your saliva, aside from
ensuring your mouth is lubricated at all times, provides a window into your tissues, a mirror
into the amounts of hormones your tissues are exposed to on a continuous basis.   


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Measurement and meaning of salivary cortisol: a focus on health and disease in children.
Jessop DS, Turner-Cobb JM. Stress 2008; 11(1):1-14
Measurement of salivary cortisol can provide important information about hypothalamic-
pituitary-adrenal (HPA) axis activity under normal conditions and in response to stress.
However, there are many variables relating to the measurement of cortisol in saliva which may
introduce error and therefore may render difficult the comparison and interpretation of data
between, and within, laboratories. This review addresses the effects of gender, age, time and
location of sampling, units of measurement, assay conditions and compliance with the
protocol, all of which have the potential to impact upon the precision, accuracy and reliability
of salivary cortisol measurements in the literature. Some of these factors are applicable to both
adults and children, but the measurement of salivary cortisol in children introduces aspects of
unique variability which demand special attention. The specific focus of this review is upon the
somewhat neglected area of methodological variability of salivary cortisol measurement in
children. In addition to these methodological issues, the review highlights the use of salivary
cortisol measurements to provide information about HPA axis dysfunction associated with
psycho- and patho-physiological conditions in children. Novel applications for salivary cortisol
measurements in future research into HPA axis activity in children are also discussed.

B- Food intolerance and allergies

The prevalence of food intolerance and related complaints in the general population is rather
impressive. Many food intolerances may be clinically silent yet the long-term clinical
consequences are astonishing in their cumulative effects. In addition to continued intestinal
inflammation and problems absorbing nutrients (malabsorption), the body-wide associations
with the different food intolerances are far reaching. These include thyroid disease, type 1
diabetes, neurologic disorders, increased cancer risk and other ageing implications.


FOOD INTOLERANCE (or sensitivity to food) is an abnormal physiologic response to an
ingested food or food additive. The offending substance may be a sugar such as lactose, fiber
or a protein that has a negative interaction in genetically susceptible / predisposed individuals.  
Negative consequences can include metabolic, toxic and inflammatory responses to the food or
additive, but it is not mediated by overactivity of the adaptive immune system; ie. not an IgE
mediated hypersensitivity.

Symptoms, associated with food intolerance, occur because a substance in a meal triggers a
significant toxic reaction by either making direct contact with intestinal cells or by interaction
with an intermediary substance, which upon activation reacts with the intestinal cells. This
contact triggers an inflammatory cascade, which results in damage to the lining of the small
intestine, specifically damage to mucosal barrier layer. The inflammatory cells release
mediators such as histamine, serotonin and cytokines, which attract local lymphocytes that in
turn release antibodies directed against the offending food substance. Most of the antibody
released is secretory IgA (SIgA) which arguably is part of the innate immune system. On
future exposure to the same food, SIgA may act as an immune exclusion mediator preventing
the food protein for example from reaching the intestinal lining.

FOOD ALLERGY (or hypersensitivity) refers to a group of transient disorders that are
characterized by an exaggerated adaptive immunologic response to specific foods resulting in a
variety of symptoms. Food allergy is caused by an allergen, a substance foreign to the body
that in many cases triggers a classic IgE mediated immune response with associated
hypersensitivity reaction. Some food allergies trigger an IgG response if they reach the blood
stream. Food allergies are subject to oral tolerance, and the anticipatory nature of the immune

Several forms exist that can be categorized into:
•        IgE mediated or immediate onset
•        Non-IgE mediated or delayed onset
•        Combination of IgE and Non-IgE mediated

Food intolerance, a genetic inability to handle selective food proteins, is associated with several
misnomers and misconceptions.

Fallacy #1: Food Intolerances and food allergies are two names for the same condition.
Intolerances continue to be confused with transient allergies to food. While food allergies are
immunologically explained by the different forms of hypersensitivity reactions, they are distinct
from intolerances which are life-long genetically determined.

Fallacy #2: Food intolerances are viewed as diseases of childhood.
Intolerances are more likely to be symptomatic in children but are found in adults of all ages,
because they arise from genetic factors. Also, many adults on careful examination exhibit
nearly silent forms of intolerance that present with sub-clinical pathology.  However, even at
low, almost latent levels of disease, the reactive substances are perpetrators of low grade
intestinal inflammation that has substantial impact on well being.

Fallacy #3: Food intolerances are only present in symptomatic patients.
Many cases of food intolerance can be asymptomatic depending on the severity of the toxic
inflammatory response they trigger in the intestines. In fact, low grade intestinal inflammation
can sometimes be the only manifestation of food intolerance with no significant clinical
symptoms but with a continuous recruitment of inflammation-provoked bodily defenses.

Food intolerance prevalence is naturally underestimated in a symptom-driven heath care
system. The attempts thus far to raise awareness of this malady still fall far short of even
minimal expectations due to inadequacy of conventional testing methods.  

Fallacy #4: Food intolerances are simple enteropathies.
Food intolerances are usually more than a simple, uncomplicated enteropathy. They may
predispose patients to autoimmune diseases and cancer in addition to premature ageing,
because they are inducers of chronic stress. As a hidden source of inflammation, they
continuously limit nutrient absorption and waste energy and other limited bodily resources.


Food intolerances or food-sensitive enteropathies are clinical syndromes that damage the small
intestinal mucosa and can result in altered intestinal permeability.

The intestinal damage ranges from a barely measurable increase in inflammatory cells
(intraepithelial lymphocytes) in the mucosa and submucosa without visible damage to the
mucosal barrier to extreme villous damage and patchy mucosal sloughing. The intestinal lining
damage may or may not be reflected in the degree of symptoms and systemic affliction
observed on examination.

Patient may be completely asymptomatic (with an ongoing low grade inflammatory insult to
their gut)
OR present with:
•        Diarrhea: the most common GI symptom; it can vary from soft/loose stools, to
abundant loose stools, to liquid/watery stools to hemorrhagic watery stools
•        Constipation
•        Vomiting
•        Malabsorption: increased stool fat and carbohydrate excretion
•        Changes in intestinal permeability
•        Malnutrition
•        Anemia
•        Folate deficiency

The GI symptoms usually reflect hypermotility: vomiting, colic and diarrhea. However,
constipation (result of hypomotility or of extreme muscle spasms) can be prominent.


Gastroesophageal reflux and occult bleeding of small intestinal origin also may be present.
SKIN: Urticaria / atopic dermatitis / perianal rash
RESPIRATORY: rhinitis, asthma
HEINER SYNDROME: a chronic pulmonary disease caused by hypersensitivity to cow’s milk.
CNS: headaches, migraine, sleeplessness, irritability
OTHER: Anemia, Folic acid deficiency, Vitamin K deficiency


Elevated serum total IgE will support a general diagnosis of allergy, but normal total IgE levels
do not rule out allergy. In addition, non-allergic conditions elevate total IgE levels. In
percutaneous skin testing, the negative predictive accuracy (95%) is much higher than the
positive predictive accuracy (50%). A positive skin prick test is associated with clinical
symptoms approximately half of the times. Many patients have apparent false positive test
results as they are both asymptomatic and completely

Measurement of IgE antibodies for specific food derived antigens varies in reliability from one
lab to another as well as from one method to another. Serum IgE and skin testing produce
comparable results as they both respond to the presence of specific IgE in serum or on
cutaneous mast cells. Skin testing results depend on the ability of mast cells to bind antigens
and release histamine. The skin and serum tests do not always correlate because IgE
concentration is highest on the mast cells in the involved organ.  Also, the mechanism of action
is complex as evidenced by inconsistencies between clinical observation and testing. Both the
skin and serum tests may be negative in patients with definitive immediate type
hypersensitivity. Also, both may be positive in the absence of observable disease.


Gluten intolerance is more common than is reported in the older literature. Historically, the
diagnosis relied on biopsy of the small intestine. Patients with less severe or vague symptoms
were in most cases excluded as candidates for biopsy. In addition, a normal biopsy does not
exclude the disease. Inflammation could be patchy or tissue may show some degree of
response that falls short of villous atrophy and other diagnostic criteria. With the advent of
biochemical markers for gluten intolerance, several studies have proven the presence of
specific antibody-verified, gluten-free diet validated, gluten intolerance in a large sector of
society (12 – 18 %). A step forward in redefining the incidence of the disease was the
introduction of broader definitions of the disease entity. Newly added subtypes allow inclusion
of variants previously not included among gluten intolerance patients.

Silent gluten intolerance: a completely asymptomatic form usually associated with gross
damage to small intestinal mucosa and positive biochemical markers (anti-gliadin & other

Latent gluten intolerance: may be vaguely/mildly symptomatic and is associated with grossly
normal intestinal lining that shows signs of low grade intestinal inflammation.  It is associated
with increased intra-epithelial lymphocyte counts and biochemical markers are usually


Predisposed individuals usually carry HLA-DQ2 as the main susceptibility genotype. The major
histocompatibility complex II – DQ2 is found in 98% of patients of northern European
descent. HLA-DQ8 is another susceptibility genotype present in non-caucasian patients. The
expression of DQ2 or 8 allows lymphocytes in the gut to recognize the gluten protein as an
antigen and triggers the local immunopathologic response that results in intestinal inflammation
including SIgA release.  SIgA is both the initial and major subclass of mucosal antibody to
respond to foreign objects. In addition, the guts response to a major food protein as a foreign
antigen can be considered an autoimmune reaction.

Food intolerances or food-sensitive enteropathies are clinical syndromes that result in damage
to the small intestinal mucosa, which can alter its permeability. Cow milk intolerance is a
specific, genetically- dictated intolerance to the major milk protein, casein.


It is defined as cow milk induced small intestinal mucosal damage that is reversed by a cow
milk-free diet and reoccurs on challenge. It is an abnormal physiologic response to casein in
genetically predisposed individuals. The reaction includes metabolic, toxic and
immunopathologic (inflammatory) responses to casein.

Milk intolerance is caused by casein and other milk antigens/proteins. Casein triggers a toxic
reaction on contact with intestinal cells. This contact triggers an inflammatory cascade
resulting in damage to the mucosal barrier. The inflammatory cells produce mediators that
signal local lymphocytes to produce antibodies against casein.

Damage to small intestinal lining and clinical symptoms vary widely between individuals. In
severe cases, the problem is apparent in early age (< 3 years of age). In milder cases patient
may be completely asymptomatic, yet suffering an ongoing inflammatory insult to their small
intestine. The mucosal barrier damage is in the form of mild to moderate villous atrophy
(villous shortening) in a patchy discontinued manner.

Lactose intolerance on the other hand, is a common condition caused by deficiency in the
intestinal brush-border enzyme lactase. Its effects are largely dose dependent. In many cases, a
transitional or reversible lactose intolerance is observed. This is commonly experienced in
patients with food intolerances where the sloughing of the mucosa leads to a decreased
availability of the lactase enzyme. The sloughing results in loss of the disaccharidase-containing
mature enterocytes leading to a reduction in lactase small intestinal activity. Usually when
patients implement a strict avoidance program of the offending food, their lactose intolerance

It is defined as egg-white-induced, small intestinal mucosa damage that is reversed by an egg-
free diet and reoccurs on challenge. It is an abnormal physiologic response to ovalbumin in
genetically predisposed individuals. The reaction includes metabolic, toxic and inflammatory
responses to ovalbumin. Egg intolerance caused by ovalbumin occurs with hen and most other
bird eggs. Ovalbumin triggers a toxic reaction on contact with intestinal cells. This contact
triggers an inflammatory cascade resulting in damage to the mucosal barrier.

It is defined as soy protein induced small intestinal mucosa damage that is reversed by a soy-
free diet and reoccurs on challenge. It is an abnormal response to soy proteins in genetically
predisposed individuals. The reaction includes metabolic, toxic and inflammatory responses to
soy. Damage to small intestinal lining and clinical symptoms vary widely between individuals.
In severe cases, the problem is apparent in early age (< 1 year of age). In milder cases patient
may be completely asymptomatic, yet suffering an ongoing inflammatory insult to their small
intestine as shown by secretory IgA release. It seems there are more soy intolerance patients
with IgA deficiency than there is in the general population.

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I live in a land where common sense is not that common; where the phrase “conventional
wisdom” is no wisdom at all.
I live in a land where consistency and stability are as elusive as chasing a rainbow.
I live in a land where happiness has long been dethroned and been replaced with the pursuit of
evenness of mood.
I live in a land where authority is such an intolerable oppressive force.
I live in a land where logic and reason always trump imitation and conformity.
I live in a land where the abstract is foreign and obscure, while concrete wins the day every
I live in a land where authenticity and rebellion are a way of life born out of disconnection with
the ways of the wider world.
I live in a land where necessity is the only and yet most dreaded way to people’s world.

As the third child for a designed family of four, I started accruing seeds for a further left sided
move on the spectrum while still in the womb. Of course the resentment by my somewhat
sensitive yet constantly overwhelmed mother started at conception and continued into my early
years. My mother was working then 9 or 10 hours days in an effort to pay off the family
house, which added to her bad temper and intolerance to my eccentricities and idiosyncrasies.
She also harbored all types of negative feelings towards my baby sitters [my paternal
grandmother and her live in daughter], which restricted them and clouded their traditional
judgment in raising me. This led to a fragile bond between me and my mother where she often
presented danger and was a source of fear when she was supposed to be my mountain of
safety. I cannot tally the number of times I found myself waking up to a beating from her due
to a multitude of real or imagined reasons. I cannot remember a single time when I was
allowed to have a friend over since my mother was absolutely opposed to having her peace
disturbed. Needless to say, her attitude combined with my limited ability to communicate killed
any chances I had at having stable friendships.  

This in turn led my father to try and form a secondary bond, which he started at a later age (3
years of age), way beyond the time when the damage had already been done. However this
secondary bond helped a little. When I was about 7, my father, whose presence was so
essential for me, developed an obscure illness. No one really knew what it was. All we knew is
that he woke up one day with back pain. He felt it would be necessary for him to stay in bed
for a few days until the pain went away. In fact, despite literally dozens of doctors trying to
figure it out, and hundreds of bottles of medicine, he ended up in bed for 5 straight years.
Meanwhile, my already overwhelmed mother grew even more overwhelmed and loud and
abusive. I used to spend hours by my father's bedside every day, not knowing what else to do
but feeling that even when he was asleep or just spaced out, it was still a safer place for me to
be in than anywhere else. He rarely spoke to me or to anyone else during this time. He just lied
there on the same side of the bed day after day with the same unchanging frown face saying
nothing and doing nothing. It was as if his world stopped moving, and with it my world too. I
can’t forget how terrified I was every time I looked his way and could not see him visibly
breathing. I had this idea that he might just stop breathing and then I would not be able to talk
to him again; so I spent most of my time observing his breath, awake and asleep alike. I
remember getting up several times each night to check on him.

And then a little over 5 years later, he got up one afternoon, bathed himself, put on his suit and
told us he was going to town for a beer. He was somewhat functional again, able to hold a job
and drive a car. However, he remained absent for most of the other parts. I never saw him
laugh after that, or engage any of his kids in any shared pleasurable experience. He seemed to
be ok with most of what we did as long as we kept out of the way. He only intervened with
things he considered to be very important, like putting suffocating tabs on my older sister in
her teenage years.

Of course the bond with my father turned into resentment when around puberty, I went
invisible, not being able to fit in or to construct meaningful relationships or excel at any sports
since I was shy and clumsy. My father with his relative ignorance knew something wasn’t
right but could not put his finger on it. He resolved to prevent me from ever masturbating since
he thought that masturbation was the origin of all my problems. Since then the poor guy stood
guard on me whenever he could until I left the house to college after graduating high school.

One time when I was 15, my mother asked me to go check on my dad since he was late
hunting. She pointed me to where he would usually be in the woods, so I went there. From a
distance I clearly saw him trying out different positions he could use his hunting rifle to shoot
himself. I don't know how, but I mustered the courage to start yelling for him. When he heard
me, he kind of gathered himself and we both walked back home. We never spoke about it, and
this is the first I have ever said anything to anyone about it. In fact for many years I had
suppressed this memory. I know now that this was the most traumatic thing I have had to
endure. It is so liberating to finally get it out.

So, I went to college without a penny in my pocket, slept on my bag in the street for 3 weeks
not knowing where to register my courses or how to pay for them. I developed a bad case of
pneumonia and was effectively homeless in war-torn Beirut during the eighties. One day I
heard a man calling me by my last name, I turned around and the guy knew my father and
recognized me by resemblance. I introduced myself and he took me in, gave me a bed to sleep,
helped me register and paid my tuition. I don’t know if I ever would be writing this book if it
were not for this kind man. He never asked for his money back from my family or me; and he
refused any reimbursement despite being offered at multiple occasions. So much of what I
have done since seems unconsciously to be steered toward preventing the first homeless

My college journey was mostly uphill and stormy. I excelled perfectly in certain subjects and
suffered miserably in others. However I made it through undergraduate studies with a decent
average. The social stuff improved much that I had a steady girlfriend during my junior and
senior years. My parents visited me one time during this period about 18 months into my
enrollment. They showed up at my dorm room one day to tell me they are planning to buy a
new car and left shortly after, while I was wondering where the next dinner will come from.
Thankfully I had forged a relationship with the owner of a fast food store close to campus,
where I brought in new customers [classmates mostly] and in return he handed me fried beans
(falafel) for free. It was quite the steady diet.

Somehow and after a one year sabbatical I managed to enter medical school at the same
university, but at that time I had managed to work [tutoring rich, spoiled kids] which earned
me enough money to manage the next 2 years. Of course the money ran out in the middle of
the second year of school with all that means for a suffocating medical student. Needless to
say I had so far lived the life of a rebel looking for a protest. I sat through countless sit ins and
was arrested for disobeying campus security and law enforcement officers multiple times,
none of which included a visit from my family in jail. In fact when I rarely visited them, they
ridiculed my activism and discouraged me from continuing any extra-curricular activities. I
guess because they thought I was too fragile to get mixed up that way. Long story short, I had
to repeat my second year of medical school because as an elected class representative and a
member of the curriculum committee I argued for the superiority of self-education over
institutional learning. In addition, I had missed too many classes getting arrested and stuff.
Besides, after I ran out of money I developed a sense of fatigue coupled with difficulty
sleeping and inability to concentrate!

I remember the day when as a third year medical student I went back to campus to see some
old friends and hang out only to find out that virtually all the people I knew had graduated and
left. I felt lost. That was the turning point in my social life. I was too overwhelmed to try and
re-establish contact with any of these folks. At the same time I was treated like a leper in the
hospital being a rebel and behaving differently and not being uniform! Since that day, my social
life was lost and I was alone. It took me over ten years to regain some social contact and
establish at least some pseudo-friendships mostly from within my framework of mission but
rarely in the open society.

I had one girlfriend during my third year in medical school who ended up sleeping with my
roommate, which further isolated and devastated me. She said she was fed up with me. She
said that whatever worked with everyone else does not work with me and that she was at a
loss as to how to conduct herself around me let alone to make me happy. It goes without
saying she was a neurotypical who could not understand my sensitivity or knew how to handle
it. I had a few other attempts at an intimate life but they consistently ended in failure due to my
longing and yearning for my undergraduate girlfriend with whom I was still hopelessly in love
despite her cutting me off from her life completely. This was a sensitive one and we formed a
powerful emotional bond that had prevented either one of us of having a meaningful intimate
life separately after the two of us broke up. She sadly passed on at a very young age having
had no chance to examine her life or to come to terms with who she is. She died in a
mysterious car accident a few years back driving from Delaware to Maryland on a Sunday
afternoon. She had completely dedicated her life to her career until that fateful point.

These years of isolation form the basis of this book. My time was mostly spent with repetitive
depression episodes, constant anxiety and palpitations, chronic sleep deprivation and
debilitating fatigue. These years also included a tremendous amount of personal and
professional growth, long years of reading, searching and unlearning. I am glad these years
culminated in this book and hopefully in a new life for some who may benefit from it. I
specifically hope to continue to help others with similar personality achieve their potential and
find their way around liberation and illumination.

Professional philosophy and experience:

Conventional medicine is excellent at going the depth in ferreting out the littlest scientific details
and then jumps to categorizing symptoms and diseases in ways that justify one pharmaceutical
drug per symptom on average. Integrative medicine relies on the understanding of physiology
& pathophysiology, made available in large part through conventionally funded research, to
reconstruct the broader picture and look at the patient in her entirety. In addition integrative
medicine relies on herbology and time-honored input from various cultures to capture the
whole biological model of human health.

I am a medical doctor by institutional training. I graduated in ‘98 and have been busy ever
since unlearning and unmuddying myself. I have been diligently washing the dogma out and
internalizing the available facts instead. I have been occupied with threading myself out of the
“healthcare system” into personalized health care. My journey has taken me from the
suffocating dark coalmines of the reductive to the sun-marinated enlightenment of the
integrative. Twelve years into it I know that every moment brings me a step closer to the light.
Studious distractive imbibition leads to gradual enlightenment. At this stage I am ready to share
some of my experiences and to invite you to join in on a liberating journey of guided
transformation. You are invited to absorb the means to shed the bicameral in favor of complete
reconciliation. You are invited absorb the means to shed uniformity in favor of a customized
life. I am also ready to share with you the constitutional wellness approach to autism and
sensitivity and to work with you on evolving & further broadening that approach through
cooperation and collaboration.

In my capacity as a healthcare consultant over the last 12 years, I have been working with
mostly wholistic physicians – and some mainstream ones - to individualize healthcare
interventions to sensitive patients of all ages. I have had the unique opportunity to work with
thousands of physicians on understanding the needs of their sensitive patients and
implementing treatment programs which sink in with their constitution. I taught and I learned
through these exchanges more than any medicine textbook or medical school could teach
anyone. In fact, the most difficult part was unlearning the dogmatic ideas I had been taught as
a medical student and most important of all, my experience had a personal healing implication.
Validating our lives through the lives and hardships of other ordinary strangers is such an
invaluable American tradition. It has helped me handle and dispose of most of my
psychological load. It has also helped me gain piercing and broad insight into the experiences,
health concerns and hardships facing other sensitive people in everyday life. This book is me
paying back some of the generosity and goodwill that was extended to me.   

I also consult on bio-identical hormones replacement and gastroenterology and wholistic and
integrative medicine in general. I live a happy, satisfied and fulfilling life in Renton, western


This book will work best for you, when you absorb it in its entirety. Breaking it down into
individual chapters and sections and paragraphs will irreparably damage the meaning and intent
behind the theory. The same applies to the following list. I hope my individual take on the
material referenced proves helpful in your choices. Most of these books got me through my
darkest days. Additionally, these books form in large part the scientific foundation upon which
this book stands. I hope the unifying theory of sensitivity and the works of these great authors
will help you in some of your darkest hours.

NuVision Publications (August 10, 2007)

Rousseau is one of the greatest integrative thinkers of all times. In his masterpiece Emile
Rousseau argues for probably the first time in history that children are born essentially good
and that it is up to the environment in which they grow to remain good or to change. Basically
he believed that children are born with an inherent personality. The book is a narration about
raising an imaginary child with a clear preference for natural law over manmade law. The book
probably represents the way he would have liked to be raised.

W (I748); London.

William cadogan’s writings were the first by a physician to give advice to parents on raising
kids. Cadogan is a darling of mainstream pediatricians and yet I can’t seem to find anything
wrong with him. Go figure!

(August 1993)

This timeless book is about the life-long development of humans with focus shifting from one
issue to another at different stages of life. It is ALL based on mastery of solving problems
relevant to each stage. Very good views of connectedness value in development and achieving

IL – Thomas [latest edition 2006 by transaction publishers]

At the time this book was first published, it was revolutionary in many ways. It was almost
prophetic in predicting that the main difference between extraverts and introverts is in their
threshold for response to stimulation. The arousal theory put forward suggested that introverts
have a lower threshold for response to sensory stimulation. That was over forty years ago and
we are yet to make real progress on gaining the equal footing in society to both personalities.

2000; publisher ALLYN & BACON

This is a basic psychology textbook on personalities. It is rather mainstream in its content.
However, the brilliance of Charles carver, the main author makes the book stand out among
many similar books. This is also one of the rare textbooks that mention innate sensitivity.


This is a classic book on thyroid from a wholistic perspective.


This is a greatly authoritative book on the thyroid axis and its interactions with the rest of the
neuroendocrine system and the rest of the body. It is a textbook, but it was chosen because of
the progressive nature of the authors’ attitude. It is not the most up to date on the latest
molecular discovery in thyroidology but it sets the tone for advancements to come later. The
book contains a good section on the developmental effects of thyroid hormones.


This is one of the earliest books to link psychology, hormones and the brain. At the time of
publication it was truly revolutionary.


This is a rare nutritional book that maintains a non-judgmental attitude and does not prescribe
one size fits all diets. The author’s life work centers on individualizing diet to meet each person’
s metabolic uniqueness.

PHYSICIANS BY BRYAN JEPSON; Sentient Publications; 1 edition (July 25, 2007)

This is a wonderful book with plenty of complementary properties to this book. It reads like a
mini-encyclopedia of alternative remedies. However, it lacks focus, a model and hierarchy. The
book you are reading now is an essential prequel for the book by Dr Jepson.

SABOTAGE US BY JOHN J RATEY; Bantam (June 1, 1998)

This is a very helpful book since it tries to put psychologic and personality problems on a
continuum that takes into account relative severity of problems. In fact many “disorders” as
the medical profession calls them, have personality counterparts with similar but milder forms
that are not as intrusive on functioning. This book opens the eyes to subtle personality

edition (August 26, 2004)

This is the definitive book on stress for our generation. This book presents current state of the
art knowledge about stress and its impact on every aspect of our lives. It is focused on adults
and ageing.

BY JOSEPH LEDOUX; Simon & Schuster (March 27, 1998)

Joseph Ledoux is one of the best contemporary neuroscientists and so is his work.

Penguin (Non-Classics) (January 28, 2003)


It is very hard to pick and choose amongst the writings of this great psychologist. His work
should be taken in its entirety. Some of the volumes may be out of print but the Philemon
foundation is currently in the process of putting together a broader collection that will include
never before seen material.


This is a good selected collection of Dr Jung’s writings. It serves as an introduction to Jung’s
philosophy for the more deliberate of us who would like to sample the complete collection
before investing their time and money in it.

edition (October 16, 2002)

In short Dr McEwen was asked by his publisher to write a book with less than five scientific
terms per sentence. And so he did, with four scientific terms per sentence. The work of Dr
McEwen presented me with great help on my way of understanding the biologic basis or
stress, hormones and functional neurology. This book does not give justice to the author but it
is his only published book as far as I know. All his other work is in professional scientific

KANDEL; W. W. Norton; 1 edition (March 19, 2007)

This is a book by one of the living giants of neuroscience. Many generations of physicians first
learned about the brain through his writings. His work has opened doors to restoring memory
in diseases of ageing.


A brilliant and insightful psychologist, Elaine Aron is without a doubt the number one trusted
advocate of sensitive people worldwide. This is only one of a series of books she has on the
subject and yet she still finds time to see patients one on one. This is a wonderful validating
book for sensitive adults. It has some practical advice, but it is mostly for validation and to
instill a sense of belonging.

& SCHUSTER) 2005

This is a rare book with a very specific purpose. If you are on antidepressants and you wish
you were not, stop everything you are doing and purchase this book. As far as I know it is the
only book that gives a practical program for quitting antidepressants. Most psychiatrists,
family physicians and OB-GYN doctors are proficient at prescribing antidepressants. I am still
longing to meet one who is proficient at discontinuing antidepressants in patients who do not
need them anymore. The pharmaceutical industry is naturally very happy about that. Dr
Glenmullen is a rare enlightened psychiatrist who is ready to share his expertise about
antidepressant dependency and about proven ways to discontinue them.


This is the classic that dwarfs all other classics. When this book was first published in 1956 it
was truly prophetic and radically redirected the worldwide conversation about the mechanisms
of stress and the impact of stress on health and ageing. It is still fascinating reading material by
the scientist and the layperson alike. Dr Selye mentions that he wrote this book after 20 years
of observing all sorts of individuals speak in his name and claim authority on the subject matter.

DEVELOPMENT BY JOHN BOWLBY; Basic Books (August 21, 1990)

John Bowlby in collaboration with the pioneer Mary Ainsworth gave the world the theory of
attachment. The contributions of Mary Ainsworth to child psychology are innumerable. This
book is a summary of their collective work.

FRY AND MARY D SALTER AINSWORTH; Penguin (Non-Classics) (July 30, 1953)

This is the original book from 1953 on attachment theory and types.

AND SALLY WALL; Lawrence Erlbaum; 1 edition (January 1, 1979)

This is the updated version with all the subsequent research on attachment theory included for
those interested. By the time of publication however, they had not had the chance to follow the
initial cohort of Dr ainsworth into adulthood to complete the picture of attachment over the life
cycle. This is a relatively expensive book due to limited availability.


Back in the fifties and sixties, you could not be counted as an intellectual if you have not read
Gibran. In fact, you could not get a date with an intellectual if you have not read Gibran. He
ranked up there with Jack kerouac in influencing the progressive movement. Personally, I
think it is the suffering and longing of Gibran that inspired millions. Putting the conclusions his
suffering led him to on display in a brilliant style for everyone to read made him an icon and a
true representative of all immigrants to the new world.

University Press (May 13, 1997)

This is not a book that sensitive people ought to focus on. It is mostly applicable to insensitive
people’s behavioral patterns including learning through verbal narration, vicariously learning
through observation and mentally manipulating their environment to elevate their self-esteem
[self-efficacy]. Bandura is not so much into the cognitive process of learning as modern
science is discovering it although he touches on the topic. However, this book along with
Bandura’s other book ‘Social Learning Theory’ contain valuable information on every
insensitive person we meet.

Goddard Press, Inc. (January 25, 1999)

This book is a good guide on early life development. It gives background information on what
to expect from a growing baby and means to enhance mental and emotional development. The
book is nominally meant for the first 18 months of life. However, in practice for sensitive and
autistic children the stages described may take a significantly longer time than eighteen months.
This is perfectly ok.

Books (a division of harpercollins publishers) 1969

This is a relatively short book, less than 200 pages but it is loaded with the wisdom of the
master himself. This book focuses on mental growth of children for a change. It takes the
process from the womb to adolescence. Are you not amazed at how much emphasis modern
allopathic pediatricians put on physical growth and how little they are trained to focus on
mental growth?

COOK; International Universities Press (1952)

This book along with “The Psychology of Intelligence” another book by the same author are
timeless masterpieces of understanding of how children think.

WEALTH OF NATIONS BY ADAM SMITH; Prometheus Books (1991)

Adam smith theory was mentioned in the text, so here is the reference. I am not really
recommending this book for summer reading or for understanding the sensitive personality
either. However, it is helpful in understanding the self-centered, materialistic capitalist world
we live in. To fully understand capitalism and free markets you have to go back 500 years to
Europe to the days of the reformation.

ET AL. (editors); the MIT Press (2002)

This is your basic boring mainstream textbook. It is like all other textbooks, occupied with
needless details and almost invariably forgetting to paint the big picture. This is a screaming
example of your basic reductive process in science today. It is also based almost exclusively in
text with very few rudimentary visual illustrations. It is included here for the work of Dr
Elizabeth Hampson which is cited in the text especially the chapter on hormonal influences.

Press; 1st edition (August, 2007)

Here is a surprisingly well written book with real life problems tackled. The book does a good
job explaining a wide array of emotions. However, the book does not offer as many practical
solutions nor does it offer distinctions between the needs of sensitive vs. insensitive people. In
my opinion this book ranks third after Paul Ekman’s [emotions revealed] and Dr Carver’s book
[auto-regulation of behavior].

Future Horizons; 1st edition (April, 2003)

This and 3 other books by the same author are an invaluable tool for the autistic child and
adolescent to learn through visual means. These are necessary skills for social and
interpersonal interaction. Many books of this genre are needed to aid children with concrete
mental processing.


This is the book of emotions and facial expressions from the master himself. Paul Ekman spent
most of his life figuring out variations in facial expressions and interpreting the complex human
and behavioral properties which stand behind facial expressions. This is his book for lay
people. He has several more technical books which are only relevant to someone who is
exceptionally interested in the topic.

(SEPTEMBER 30, 2004)

Emotions, emotions and emotions some more; this is a pretty good book with a lot of depth on
the science behind emotions for the highly interested. The book still wisely comes out on
numerous occasions as saying, this is what we understand today but it is far from complete
and not everything we know today will turn out to be true either.


Autism: a constitutional personality character, defining individuals who are happiest and most
stable when least stimulated (or alone). The term ‘autism’ however is rather superficial and
non-descriptive. Autism literally means someone who likes to be alone. It is derived from
‘auto’. The broad sensitive personality and its variant the autistic personality, includes so much
more than the tendency to be alone. The core autistic personality centers on heightened
sensitivity to stress and relative aversion to novelty. The autistic personality also comes with
profound depth & breadth of processing of sensory input which leads many autistics to
frequently feel overwhelmed and consequently lag behind on social development and
interaction. Sensitive or more accurately extremely sensitive personality may be a more
descriptive term than plain ‘autism’.

Asperger’s: includes some of the least sensitive on the autistic part of the spectrum – high
functioning autistic personality. They usually have a wider range of communication skills but
the same essential personality as any other autistic or sensitive person. People deemed as
asperger’s are more publicly visible and often possess unique scientific or artistic or
professional skills. Other autistic people do not lag behind intellectually; however they may not
get the chance to show their gifts as often due to their slower interpersonal skills development.

Temperament: the combination of mental, physical, and emotional traits of a person; natural
predisposition. The term was cultivated in a culture of the behaviorist theory, emphasizing
behavior and learning glorified behaviors without regard to the origins and processes leading to
a specific behavior. Besides, this author does not frequently use the term since it has a rigid
and dogmatic intonation. It implies no personality evolution and no changes with experience,
which is not realistic.

Homeostasis:  (derived from two Greek words for “to remain the same”; balance or
equilibrium is implied) a relatively stable state of dynamic equilibrium or a tendency toward
such a state between the different but interdependent elements or groups of elements of an

Physiologically, homeostasis is a state of metabolic equilibrium actively maintained by several
complex biologic mechanisms which operate via multiple systems to offset disrupting changes.

In other words, it is the ability of an organism to maintain a constant internal environment (i.e.
body temperature, fluid content, etc.) through regulatory mechanisms that compensate for a
changing intrinsic or extrinsic environment.

Brief history of Homeostasis: (
“The development of the concept, which is one of the most fundamental in modern biology,
began in the 19th century when the French physiologist Claude BERNARD noted the
constancy of chemical composition and physical properties of blood and other body fluids. He
claimed that this "fixity of the milieu interieur" was essential to the life of higher organisms.
The term homeostasis was coined by the 20th-century American physiologist Walter B.
Cannon, who refined and extended the concept of self-regulating mechanisms in living

Stressors: (challenge or threat to homeostasis) is any intrinsic (physiologic) and extrinsic
(environmental) force that challenges stability of internal milieu.

Stress: or disharmony of internal environment, is a state of challenged or threatened
homeostasis as a result of stressor application.

Stress Response: or stress adaptation, is the collective measures undertaken by the organism in
an effort to restore homeostasis after stressor application.

Mesocorticolimbic system (MCL): The MCL includes extra-nigrostriatal dopaminergic
pathways traveling through multiple components of brainstem and cerebral cortex [specifically
reticular formation (VTA – ventral tegmental area), amygdala, hippocampus, nucleus
accumbens, medial prefrontal cortex, etc…]

Mesocortical component of MCL system: includes projections to and from pre-frontal cortex;
thought to be involved mainly with anticipatory and cognitive properties of stress; also involved
in stress response termination.

Mesolimbic component of MCL system: includes projections to and from the nucleus
accumbens and is thought to be involved in the central reward & motivation system with
implications in dependency and addiction

Amygdala: the major center for fear processing and conditioning; may activate the stress
system independently from higher brain centers. Repetitively thinking past traumatic or scary
or hurtful experiences many times establishes a facilitated, self-reinforcing path for these
fearful experiences through the amygdala and result in permanent behavioral inhibitions. These
facilitated fearful pathways may lead to avoidance of future situations of seemingly similar
nature and consequently profound negative impact on one’s social life.

Hippocampus: major explicit memory retention and retrieval center; involved also in termination
and containment of stress response (prevents overactivation).

Arcuate nucleus: one of the hypothalamic nuclei involved in analgesia and pain; major site of B-
endorphin secretion from POMC; secretion is positively modulated by CRH

The hypothalamic paraventricular nucleus is responsible for CRH (corticotrophin releasing
hormone) and arginine vasopressin (AVP) [antidiuretic hormone] synthesis and secretion.

The locus ceruleus is responsible for the central sympathetic system. It produces
norepinephrine [noradrenalin] in response to stress thus initiating the sympathetic fight or flight

stress cascade; stimulates ACTH release by pituitary gland; enhances norepinephrine release by
locus ceruleus; CRH has peripheral pro-inflammatory effects through the CRH-Mast cell-
Histamine axis. CRH is a very important pro-anxiety hormone.

Vasopressin: plays an essential role in maintaining water balance; stimulates CRH; synergizes
with CRH to increase ACTH release. Vasopressin is one of the main hormones released during
stress. It has many body wide effects including increased blood pressure and suppression of

Serotonin: mediates sensory input to high brain centers and amplifies the central stress
response. Serotonin enhances CRH and AVP release by hypothalamus; enhances
norepinephrine release by locus ceruleus. In return cortisol increases the number of serotonin
receptors. Serotonin is a major neurotransmitter primarily involved in helping people achieve
dominance in their affairs and gaining a sense of control over the direction of their life. It is a
major hypoglycemic agent. This means increased serotonin lowers blood sugar and enhances
appetite. It is also a major secretory hormone, increasing fluid and lubrication on mucus

Acetylcholine: mediates higher input and amplifies the central stress response; enhances CRH
and AVP release by hypothalamus; enhances norepinephrine release by locus ceruleous in the
central nervous system. Acetylcholine promotes a type of calm alertness in the mind.
Peripherally, acetylcholine in the main mediator of the parasympathetic nervous system
entrusted with imparting a sense of safety and tranquility throughout the body. Its major
function is to counterbalance the sympathetic adrenalin. Acetylcholine has been called the “rest
and digest” neurohormone. It seems to improve the hardness of the erection and helps delay
ejaculation in men.

GABA: contributes mostly to termination and prevention of overshooting by the stress
machinery; inhibits CRH and AVP release by hypothalamus; inhibits norepinephrine release by
locus ceruleous

Neuropeptide Y: the most potent orexigenic factor, participates in feeding habits and timing
determination; stimulates hypothalamic CRH release; inhibits locus ceruleous norepinephrine
release; May prove important for ADH personality kids.  

Substance P: increases in chronic pain/chronic inflammatory conditions for compensation;
inhibits CRH production by hypothalamus; stimulates norepinephrine release by locus
ceruleous; may prove important for autistic kids.

ACTH: is an anterior pituitary neurohormone secreted in response to stress via a
CRH/vasopressin burst; In turn ACTH stimulates the adrenal glands to secrete cortisol, DHEA
and other vital hormones.

Cortisol: inhibits CRH and Vasopressin production by hypothalamus; inhibits norepinephrine
release by locus ceruleous; inhibits pituitary ACTH release; stimulates neuropeptide Y
expression; stimulates adrenalin release by adrenal glands. Physiologic to moderately elevated
cortisol enhances alertness, focus, a resolute attitude and appetite. Extreme cortisol increases
may lead to near complete inhibition of judgment centers. Cortisol is anti-inflammatory. It
mobilizes the immune system short-term and helps dismantle it long-term.

Sensory overload: simultaneous or cumulative exposure to sensory stimuli occurring over a
short period of time and exceeding the body’s ability to process these stimuli in a timely

Innate Sensitiveness (sensitivity): a collective personality complex characterized by heightened
reaction to stress coupled with an innate sense of preference for natural laws and natural living
over man-made constructs.

Eustress: pleasant exposure to stress of magnitude commensurate with average exposure to the
person involved

Psychologic load: the collective experiences retained from childhood through the current day.
Essentially the group of events and associated emotions, which shape our existence;

Stria terminalis is the seat in the brain of CRH mediated anxiety. Light exposure potentiates
CRH-mediated anxiety. It is said that CRH mediated anxiety in the Stria terminalis is responsible
for long term or sustained anxiety but I think this is mostly applicable in adrenal failure and/or
out-of-control stress [perceived or actual].  

Hypogonadism/Hypogonadal: sub-optimally functionally gonads, ovaries or testicles. In men it
may mean lower testosterone levels associated with excessive estrogen, reduced vigor and
masculinity. In women it may mean menstrual irregularities, severe premenstrual problems,
cessation of menses, hair growth on arms and chin …

Mania: excitement of excessive proportions manifested by elevated mental and physical
activity, disorganization of behavior, elevation of mood, irritability, creativity and in extreme
cases self-destructive behavior. This is said to be the state in which jack Kerouac wrote his
book, ‘ON TH ROAD’.

Hypomania: a milder degree of mania characterized by elevated mood and activity, irritability,
creativity, and rarely out of character self-destructive behavior.

Prepartum: the period immediately preceding giving birth to a child; refers to the mother

Peripartum: includes the few weeks preceding and the few weeks following giving birth to a
child; refers to the mother

Postpartum: the few weeks period immediately following giving birth to a child; refers to the

Prenatal: the time a fetus spends in the womb

Postnatal: the few weeks immediately following a child birth; refers to the baby

Introvert: a person who looks inwards for answers and prefers to be alone over being in the
company of others. The introverted personality complex is characterized by higher sensitivity
to stress, broader and more thorough mental processing, rich emotional recall and usually
excessive early life stress.

Extravert: a person who looks outwards for answers and is happiest when in the company of
others. The extraverted personality complex is characterized by lower sensitivity to stress,
relatively shallow mental processing and poor emotional memory.

Dehydroepiandrosterone (DHEA) and androstenedione (ANDR) are two hormones produced
abundantly by the adrenal glands. Traditionally these are called androgens in reference to the
male sex hormones. The origin of the terminology comes from the fact that DHEA and ANDR
can both be converted to testosterone. However both DHEA and ANDR are present in the
female body, albeit in somewhat lesser quantities than in males. In fact DHEA is essentially an
anti-cortisol hormone whose main function is to restrain the pro-catabolic influences of
cortisol. Besides, both DHEA and ANDR can also be converted to estrogen in males and
females alike.

Originally designated as the “male” sex hormone; in fact men and women have testosterone in
their body. Men on average have more testosterone than women. Testosterone is known for its
contribution to the apparent male sexual characteristics. It promotes asymmetry in facial
features. This hormone helps in building muscle and dissolving fat. It works together with
growth hormone and insulin for some aspects of its functions. Men with higher testosterone
are not necessarily more aggressive or violent. They may be more aggressive in pursuit of their
goals however.

A bohemian is someone who lives in harmony with his or her inner self. Usually bohemian
individuals strive to find their individuality in every aspect of their life. They have an original
sense of fashion and a life style that is self-defined and not influenced by prevailing trends in
society. More often bohemian individuals have a self-modeled belief system and their own
interpretation of the world and what is best for humanity. Their belief system may not be
based on any external religious or societal convention but is derived from thorough original
thinking and yearning. Some do not even have a belief system at all.

Cell cycle:
This is the cycle of life on a molecular level. Each cell in our body has a pre-programmed role.
A cell is born through the splitting of a mother cell into two daughter cells [other mechanisms
apply]. Once this cell is born it typically develops and differentiates in a direction that ensures
fulfillment of its purpose. However, cells are not immortal machines. When a cell ages and
becomes incapable of fulfilling its role or alternatively when a cell develops an irreparable error
in function this cell usually withers and disintegrates into its individual ingredients [this is called
apoptosis or programmed cell death]. These ingredients are for the most part recycled and
entered into making new cells. The waste is discarded of promptly. One of the most popular
theories of cancer focuses on failure of programmed cell death to happen leading defective or
erroneously operating cells to be immortalized and continue reproducing the error over and
over until a clinically significant cancer develops. There is some evidence to prove that stress
provides for a dampening effect over the ability of the body to recycle its cells as efficiently. It
is said that prolonged or repetitive stress may suppress some of the clues and motives cells
need to initiate their death when time comes. Some of these clues may come through the
immune system that is silenced to a large degree by stress.

Attachment: the emotional bond, which forms in this context between parent and child.
Attachment is profound human need centered on finding safety and anchorage in the world and
forms the basis for the child’s future social and intimate life.

Screeners: individuals who show a low emotional arousability in the face of novelty or
excitement or change. They are typically able to screen out any background information in the
environment in favor of the target they are interested in. For example, if an insensitive person
moves to a new town, they are able to screen out all the new scenery and landmarks in favor
of settling down at a house and a job. They are able to select their target of attention at the
expense of the background.

Non-screeners:  individuals who show increased emotional arousability in the face of novelty
or excitement or change. They are typically unable to screen out the background in favor of
the target they are interested in. they have to sort out all the background before they can focus
on the target. For example, when a sensitive person enters a room with one hundred people in
it looking for one person; she might find herself overwhelmed by the people and ambiance
around that she misses the person she is looking for.

Social “Phobia” [Distress upon meeting strangers]:
The judgment in the name notwithstanding, social “phobia” is a component of the sensitive
personality characterized by difficulty handling strangers and forming new relationships. The
term social phobia is viewed by mainstream medicine as a separate entity. However, distress
upon meeting strangers is part of being sensitive and having exposed to excessive stress early
in life.

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