Externalizing disorders affect boys
The second outstanding sex
difference in neuropsychiatry is that male-predominant disorders and
female-preponderant diseases belong to distinct behavioral classes. Most male-preponderant syndromes can be
classified as belonging to the axis of
disorders of excessive turbulence (externalizing disorders) and/or of
deficient language. However, most people consider that language handicaps
are not psychiatric disorders, and that
is why we covered them in the section on neurological sex differences. Most female preponderant disorders can be
considered internalizing disorders.
The externalizing disorders which occur
more frequently in boys and men are Tourette's disease, hyperactivity, conduct
disorder, and the various dependencies such as substance abuse, gambling and
sex addiction -which affect men many times more frequently than women. Details
about male risk for externalizing disorders are provide in table 5.
Table 5
Externalizing
disorders
|
Disorder
|
Male to female
prevalence
|
References
|
|
Alcoholism
|
(14.1:1)
|
Yamamoto, 1993
|
|
Antisocial personality
|
(3.4:1)
|
Barry et al,
1997
|
|
Hyperactivity
|
(6.7:1)
|
O’Leary et al,
1985
|
|
Tourette’s disease
|
(9.3:1)
|
Burd et al,
1986
|
|
Compulsive gambling
|
(1.4:1)
|
Buchta, 1995
|
|
Paraphylia
|
(50:1)
|
Zaviacic, 1993
|
|
Drug abuse
|
(2.2:1)
|
Brown, 1988
|
One of the important reasons women are catching up to
men in cigarette addiction, or so they
say when questioned, is that cigarette
smoking keeps weight down, an aspect which women claim to fancy more than men.
A vignette on a case with attention deficit disorder and hyperactivity (ADHD)
S7 is a 9 year old boy, who, like S1, was recently seen in a local
hospital neuropsychology service thus coming to my attention recently. His father is a “compensated” hyperactive
himself: he manages a busy
restaurant -an occupation he enjoys and
is good at despite his childhood hyperactivity and learning disabilities. S7’s teachers knew in his first year that he
was a hyperactive child: he was
distractible and agitated. He is
disobedient, impulsive, remorseless,
jealous, argumentative, and gets
along very poorly with other boys.
Cognitive evaluation revealed normal IQ,
but he was often unable to finish a task -revealing a major problem
maintaining attentional focus. His
language was normal, but his memory
scores reached only borderline-normal levels.
Visuospatial functions were normal,
but he had a dysexecutive
syndrome (poor planning, poor judgment,
little flexibility). He has difficulty
with several school subjects and receives special education services. This child’s parents had the good sense to
get him involved in intensive sports activities which help him blow off some
steam. The neuropsychologist recommended that Ritalin (methylphenidate) be
prescribed in this particular case.
Kleine-Levin syndrome affects nearly exclusively
boys, and is also an externalizing
disorder. It usually appears at
adolescence and is transitory. It comprises
hyperphagia (extreme and compulsive over-eating), aggressiveness or extreme acting out, and hypersomnia (excessive sleep). It is believed to follow from hormonal
changes in the brain (probably the hypothalamus) occurring at puberty, but this remains to be proven. What then is meant by an externalizing
disorder ? Psychiatric disorders are
termed externalizing disorders when most of the behavioral problem has to do
with such things as acting out,
impulsivity,
destructiveness,
aggressiveness.
A vignette on a case of Kleine-Levin syndrome
Christopher Gillberg reported case F, with Kleine-Levin syndrome, in a 1987 issue of the Journal of the American Academy of Child and Adolescent Psychiatry. Until age 15, F was a happy, sociable and
normal boy. After a fever, he became sullen and withdrawn and showed
autistic traits. He had a period of
hypersomnolence (slept too much) and hyperphagia (ate too much). Then he recovered. However,
he had seven more such spells, each
time of decreasing intensity. His EEG
(electroencephalogram), CT scan (brain imaging) and blood tests were
normal. There was no consumption of
drugs. As often happens in this
clinical syndrome, the boy was
misdiagnosed for a very long time. He
was first believed to have an encephalitis (infection of the brain). It took two years and 25 consultations with
pediatricians, child psychiatrists and psychologists before the correct
diagnosis was finally made. Because
the prognosis (predicted outcome) for Kleine-Levin syndrome is very good, early correct diagnosis would have spared the
family a tremendous amount of anguish and expenditure.
N.B. Kleine-Levin syndrome
sometimes comprises symptoms of aggressiveness and hypersexuality, but neither of these occurred in the present
case.
One of the most disturbing aspects frequently seen in
externalizing disorders is aggressiveness.
Pathological aggressiveness is more often seen in the male sex. Table 6 provides details of several
disorders comprizing high levels of aggressiveness which are clearly male prevalent.
Table
6
Male prevalent early onset syndromes comprising neurogenic
aggressiveness
|
Neurogenic
syndrome
|
Reference
|
|
Neophobic aggressive
outbursts
|
|
|
Psychosis
|
Lewis et al, 1985
|
|
Rett syndrome*
|
Oliver et al, 1993
|
|
Autism
|
Smith, 1985
|
|
Sporadic aggressive
explosions due to irritative brain disorders
|
|
|
Hypothalamic hamartoma
|
Berkovic et al, 1988
|
|
Episodic dyscontrol syndrome
|
Elliott, 1984
|
|
Epilepsy
|
Gillingham, 1988
|
|
Syndromes comprising
chronic behavioral turbulence
|
|
|
Tourette’s disease
|
Comings et al, 1985
|
|
Character disorder
|
Miller, 1987
|
|
Hyperactivity disorder
|
Farrington, 1989
|
*Rett’s syndrome is an X-linked
condition which is fatal to the male sex prior to birth.
Internalizing disorders affect
mostly women.
The internalizing disorders more prevalent in female children and women
are depression, phobia or extreme
incapacitating fear of specific things
such as crowds or open spaces (agoraphobia), spiders (arachnophobia), enclosed spaces (claustrophobia), anxiety disorders including panic disorder,
hyperventilation syndrome, tension headache, as well as most of the neuroses
(conversion disorder, hysteria, dissociative neurosis, etc.) and anorexia
nervosa. Details concerning the female risk for internalizing disorders are
presented in table 7.
Table 7
Internalizing
disorders
|
Disorder
|
Female to male
prevalence
|
References
|
|
Anorexia nervosa
|
(10:1)
|
Rastam et al,
1989
|
|
Depression
|
(1.9:1)
|
Kivela et al,
1988
|
|
Phobia
|
(1.9:1)
|
Dick et al,
1994
|
|
Anxiety disorders
|
(2.3:1)
|
Angelopoulos,
1994
|
|
Neuroses (conversion, hysteria, dissociation, etc.)
|
(5.4:1)
|
Peiro et al,
1996
|
|
Elective mutism
|
(1.5:1)
|
Domènech,
1996
|
|
Post traumatic stress disorder
|
(1.5:1)
|
Garrisson et
al, 1995
|
An interesting example of a female-prevalent
internalizing disorder is somatization (also known as Briquet’s syndrome). Somatization is a neurotic disorder
consisting of numerous vague complaints of physical discomfort which cannot be
medically substantiated. One of the
major psychiatric classification systems (DSM-III) used to require that women
have 14 uncorroborated physical complaints, whereas only 12 were required of
men -for the diagnosis to be posed. The
later versions of DSM modified this strange procedure, removing the gender-specific criteria. When the same criteria are applied to men and
women for this type of disorder, at
least three times as many women are diagnosed as men. These disorders are called internalizing
disorders because most of the problem has to do with internal suffering, dominated primarily either by feelings of
sadness or of fear. Even anorexia can
be considered essentially a phobia ... of
fatness. Because there are numerous
signs of hormonal imbalance such as amenorhea (absence of menses), and lanugo
(prolonged presence of baby hair), and
because this disorder typically appears at adolescence and is most often
transitory, this latter disorder has been postulated to result from hormonal
changes in the hypothalamus at puberty.
One author has even proposed that anorexia nervosa is the female analog
of Kleine-Levin syndrome. We saw above that the only language disorder which
affects girls more than boys is elective mutism, an anxiety disorder. We also know that boys are more at risk for
virtually all sorts of epilepsy. There
is one exception however, namely
pseudo-epilepsy -which affects girls
more than boys. This syndrome is more an
anxiety disorder than anything else.
Pseudo-epilepsy, self-induced
convulsions, occur most commonly in
passive and emotionally dependent people who are very anxious. Even though there is no overall sex
prevalence for the obsessive-compulsive disorder, boys and men are more often subject to
aggressive compulsions, and women to
self-oriented compulsions such as cleaning, hand washing, and trichotillomania
(hair twirling and pulling). And
remember that the early-onset, more severe forms, affect boys more often than
girls.
A vignette on a case of depression
D’Mello described Mrs A., a
32 year old depressive woman, in a 1983 issue of the Journal of Clinical Psychiatry.
Mrs A had been suffering from multiple depressive episodes over fifteen
years. She had been successfully
treated with tricyclic antidepressant (serotonin agonist) medication. She suffered from insomnia, anorexia,
anergia (low energy), and
dysphoria (extreme sadness and dejection).
At age 32 she had a depressive episode which was treated with the
tricyclic antidepressant protriptyline.
She soon developed dry mouth, constipation and eventually, severe
epigastric distress (stomach ache) with marked abdominal distention. It was determined that the severe
epigastric distress was caused by aerophagia:
her anorexia, dry mouth,
excessive drinking of water,
constipation, and additional
effects of the tricyclic antidepressant medication had all concurred in
producing swallowing of air and pocketing of this air in the abdomen. Additional treatment was required to solve
this particular problem.
Female-prevalent disorders are stress related, but the biological underpinnings are very
complex.
It is very difficult to distinguish familial and interpersonal stress
caused by a behaviorally disordered child from stress antedating and
precipitating the behavioral disorder in that same child. It is also difficult to tease out the effect
of stress caused by the hereditary vector.
All the neuropsychiatric disorders,
male and female-prevalent, are to varying degrees heritable. That means that one or both parents are
relatively likely to suffer from some disorder within the hereditary
spectrum, thus stressing the
child. I never cease to be intrigued
about how psychologists can claim to ever be dealing with «psychosocial stress»
in a given individual, giving no thought
to the eventuality that something biological might be involved. Nevertheless,
it has been observed that so-called psychosocial stress is a more
significant and prevalent precipitator of female-prevalent chronic
disorders. Depression, phobia, anxiety, somatization disorder,
anorexia nervosa and elective mutism are all more prevalent in people (mainly
of the female sex) undergoing interpersonal stress (dysfunctional families,
bereavement, financial crisis, etc.).
The male-prevalent disorders are also stress-related, but they seem to me to be less so (or are
less linkable to ongoing stress in adulthood).
One of my reasons for believing this is that the female-prevalent
disorders resemble the classical stress syndromes (post-traumatic stress
syndrome for example), whereas the
male-prevalent syndromes do not. For
example, psychopaths have nerves of
steel, no sleep disorder, no
anxiety, no sadness, and do not suffer much emotionally. Furthermore,
psychometric investigations of college students have generally found
higher scores on scales of post traumatic stress disorder in women than in
men. One study investigating
psychological effects of natural calamities found that women had higher scores
on scales of post traumatic stress disorder.
In 1995, Sarah Ullman published results of a randomized community survey
of 2,364 Los Angeles residents, in an investigation entitled “the Epidemiologic
Catchment Area study”, to examine the
relationship of traumatic events to Diagnostic and Statistical Manual of Mental
Disorders-III (DSM-III) criteria symptoms for post traumatic stress disorder
(PTSD). Women manifested the syndrome more often than men. In a study carrried out in 1989 in Japan
(Tokyo) a well-known State-Trait Anxiety Inventory was administered to a representative
community sample of 1,234 men and women whose ages ranged from 25 to 92 years.
Women showed significantly higher anxiety than men. Of course women’s stressors (rape, marital
violence, poverty) are not the same as men’s (military combat, dangerous
occupations, financial responsibilities),
but the results may reveal, I
think, weaker resistance of mental
health to stress in women.
That women develop mental health problems with stress
more than do men does not necessarily mean that women manifest a greater
physiological stress response during stressful events themselves -especially in parts of the body outside of
the brain. And in fact, it appears that if there is any sex
difference in the immediate physiology of stress, it is the male sex which manifests a greater
response. Physiological components of
the stress response include cortisol and adrenalin secretion by the adrenal
gland, as well as various indicators of
autonomic nervous system arousal of the sympathetic branch (increased skin
conductance associated with sweating, increased respiratory and heart rates,
etc). Cortisol is the main hormone
involved in the stress response. It is a
steroid hormone like testosterone and estrogen,
but it is not a sex hormone. There is relatively greater conversion of
cortisol to cortisone (a cortisol metabolite) in normal women than in matched
men providing multiple blood samples (without any additional stress), suggesting a more active physiological stress
response in women -even in the absence
of a highly stressful event. On the
other hand, several studies have found
that men secrete more cortisol when faced with substantial stress than women
do, a finding which argues for greater
stressability of men, not women, as could be superficially expected from our
review of sex-typical prevalences of psychopathology above. Adrenalin is the second most important
hormone involved in the stress response.
There have been many investigations of adrenalin secretion during or
soon after stress in male and female animals.
Males have generally been found to secrete more adrenalin than females
when stressed. In most of the relevant
investigations, the heart rate response to stress does not seem to differ
between males and females. A few studies
found a slightly greater heart rate response in women. In animals (mice, rats, monkeys) and in
humans, stress reduces testosterone
level, especially in males. None of the above argues for greater
physiological (short term) stressability of females -at least as can be judged from indicators
found in the periphery of the brain (except perhaps for the heart rate
indicator).
However, there
is evidence of brain differences between the sexes in the response of
neurotransmitters to stress, and even
that these sex differences are mediated by sex hormones. A very interesting investigation was carried
out on this subject in 1993 by a team of Japanese researchers. Sex-dependent
changes in dopamine (DA) and serotonin (5HT) metabolisms under restraint stress
were investigated in correlation with sex hormones. Male and female rats were
divided into normal groups (in which female rats were further divided into
proestrus, estrus, metestrus and diestrus subgroups), and castrated,
estradiol-given, progesterone-given, and testosterone-given groups. Each group
was subjected to the same restraint stress (the animal is immobilized, a
subjection which is well known to be highly stressful), and DA,
3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5HT and 5-hydroxyindoleacetic
acid (5HIAA) in the cerebral cortex, thalamus and brainstem were measured by
the HPLC-ECD method. DOPAC and HVA are
dopamine metabolites, and 5HIAA is a
serotonin metabolite. In the normal
female group, DA and 5HT and their metabolites showed remarkable increase under
the stress during proestrus and estrus phases. These phenomena were not
observed in the castrated female group, suggesting that estradiol and
progesterone are related to stress reactions of DA and 5HT metabolisms. In male
rats, however, no distinct difference in the stress reactions of monoamine
metabolisms was noted between the normal and castrated groups. In comparison of
the hormone-given groups with the castrated groups, the increase in DA and
DOPAC in the brainstem for both sex and the increase in 5HIAA in the brainstem
for females, were notable. In the
progesterone-given group, DOPAC, HVA and 5HIAA were increased in female
cerebral cortex, but not in male cortex. DA metabolism showed no great
difference between the testosterone-given and the castrated groups for both
sexes, but 5HIAA was increased in female cerebral cortex and brainstem. These
findings suggest that stress reactions of DA and 5HT metabolisms in the brain
differ according to sex, and that estradiol and progesterone accelerate the
stress reactions of DA and 5HT metabolisms.
Another investigation on similar mechanisms in rats led the authors to
the following conclusion and speculation:
« ...corticosterone facilitates adaptation to single restraint but impairs
adaptation to repeated restraint [in
rats]. As failure to adapt to repeated stress is an animal model of depression,
results as a whole suggest that increased corticoid levels and decreased 5HT
functional activity may have a role in the development of the illness and its
greater incidence in women ».
Ingenious experimentation has even begun to map the brain’s
physiological response during stress as a function of an animal’s gender. In one such study carried out on rats,
restraint and formalin injections into a forelimb were used as stressors and
2-[14C]-deoxyglucose (2DG) autoradiography was used to evaluate regional brain
glucose metabolism, an index of neural activity. Analysis of blood samples collected during
the 2DG procedure confirmed that stress elevates plasma glucose levels
signficantly more in females than in males. Moreover, females showed higher
brain glucose utilization in all regions examined, including sex
hormone-responsive regions such as the medial amygdala, medial preoptic nucleus,
the ventromedial nucleus of the hypothalamus, and arcuate nucleus, as well as
the CA1 layer and dentate region of the hippocampus, the posterior parietal
(sensorimotor) cortex, medial and lateral habenula, and splenium of the corpus
callosum. The sex differences were apparent regardless of whether animals were
injected with saline (a less painful injection) or formalin. Interestingly, the
medial preoptic area, which shows robust neuroanatomical sex differences,
demonstrated greater activation in response to formalin than to saline only in
females. In some brain regions of both males and females, glucose utilization
was higher on the side of the brain contralateral to the saline or formalin
injection site. These findings suggest that there are widespread,
gender-related differences in neuronal as well as endocrine activation in
response to highly stressful conditions.
In monkeys, severe early
postnatal psychosocial stress caused by rearing in isolation chronically
disturbs male behavior more profoundly and more frequently than female
behavior.
The brain’s response to the physiological components
of the stress response (e.g., cortisol secretion) may also in itself be sexually
dimorphic. Indeed, it seems that estrogen has a protective function against cortisol in
the brain, particularly in the oxidative
destruction of neurons wrought by stress-induced brain cortisol. One study found that oxidative stress-induced
cell death caused by the neurotoxins amyloid beta protein, hydrogen peroxide
and glutamate in the clonal mouse hippocampal cell line HT22 is inhibited by
the antioxidant effect of 17-beta estradiol. Other steroid hormones, such as
progesterone, aldosterone, corticosterone and the steroid precursor
cholesterol, did not protect the cells. The neuronal protection afforded by
17-beta estradiol was estrogen receptor-independent. These data demonstrate a
potent neuroprotective activity of the antioxidant 17-beta estradiol, which may
have implications for the prevention and treatment of Alzheimer's disease.
The interaction between age of onset and the effect
of stress.
Though adult males seem to present a more vigorous peripheral bodily
reaction to stress, suggesting that they
are more stressable, adult females seem
to present a characteristic delayed response to stress occurring in the brain
from puberty through adulthood. It has
now been documented that prolonged central nervous system effects of stress
include degeneration of hippocampal and other neurons, via the effects of cortisol. The human female brain could be sensitive to
the deleterious effects of cortisol in a manner different from what occurs in the male brain: the female brain’s response being perhaps
somehow delayed and perhaps destabilizing more selectively the serotonin brain
network. In human males, perhaps the effects of cortisol on the brain
are more immediate and destabilize more selectively the brain dopamine
network... Therein lies a speculative
explanation of why women would develop more stress-related psychopathologies. Psychopathology severe enough to be
recognized as an official mental disorder does not develop in the short
term, but usually over several years. It would be absurd to think that a
psychopathological syndrome could result directly form morbid peripheral
physiology without some central nervous system abnormality intervening. However,
the above account may be a little too simplistic to fully account for
the relevant facts. Effects of stress
on the brain seem to depend on the age of the animal. Offspring of rats stressed during pregnancy
manifest brain changes in several of the sex dimorphic nuclei and in the
cortex. In particular, the preoptic nucleus of the hypothalamus is
substantially reduced in size once the prenatally stressed offspring reaches
adulthood. Furthermore, the asymmetry in cortical thickness (favoring the right
side) normally observed in male rats, is
not observed when that rat’s mother has been stressed during pregnancy. Finally, the spinal bulbocavernal nucleus also does
not develop to full size in prenatally stressed rats. These effects are observed only in
males. When one thinks of it, this is not so surprising: masculinization of the male fetus brain is
androgen dependent, and a stressed
mother is androgen deficient, so the fetus’s brain could be left unmasculinized
in that manner. However, there are
numerous other indirect findings suggesting that prenatally stressed male rats
have weakened development of brain areas that are not sexually dimorphic. So it
could also be that stress contributes to the masculine propensity to show early
onset psychopathological disorders, and
the feminine propensity to show stress-related psychopathological disorders in
adulthood. A gigantic epidemiological
study carried out by the American National Institute of Mental Health in 1967
supports this point of view. One broad
category of psychopathology surveyed in hospitals and clinics throughout the country was
labeled «neurotic disorders ...that are highly reactive to situational
stress». Between the ages of 5 and nine
years the female to male prevalence ratio was .51. Between 10 and 14 years of age, it was 1.06,
and between 15 and 19 years of age it was 1.77.
A vignette of a case of elective mutism
Atoynatan described in a 1986 publication the case of a girl named
Ruth. At age three, shortly after her family moved and her
mother’s miscarriage, Ruth gradually
stopped talking to boys and men -whom
she claimed to be afraid of. The only
man she would occasionally talk to was her father. She had been friendly to men prior to
this. Ruth had been and remained
disobedient, capricious, defiant and idiosyncratic. Ruth’s mother had been treated roughly as a
child, making her shy and very reserved
it was thought. She had several
psychopathological traits (anxiety attacks, phobias, illusions,
nightmares, unjustified symptoms
of stress). It is at the time these
symptoms took the form of depression that Ruth developed her selective
mutism. Then the mother’s psychological
and emotional state improved during a prolonged regimen of psychotherapy. In parallel to these improvements, Ruth also gradually started talking normally
to boys and men.
Is the right hemisphere more fragile in females and
the left hemisphere more fragile in males ? A few neuropsychiatrists have put forward
the speculation to the effect that the main cause of gender differences in
neuropsychiatry are due to a sex difference in asymmetric fragility of the
hemispheres, but I believe most
specialists remain unconvinced.
Metabolic imaging of the brain,
neuropsychological testing and electroencephalographic investigations
have shown that depression and anorexia nervosa are associated slightly more
with right than left hemisphere abnormality.
On the other hand, investigation
of depression secondary to a localized brain lesion has concluded that the left
frontal lobe is the most critical brain area. There is not much convincing
evidence available, as far as I was able to determine, suggesting any asymmetry
of hemispheric disturbance in other female-prevalent disorders such as phobia
or anxiety. One interesting study investigated the asymmetry of galvanic skin
response (GSR), a measure influenced by
sweat, which is in turn controlled by a
primitive part of the nervous system called the autonomic nervous system. It is known that the autonomic nervous system
is not controlled in the same way by the two cerebral hemispheres. At any rate,
the study found a relative left-hemispheric GSR dominance in panic
patients and a relative right-hemispheric GSR dominance in generalized anxiety
patients. This hint of a greater
involvement of the right hemisphere in pathological anxiety has recently been
bolstered by a study of 309 patients who had a stroke (a cerebrovascular
accident in one hemisphere) and subsequently developed a pure clinical anxiety
disorder. A large proportion of the
cases had a right hemisphere stroke. One
study investigated a sample of 42 females and 10 males (mean age 34.3 years)
with conversion symptoms (neurologically implausible body symptoms such as
forearm paralysis believed to be of psychological origin). The conversion symptoms occurred on the
subjects' left side in 63%. The probability of this distribution occurring by chance
is .07 (2-tailed test). For the females, the distribution was even more skewed;
the symptoms occurred on the left in 30 cases, or 71%. The majority of similar investigations have
reported trends in the same direction.
There is no disagreement about the fact that
developmental language disorders are much more associated with (and also caused
by) left hemisphere than right hemisphere disturbance. However,
boys are more at risk for just about every developmental disorder, not just the language disorders. There is little if any evidence to the effect
that character disorder, or even its most extreme form, psychopathy, is a left hemisphere disorder. There is electroencephalographic,
neuropsychological, and even brain imaging evidence to the effect that
hyperactivity is more a right than a left hemisphere disorder, and yet boys are more often affected.
Student’s tribune: Mania and
agitation versus depression and lethargy
result from right and left lesions respectively
My student, Caroline Larocque
has recently completed a research project on psychomotor agitation or mania and
psychomotor lethargy or depression caused by unilateral brain lesions. She
found that the lesion is much more often located in the right hemisphere for
agitation and mania in adults, but not
for acquired childhood hyperactivity.
She also found that psychomotor lethargy and/or depression are more
often caused by left hemisphere lesions,
even in children. However, these effects were strongly significant in
girls and women, but barely so in boys
and men, suggesting again that
neuropsychiatry does not support a simple notion of hemispheric fragility being
segregated by gender.
One common effect of a unilateral lesion is
contralateral hemineglect. A right
hemisphere lesion will typically cause a patient to neglect visual, auditory or
somesthetic (tactile) stimuli located on his or her left body side. Congenital
dyslexia and hyperactivity are both highly male-prevalent brain disorders.
Recent findings of left hemineglect in congenital hyperactivity argue against a general postulate of left
hemisphere fragility in boys, on the
contrary.
Student’s tribune:
Developmental hyperactivity and dyslexia result from right and left
hemisphere dysfunctions respectively
My student Marie-Anne Archambeault recently completed her thesis on
performance deficits on each side of the body in unilaterally brain damaged
children, in developmentally dyslexic children and in developmentally
hyperactive children. She found that
children, as adults, show neglect and motor weakness on the body
half opposed to the brain lesion. There
is a simple explanation for that: in
the normal brain the right or left body half is controlled by the brain
hemisphere opposite to it, both
sensorially and motorically. What was
more interesting was that dyslexics and hyperactives showed the same
lateralized weakness and hemineglect as the brain damaged children. The dyslexics neglected significantly on
the right body side suggesting a left hemisphere dysfunction and the
hyperactives neglected significantly on the left body side suggesting a right
hemisphere dysfunction.
Finally, there
is a very slight trend in the evidence suggesting that Tourette's disease, a
male prevalent disorder, may involve
more pathology of the right hemisphere.
It is important to take note of the fact that many findings of
psychiatric effects resulting from unilateral brain lesions have not, at least at present, given any indication of
a sex difference. For example, orgasm seems to be harder to achieve in both
sexes after right hemisphere lesions than after left hemisphere lesions. In short,
it seems incorrect to make a
general statement about a uniform sex difference in asymmetry of fragility of
the hemispheres of the brain.
Rather, it seems that sex
differences in neuropsychiatric disorders relate to a variety of hemispheric
disorder asymmetries -sometimes located in different areas within the
hemispheres, as well as to disorders
without asymmetric hemispheric disturbance.
Do human females have a fragile serotonin network
and human males a fragile dopamine/noradrenalin network ? Only a few
neuropsychiatrists have dared go out on a limb and propose that the fundamental
reason for sex differences in psychiatric disease prevalence is a fragility of
specific brain neurotransmitters.
Pierre Flor-Henry, for example,
has stated that women have a fragile serotonergic brain network and men
have a fragile dopamine/noradrenalin network.
The model certainly explains female prevalence in insomnia, migraine,
depression, panic disorder, anorexia nervosa, bulimia, lower pain thresholds
(including recognized syndromes such as maxillary joint pain syndrome), and higher prevalence of obesity. All these disorders are treated with
serotonin reuptake inhibitors -though I
would not want to argue that this treatment is always extremely effective.
Serotonin reuptake inhibitors even seem to be just as effective in treating
most anxiety disorders and phobias as are the so called anxiolytics
(anti-anxiety drugs) which belong to the class of drugs called benzodiazepines
(GABA agonists). Post-mortem
investigation of clinically depressed patients has identified specific
forebrain anomalies in the serotonin neuron network. In unmedicated depressed
patients studied post mortem, several studies found a significant cortical
increase in serotonin (5HT-sub-2) receptor binding over control values. Antidepressant-treated patients dying while
depressed had 5HT-sub-2 receptor densities not significantly different from
control values. Patients who died euthymic (i.e., recovered) showed a marked
reduction in 5HT-sub-2 receptor binding when compared with controls. However, in another study a drop in 5HT-sub-2
receptor binding was observed in the limbic structure called the
hippocampus. A recent positron emission
tomography (metabolic brain imaging) study looked specifically at the serotonin
network in living depressives by injecting into the blood stream with the
standard radioisotope a serotonin ligand (a molecule that has an affinity for
serotonin receptors). A forebrain
deficiency in the serotonin network was found.
There exist inhibitory self-recurrent serotonin loops making the whole
issue very complex, but
altogether, the research shows without a
doubt that serotonin neuron networks are critical in depression. One piece of evidence presents a more
direct argument for human female fragility of serotonin brain dynamics. The
increase in plasma prolactin (a primarily female hormone) which follows
intravenous administration of L-tryptophan (LTP) (a metabolic precursor of
serotonin, i.e., a molecule used by
neurons to synthesize, create,
serotonin) was used to assess changes in brain 5-hydroxytryptamine (i.e., the neurotransmitter serotonin, also known as 5HT) function in normal male
and female subjects, following a three week period of dieting. In women, but
not men, there was a marked increase in the prolactin response to LTP,
suggesting that dieting had caused alterations in brain 5HT-mediated responses.
In contrast, dieting did not alter the prolactin response to thyrotropin
releasing hormone in either men or women, indicating that the changes in
response to LTP could not be attributed to an increase in pituitary reserve of
prolactin. These same authors (Goodwin
and colleagues) also published another report on sex differences in effects of
dieting on dynamic relations between other hormones and brain serotonin. The
authors concluded that dieting alters brain 5HT function in women but not in
men, and that biological factors as well
as greater psychosocial pressures to diet may contribute to the high prevalence
of eating disorders and depression amongst women. This study has been recently replicated and
the same findings were reported.
Flor-Henry's model certainly also fits with the known
male prevalence of hyperactivity -which
is treated with amphetamine agonists (ex: Ritalin) -themselves molecularly related to
noradrenalin, and Tourette's
disease, stuttering, and juvenile
schizophrenia, all of which are best
treated with dopamine (D2-receptor) antagonists. One of the fundamental roles of the dopamine
neurotransmitter is the modulation of pleasure. For example,
patients with Parkinson’s disease are known to be anhedonic (pleasureless). The pleasure they used to derive from food, sex, cultural activities dwindles very
significantly. These patients have
pathologically low levels of brain dopamine in one of the main dopamine neuron
networks, called the nigrostrial
network. We have seen (in chapter 2) that the male
mammal usually has slightly higher brain dopamine concentrations than the
female mammal (though this has not been consistently found), this certainly being the case for
humans. A few years ago, evidence was reported of presence of an
abnormal gene on chromosome 11 controlling aspects of one dopamine receptor
molecule (D2) in alcoholics, Tourette
patients and psychopaths. Since these are all male-prevalent
disorders, the hypothesis of a sort of
fragility of the dopaminergic network in boys and men began to take credence in
the scientific literature. Replications
of this specific finding were, however, not very conclusive. Very recently, several research teams, in Israel and in the
United States, found that an abnormal
variant of another dopamine-controlling gene is over-represented in heroin
addicts, gamblers, and even in people with spinal cord injuries. Of course,
these disorders are all male-prevalent.
Specifically, it was the D4DR
gene, involved in the metabolism of the
D4 dopamine receptor, which was found in mutant form. Several of these researchers are suggesting
that this gene, via abnormal dopamine
metabolism, favors risk taking
behavior.
It is noteworthy that Ritalin and amphetamine are
known to alleviate psychopathic excess (a highly male-prevalent psychiatric
disorder). However, since there is little internal distress or
suffering in psychopaths, psychiatrists
are reticent to prescribe such a drug regimen.
Furthermore, there is little
reason why non-incarcerated psychopaths would comply with such a regimen. The idea of
fragility of the central nervous system noradrenergic axis in men is still controversial. One investigation looked at beta-adrenergic
receptor binding in frontal cortices obtained at autopsy from 21 suicide
victims (mean age 36.4 years) who died predominantly by violent,
nonpharmacologic means and from 21 control subjects who were matched for age,
gender, postmortem delay, and degree of violence associated with death. There was a significant 28% increase in the
number of serotonin-sub-2 binding sites and a 73% increase in beta-adrenergic
antagonist binding in the frontal cortices of suicide victims compared with controls. Of course there were many more men than
women in this sample because violent non-pharmacological suicide is more
typical of men. Animal models relevant
to a « neurotransmitter fragility » concept of sex differences in
psychiatry are, in principle, of paramount importance. In one investigation male and female rats
were treated with different high doses of adrenaline for five days. Their food
and water intakes and body weights were recorded. A considerable sex-difference
was found on the 5th day in body weights and plasma glucose concentrations.
Males had higher plasma glucose and lost more weight than females. Females ate
and drank more than males throughout the experiment. The adrenaline-sensitivity
of females decreased by the third day but it did not change in males. These data
suggest that females are able to activate mechanisms that compensate the
effects of high adrenaline levels while males are not, or their compensatory
mechanisms are less efficient.
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