The ADHD-Autism-Oxygen Connection:
The Larger-Head-Smaller-Brain Scenario
Molecular biology is the voice of
reason in the care of children with atypical neurodevelopmental states
(ANS); psychiatry, its belief system.
Reason is the faculty of observing natural phenomena and integrating
new observations into the existing body of information – the
natural order of things – to advance knowledge and understanding.
Belief, by contrast, is one person's opinion imprinted permanently
on another person's awareness – a file downloaded on to
someone's "hard drive of understanding" while the delete
key is deleted. The subject is stuck with that opinion and remains
impervious to observations that challenge the belief.
The central tragedy in the spreading pandemic of ADHD, autism, and
related learning and behavioral difficulties, in my view, is that reason
is subordinated to belief. Psychologists claim they can understand
the mind without understanding the body. They believe their job is
to find the right diagnostic label. Psychiatrists believe their responsibility
ends with prescriptions of what they consider to be the appropriate
mind-altering drugs. Both groups are uninterested in the observable
phenomena concerning the causative influences of toxic environment,
toxic foods, and toxic thoughts. Those who pollute or otherwise destroy
human habitat consider the state of denial among psychologists and
psychiatrists convenient and supportive of their profitability goals.
It shifts the focus to the "ADHD-autism mysteries" and away
from the real observable and demonstrable phenomena concerning the
impact of toxicities of the environments, foods, and chronic anger
on the energetic, developmental, and differentiative processes in children.
Initial Brain Hypertrophy and Delayed Brain Atrophy
Some years ago, I considered the vast array of seemingly disparate
facts of ANS and wondered if there were some common causative mechanisms
underlying the broad clinical spectrum.1 Could I connect the dots
of the ANS spectrum, looking through the prism of oxygen signaling – a
preoccupation that has served me well in my earlier quarrels with
paradoxes of biology – and develop a unifying model? I then
imagined a larger-head-smaller-brain scenario. I imagined the essential
nature of ANS to be a sequence of initial brain hypertrophy and delayed
brain atrophy. Initial hypertrophy is caused by overstimulation,
whereas the delayed atrophy represents a state of cellular toxicity
and burn-out. In this scenario, hypertrophy is induced by hyperexcitability
caused by incremental stimulation of the developing brain in the
womb – by antenatal exposure to maternal environmental, nutritional,
and stress-related factors. Many of those stressors continue after
birth. Some regions of the brain would be expected to respond to
such overstimulation by accelerated development and increased tissue
mass. Considering the limited ability of the brain tissue to overdevelop
and cope with incremental demands, one would expect the initial period
of hypertrophy to be followed by delayed brain atrophy – therefore
the larger-head-smaller-brain scenario.
The ANS spectrum covers an enormous range of symptom-complexes, including the
following: attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive
disorder (OCD), autism, Asperger's syndrome, Tourette's syndrome, tics, learning
disorders, hyperkinetic child syndrome, expressive language disorder, phonological
disorder, pan-developmental disorder, oppositional defiant disorder, and the
older term of minimal brain disease.2-8 The oxygen view of ANS presented here
has three strengths: (1) It sidesteps the clutter of diagnostic labels that
hide much and reveal nothing about the nature of clinical problems; (2) It
acknowledges the increasing number of constellations of genetic mutations associated
with ANS symptom-complexes and recognizes that there are no effective therapies
for any of them at this time; and (3) It focuses on the molecular mechanisms
that cause a child's suffering and offers a road map for effectively addressing
all relevant issues for superior clinical results.
An Illustrative Case Study
October 26, 2006: A four-year-old
child presented with the diagnosis of autism, hyperactivity, leg
cramps, rashes, and fits of anger and
biting. His vocabulary was limited to three words: mama, papa, Allah.
His father provided additional information with the following words: "He
is a smart man. He knows how to avoid injury. He will check the hot
and cold water taps well so he doesn't get hurt. With visitors, he
will first not look at them, then he becomes friendly. But he does
bite. Interacts with younger sister more than with us. He will bite
whether angry or happy. He will pull at the weak fifth finger rather
than the strong thumb and index fingers. After getting angry and biting,
he becomes quiet and tries to make friends with us. Sometimes he likes
dark and turns the lights off and then will turn them on again. Sleep
very well. Tylenol helps leg cramps. He used to sing then he stopped
after the age of three years. He used to catch melodies. Now he does
Lab evaluation: Mild anemia. High levels of IgE antibodies with specificity
for Mucor, Penicillium, Fusarium, Candida, and Alternaria species.
Increased urinary excretion of arabinoise, oxalate, subseric acid.
Treatment plan: Elimination of sugar, dairy, and wheat. Robust antifungal
plan with Nystatin and phytofactors. Sulfur antioxidants, multivitamin
and multimineral protocols, and twice-weekly subcutaneous hydroxocobalamin
(1,000 mcg) injections.
December 6, .2006: Mother's words: "[Ninety
percent] 90% less biting, crying reduced from daily to weekly, leg
cramps have cleared
up. Eye contact has improved at school. They want a five-second contact,
he now has four-second contact. His memory is coming back, he is repeating
some old words. Makes a lot of sounds now. Constipation cleared up
with castor liver packs."
January 24, 2007: "Becoming calmer, better non-verbal communication
with parents. No biting. Not breaking his fingers at all times. Overall,
10% calmer since the last visit. We think it is due to the castor liver
packs. Plays with business cards. Overall, right leg cramping is less.
Still needs paper in the mouth all the time. Said arecto, which means ‘a
little more' and attakee, which means ‘what is this?'.
No areas of lost brain function. His brain is developing for naughty
things. Ear infections caused more tensing. When school is out, he
becomes more tense. Eye contact almost normal. Not putting things in
his mouth. Teachers report continued progress. Brain progress little,
One percent in 1971, 5.96% in 1987, 11.66 % in 2006
The planet Earth is febrile now. The
spreading pandemics of ADHD and autism are two of the disturbing
faces of that febrile condition. In
1988, the Journal of the American Medical
Association published data
concerning the use of drugs for treating hyperactivity/inattentiveness
among students.9 Consider the following quote from that
results reveal a consistent doubling of the
rate of medication treatment
for hyperactive/inattentive students every four to seven years such
that in 1987, 5.96% of all public elementary school students were receiving
such treatment" (Italics added). Ten years later, the Fall 2006
Preliminary Ethnic Survey Report Pub. No. 346 of the Los Angeles Unified
School District revealed that 11.66% of children in the district were
in special education programs (Table 1).10 According to
the Centers for Disease Control (CDC), the prevalence of autism varies
from region to region in the United States. New Jersey has the distinction
of have the highest prevalence rate, more than ten percent.11 Note
that the ten percent rate refers only to one face of ANS (autism).11
A recent report on trends of diagnosed psychiatric disorders between
1989 and 2000, Psychiatric Service,
published by the American Psychiatric Association, included the following
data concerning hospital discharge
increases between 1989 and 2000: (1) affective disorder, 138%; (2)
autism and ADHD, quadrupled over the course of the study; and (3) most
common mental disorders, 39%.12
Table 1: 2006 Profile of Special Education
in the Los Angeles Unified School District
|Total K-12 Preliminary Enrollment
|Total Number of Special Education
|Percentage of children in special education program
In the late 1980s, I recognized the following four problems with the
prevailing classification of ANS of children:
- A wide overlap between the symptom-complexes of children with
ANS (ADHD, autism, Tourette's syndrome, and others) severely limits
the clinical value of these prevailing classifications.
- None of
the diagnostic labels yield any insight into the energetic-molecular
nature of a child's suffering.
- The intensity of suffering caused by ANS
varies markedly under different environmental, nutritional, and
stress conditions, indicating the causative
influences of those factors.
- Diagnostic labels are deceptively used
as valid scientific justification for giving psychotropic drugs
with serious adverse effects.
Twenty years later, I continue to be profoundly dismayed when I witness
the havoc wreaked upon tormented children with psychotropic drugs.
I am troubled when I observe the struggle of hapless parents in their
fight against school psychologists, child neurologists, and pediatricians – all
experts in choosing diagnostic labels, but none knowledgeable about
crucial issues of toxic environments, toxic foods, and toxic thoughts.
Often, I think the US Congress ought to pass a law for children banning
the use of psychotropic drugs by doctors who do not have documented
proficiency in molecular biology of nutrition and environment.
The Dysox Model
In 1999, I proposed the dysox model of ANS in order to dispense with
frivolous diagnostic labels, which reveal nothing and hide everything.1
I wanted to sharply focus on the real issues of toxicities of environment,
foods, and thoughts. I coined the pneumonic Shaloat – taking
the first letters of the words spectrum, hyperactivity, ADD, learning,
OCD, autism, and Tourette's – to refer to the broad spectrum
of ANS, including Asperger's syndrome, hyperkinetic child syndrome,
expressive language disorder, phonological disorder, pan-developmental
disorder, oppositional defiant disorder, and the older term of minimal
brain disease. Unburdened by useless diagnostic labels, the term
Shaloat allowed me to concentrate on the pertinent biologic issues
to improve clinical results. Specifically, I observed biochemical
evidence of acidosis, oxidosis, clotting-unclotting dysequilibrium,
and abnormal Krebs cycle biochemistry in most children in the ANS
spectrum. The dysox model allowed me to focus on these molecular
derangements, regardless of the diagnostic rubric used for the children.
The Expanding-Shrinking Brain Scenario
Autistic children often have large heads. In general, the head circumference
of children with ANS is larger than control subject. In 1996, in
a study conducted at the Child and Family Guidance Clinic, Swindon,
UK, anthropometric measures of consecutive clinic attenders with
pervasive developmental disorder (PDD) and related psychiatric or
language disorders were analyzed.13 The investigators combined their
data with those obtained from two schools for language-disordered
children. Based on the existing percentile charts, about one?third
of children with PDD had macrocephaly, a rate significantly higher
than in children with language disorder alone.
Advances in brain imaging technology make it possible to precisely
map out brain anatomy and functionalities. A large body of data concerning
the structural and functional findings in children in the ANS spectrum
has been published in recent years.14-16 In such data, especially in
information gained with the functional MRIs, I recognize a pattern
of an "expanding-shrinking-brain" state. Specifically, two
clear patterns of abnormalities in the morphologic and functional aspects
of the brain of children with ANS are (1) more rapid development of
some regions of the brain in the early years;14 and (2) reduced total
brain volume, decreased volume throughout the cerebral cortex, and
thinning of the outer grey matter regions in the later years.15 What
might be the molecular basis of such phenomena? I propose the following
hypothesis. The essential nature of ANS is a state of hyperexcitability
and overdevelopment induced by incremental stimulation of the developing
prenatal brain by maternal environmental, nutritional, and stress-related
factors. In most instances, the antenatal stressors continue in the
postnatal life of the infant, albeit to lesser degrees. Some regions
of the brain respond to such overstimulation by accelerated development
and increased mass in the early years. However, the ability of the
brain tissue to enlarge to cope with incremental demands is limited.
An initial period of hypertrophy is followed by delayed atrophy. Unrelenting
stressors eventually cause decompensation, and ongoing neuronal injury
results in loss of brain substance.
In autism, overstimulation results in clinically observed social discomfort,
difficulty with eye contact, and avoidance. The overstimulated and
sensitized brain learns to reduce exposure to common stimuli, which
are well tolerated by other children. This, of course, is the hallmark
clinical pattern of the disorder. In ADHD, by contrast, overstimulation
leads to hyperactivity, impulsiveness, and distractibility in early
stages. Again, continued overstimulation eventually causes a state
of burn-out and cerebral atrophy. Psychotropic drugs, side-stepping
the issues of their real need, further fan the fires of neuronal excitability,
injure the brain cells, and cause yet more brain atrophy.
Important issues in the context of intrauterine overstimulation of
the developing fetus are maternal toxins, especially those in the following
categories: (1) mycotoxin overload (secondary to overgrowth of yeast
species in the bowel and exposure in home and work environment); (2)
preservatives and pesticides in foods; (3) environmental pollutants;
(4) excess cortisol due to poor sleep; (5) hyperadrenergic state caused
by chronic stress; and (6) sugar, caffeine, and antibiotic abuse. Some
important sources of overstimulation after birth include (1) continued
exposure to maternal toxins through lactation; (2) mycotoxins related
to thrush; (3) cow milk and lactate intolerances; (4) repeated immunologic
overstimulation resulting from multiple vaccinations; and (5) environmental
toxins in the home environment. Below, I include an illustrative case
The parents of a two-year-old girl
consulted me when they noticed that their child was "regressing." She was born full-term
and weighed 7.2 pounds. There was no history of intestinal colic or
eczema. She developed normally, was an active playful child, learned
new words quickly, and responded well to names and instruction. She
could count up to ten About three months prior to the time of consultation,
she received an MMR vaccine. Within several days, the parents noticed
that she "started spacing out and losing focus....she began to
walk with right foot folded somewhat, like a ballerina." She stopped
responding to her name and instruction, and "kept holding her
ears." She had been considered to be a very visual child. After
vaccination, the parents thought she had "lost some visual intensity." Her
stools became dark and "very smelly." At times she became
very restless and hyperactive.
Biochemically, the clinical features of ANS vary in their intensity
with changing conditions of acidosis, oxidosis, clotting-unclotting
dysequilibrium, and deranged Krebs cycle biochemistry. In support of
this hypothesis, direct and indirect lines of evidence can be marshaled
in the following categories: (1) worsening nutritional deficits arising
from consumption of foods grown with chemicals and genetically modified
crops; (2) incremental global chemicalization with deepening environmental
toxicities; (3) increasing frequency of oxyradical-induced mutations
involving oxygen-driven cellular developmental, differentiative, and
detox pathways; (4) existence of acidosis, oxidosis, and clotting-unclotting
dysequilibrium in children in the ANS spectrum; and (5) commonality
of symptom-complexes between Shaloat children and adults with disorders
characterized by acidosis, oxidosis, and clotting-unclotting dysequilibrium,
such as chronic fatigue syndrome, fibromyalgia, and persistent fatigue
after chemotherapy and immunosuppressive therapies.
Redox Dysregulation and Dysox in Autism
biochemical evidence for redox dysregulation in autism is drawn from
significantly reduced activities of various redox-restorative
factors in autistic children compared with control children. Specifically,
decreased amounts or activities of the following strongly support
the oxidative hypothesis of autism: homocysteine (7.0% less), cysteine
(22% less), total GSH (31%), free GSH (30% less), inactive glutathione
(34% less), glutathione ratio expressed as unitless (tGSH/GSSG,
40% less), and free GSH/GSSG (30% less).16 Direct evidence for impairment
of the Krebs cycle biochemistry caused by mycotoxins and other
can be established in many cases of autism by documenting increased
urinary excretion of Krebs cycle metabolites. I cite one case here
to illustrate the point. The patient, a four-year-old autistic
child, presented with symptoms and signs of allergy. Urinary excretions
of several organic acids (expressed in mmol/mol creatinine) were
increased. High serum concentrations of IgE antibodies with specificity
for Mucor, Fusarium, Aspergillus, Penicillium, Candida, Alternaria,
and Cladosporium species were present. He was treated with robust
nutritional, detoxification, and anti-fungal therapies. At the
visit, the mother reported that the child began to "understand
language" and "awkwardly utter a few incomplete words." Urinary
excretion of mycotoxins and Krebs metabolites were measured again
and are compared with pretreatment values (Table 2).
Table 2: Effect
of Nutritional and Anti-Fungal Therapies on Urinary Excretion
of Organic Acids in a Four-Year-Old Autistic Child*
*Note that the shifts in lactic and pyruvic
acids in the post-treatment values occurred in the opposite directions.
Oxyradicals induce deletion mutations
in mammalian cells.17 For example, oxidizing agents – hydrogen peroxide, ozone, potassium superoxide,
and others – have documented mutagenic effects. Similarly, oxyradical?producing
chemicals – bleomycin (a chemotherapy agent), streptonigrin,
and others – cause mutations with different frequencies.
Genes – Getting
Angrier by the Decade
The body of information concerning gene
mutations associated with ANS is growing rapidly. Such mutations have
5, 6, 16, and 17.18-21 Other pertinent mutations are
found in individuals with (1) the fragile X syndrome; (2) extra
21st chromosome; (3)
the microdeletion syndrome 16p11.2; (4) the 7q11.23 syndrome; (5) the
22q1 mutation; (6) mutation of gene that codes for synaptosomal-associated
protein 25 (SNAP-25); (7) seven-repeat allele of dopamine receptor
(DRD4 7R); and (8) photoreceptor-specific gene at the retinitis
(RP) locus, which is modulated by retinal oxygen levels in vivo.22
The search for the genetic basis of various symptom-complexes of
ANS has also focused on nucleotide sequences involved with neurotransmitters,
including dopamine, serotonin, GABA, glutamate, nitric oxide (NO),
carbon monoxide (CO), and others. Notable among other nucleotide
sequences, in the present context of the ANS-oxygen connections,
are altered DNA sequences that code for oxygen-sensitive and oxygen-responsive
protein systems of the body, which may be called oxyenzymes.
Human biology is an ever-changing kaleidoscope. All biologic functions
are intricately interconnected. It should be self-evident that
such broad phenotypic connectedness must be established and sustained
by an equally broad genotypic connectivity. Stated simply, all
functions must be regulated by constellations of genes. That, indeed,
is the case. Mutations occur in clusters of genes to set the stage
for the pathogenesis common diseases. In view of these considerations,
I consider loud claims of genetic cures of ANS unwarranted. I assert
that when it becomes possible to replace clusters of mutated genes,
the clinical benefits will depend on the degree to which oxygen
homeostasis can be maintained.
Ecogenomics of Atypical Neurodevelopmental States
A number of papers published in 2007 fully supports the above perspective
of genetic connectedness.23-25 In the context of ANS, for example,
single-nucleotide polymorphisms are scattered throughout the genome,
and singular combinations of particular genes form haplotypes involved
in behavioral traits. Structural variations – additions, deletions,
repeat sequences, and stretches of "backwards" DNA – are
far more common than were recognized at the end of 2006. Indeed,
Science's 2007 Breakthrough of the Year was entitled "Human
Genetic Variation."25 It highlighted the complexity of genetic
pathways underlying clinical states. The genetic underpinnings of
clinical states are provided by altered functionalities of clusters
of genes, and the roles of changes in individual's genes are
limited. Specifically, the range of possible interactions between
such states and the neurotransmitter pathways involving dopamine,
serotonin (5?HT), and others is vast.
I propose an "ecogenomic view" of ANS that recognizes and
addresses all relevant environmental, nutritional, and stress-related
issues for superior clinical results. It's needless to point
out that there are no known gene-based therapies that hold any promise
of clinical benefits. By contrast, early intervention programs with
robust nutritional, environmental, and behavioral guidance often yield
good clinical results.
The story of gene-disease association is never a complete story. The
detection of mutation in a specific gene in people with a specific
disease never excludes the coexistence of other mutations. In an earlier
column on diabetes, I surveyed patterns of diabetes epidemics in different
regions of the world and raised two questions: (1) Why did the diabetes
genes become angry?; and (2) Why are the angry diabetes genes getting
angrier by the decade? I now offer some thoughts on the subject of
genetic influences in ANS (hyperactivity, attention deficit, autism,
tics, and related states) by asking three questions: (1) Why did the
ADHD-autism genes become angry?; (2) Why did the genes associated with
the other symptom-complexes of the ANS spectrum become angry?; and
(3) Why are these angry genes getting angrier by the decade? The simple
answer is that genes are mutating in response to the cumulative load
of toxic environment, toxic foods, and toxic thoughts. The issues of
chronic anger and mycotoxins, in my view, are especially important
in this context. In past columns, I have marshaled extensive evidence
to support my view that the common denominator in all mechanisms of
molecular disruption and cellular injury caused by toxicities of environment,
foods, and thoughts is oxygen dyshomeostasis and deranged oxygen signaling.
The Influences of Toxic Environment, Toxic Foods, and Toxic Thoughts:
Three Discoveries with Evil Consequences
The sordid story of toxic environment and corrupted food supply began
in 1840 with the German chemist Baron Justus von Liebig. He developed
a tremendously enriching scheme to turn complex soil biology into a
chemical formula for dirt. The soil evolved over million of years to
sustain its plants. Liebig's chemical formula created quick spurts
of growth. He found that nitrogen, potassium, and phosphorus could
speed plant growth, but failed to foresee how it would adversely affect
the immunity of plants and the ecosystems of the soil. Liebig is honored
as the "father of the fertilizer industry." His advice is
still visible in the KPN value (the amounts of the three elements)
on the fertilizer packages in use today. The evil in that silly notion
went unrecognized. There was no consideration then, nor now, of the
dire long-term consequences of growing food in soil that has been depleted
of all other nutritional elements. For about 167 years, a cult of craven
and control-crazed men has engaged in a global biology experiment to
maximize their profits. The long-term devastation of the planet Earth
caused by this experiment has gone unrecognized.
The second player in the sad story of soil depletion was the Swiss
chemist Paul Hermann Müller, who, in 1939, discovered the insecticidal
properties of DDT. For that he was awarded the 1948 Nobel Prize in
Physiology or Medicine. The compound proved to be highly effective
for malaria control. It was also used worldwide for pest control in
homes and agriculture. DDT is highly toxic. Imagine my surprise when
on December 28, 2007, I read the following on the Harvard University's
website (available at: http://www.cid.harvard.edu/cidinthenews/articles/SA_Readers_Digest_
DDT, it turned out, was long-lasting and extremely toxic to insect
nervous systems, but virtually harmless to humans. During the war it
was sprayed on landing sites to protect invading Allied troops, and
US forces were issued DDT with which to talc themselves for lice prevention.
Virtually harmless to humans! Here is the reality check: in 1972,
the United States banned the agricultural use of DDT. Most developed
countries did the same within a few years. Presently, American, European,
and Canadian aid agencies, the World Bank, the United Nations, and
other international agencies have urged developing countries not to
use DDT for any reason.
The third big player in this drama was Norman Ernest Borlaug, the American
plant pathologist and geneticist who was awarded Nobel Peace Prize
in 1970 for his work in genetic modifications of crops. Notwithstanding
impressive short-term gains in increasing crop yield, the adverse long-term
effects are beginning to emerge. It is my strong sense that the delayed
consequences of genetically modified crops will prove no less dire
than the effects resulting from the earlier discoveries of Leibig and
Incremental Global Chemicalization
In 1994, according to the American Chemical Society, the US produced
107 pounds of synthetic chemicals for every child, man, and woman
on the planet. Many chemicals have long half-lives and persist in
the environment for decades. I addressed this issue at length in
my book RDA: Rats, Drugs, and Assumptions (1995).
I cite here one study of the relationship between pesticide toxicity
and ANS. Children
of Latino agricultural workers are exposed to higher concentrations
of pesticides in fields and homes. Pesticides are recognized disrupters
of neurotransmitter networks. These considerations led to comparative
studies of neurobehavioral performance of preschool children from
agricultural (AG) and non-agricultural (Non-AG) communities. The
results showed detectable differences between AG and non-AG children.26
Will Every Child Have
ADHD? Will Every Child Develop Some Autistic Traits?
chemicalization continues to deepen – chemical production
in the world is increasing – the febrile condition of the planet
Earth can be expected to worsen. If destruction of the human habitat
proceeds at the current rate – no signs of relief are in sight – Earth's
fever can be expected to continue to rise. If the corruption of the
world's food supply with pesticides and genetically modified persists – thinking
otherwise seems wishful – all of the planet's children will
be affected. All this raises the obvious questions: Will every child
hyperactive? Will every child suffer attention deficit difficulties?
Will every child develop a learning disorder or some other symptom-complexes
I find the subjects of ADHD, autism, learning disorders, and the
related forms of atypical neurodevelopmental states both disturbing
It is disturbing when I consider the pandemic proportions of these
problems caused by incremental poisoning of the planet and all its
children. It is inspiring when I reflect on the heart-rending and
uplifting stories of courageous parents and triumphs of children
these disorders. I am a hard-nosed surgeon-turned-pathologist-turned-integrative
physician. My colleagues and I have cared for a large number of children
in the ANS spectrum. So, I have some sense of what is possible. The
issue is whether we, as a society, can begin to see the real problems.
Do we have the courage to think differently? Can we find the strength
to learn, understand, and do what is necessary? To be authentic,
understanding has to be liberating. Can we reach for that authenticity?
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