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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 not."

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, if any."

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 report: "The 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 significantly 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

In the late 1980s, I recognized the following four problems with the prevailing classification of ANS of children:

1. 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.
2. None of the diagnostic labels yield any insight into the energetic-molecular nature of a child's suffering.
3. The intensity of suffering caused by ANS varies markedly under different environmental, nutritional, and stress conditions, indicating the causative influences of those factors.
4. 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 study:

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
Direct 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 toxicants 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 follow-up 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.

Angry ADHD-Autism Genes – Getting Angrier by the Decade
The body of information concerning gene mutations associated with ANS is growing rapidly. Such mutations have been recognized in chromosomes 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 pigmentosa (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 biologic 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_ 1200.html):

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 Muller.

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

Concluding Comments

Will Every Child Have ADHD? Will Every Child Develop Some Autistic Traits?
If global 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 become hyperactive? Will every child suffer attention deficit difficulties? Will every child develop a learning disorder or some other symptom-complexes of ANS?

I find the subjects of ADHD, autism, learning disorders, and the related forms of atypical neurodevelopmental states both disturbing and inspiring. 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 labeled with 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?

Notes

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10. The Fall 2006 Preliminary Ethnic Survey Report Pub. No. 346 of the Los Angeles Unified School District. LA Unified School District, LA, CA..
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