Early version of autistogenesis presentation -
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This is the presentation of my systems theory of autistogenesis made at the Western Psychological Association, the Autism Society, and the American Psychological Association. Since that time, new information has continued to support this theoretical perspective and I am now moving into experimental studies to confirm.
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- 1. Autistogenesis: The systems theory with an evolutionary perspective J. Patrick Malone, M.Ed. Walden University
- 4. Method Areas reviewed include: Clinical nutrition Pediatric neurology Lipid metabolism Cognitive neuroscience Molecular biology Clinical psychology Evolutionary psychology Neurophysiology Developmental psychology Endocrinology Archaeology Biological anthropology Brain morphology Immunology Genetics Toxicology Cell biology Biochemistry Evolutionary Biology Pharmacology
- 5. Inclusion-Exclusion Criteria Journal articles Books and chapters Conference papers Dissertations All were considered eligible for inclusion . Resources not addressing associated genetic or metabolic processes, pervasive developmental disorders, autistic behaviours, or the evolutionary significance of such processes were typically excluded.
- 6. Literature Search Studies considered contained permutations of the words ; autism , developmental disorder , infant , genetic linkage , mirror neuron , docosahexaenoic acid / DHA , foetal , arachidonic acid / AA , inflammation , sensitive period , environment , androgen , testosterone , estrogen , estradiol , fish oil , milk formula , stress , breast milk , and gender . Library Holdings Medline PsychINFO ProQuest Academic Search Complete Eric Sage Online Journals Google Scholar eBray and PsychBooks
- 12. What are the consequences? anterior, inferior fronto- and temperoparietal regions somatosensory cortex, ventral premotor cortex, limbic system, orbital frontal lobes insula All of these and more will experience growth and myelination at different rates during different developmental periods … Sensitive periods !
- 15. DHA neuroprotectin D1 (NPD1) ⊢ = inhibits = promotes
- 17. Primary role for DHA without STRESS - Neurite formation is promoted while inhibiting apoptosis. - Improved neuronal differentiation . - Stimulation of neurite growth factors . - Enhanced production of phospholipids required for neurite elongation .
- 18. The precursors and the products:
- 22. Negative effects on health were detected in vivo with DHA/AA ratios of .56 or less.
- 23. Infant milk formula: Cause for concern?
- 25. Some infant foods contain DHA only …
- 26. What do we know?
- 27. Clues to male over-representation: High-dose DHA supplementation of preterm milk formula did improve Bayley Mental Development (MDI) scores at 18 months corrected age in female infants only .
- 28. The pre-pubertal surge: It works Estradiol Aromatase Testosterone Neuroprotection Estradiol
- 29. The pre-pubertal surge: It doesn’t Estradiol Aromatase Testosterone Neuroprotection Neurotoxicity
- 31. So, how do we find a gene in the human genome that can account for these factors? Genome-wide linkage analysis
- 32. Introducing the CYP19 gene: P450arom
- 33. The P450arom gene at 15q21.2
- 34. The P450arom gene at 15q21.2
- 36. Evolutionary biology MUST inform biological psychology … A maturing infant brain susceptible to change due to stress provides a powerful selective advantage. The point is to not play well with others.
- 39. For every step in the genetic, metabolic, and environmental pathway to autistogenesis, there is an opportunity for early detection, treatment, and intervention.
- 40. However, the earlier that socially engaging and “neurologically age appropriate” the intervention is to those specific brain regions, the greater chance for improvement.
Editor's Notes
- These signs provide diagnostic triangulation for a spectrum of disorders that range from bully to broken. Because signs of this disorder continuum may remain subtle well past the third year of life, and beyond the reach of more compliant neurology, there is overwhelming need for discrimination between autism and other disorders through biological assay to better frame therapeutic intervention.
- This research introduces a systems theory approach to autistogenesis that unifies current findings from several diverse fields with implications for prevention, mitigation, intervention, and biological assay.
- Meta-narrative review, the central and well established method in evidence-based medicine, provides answers amenable to the biology and the psychology of this pervasive developmental disorder.
- Inclusion criteria was necessarily liberal as there exists several journals dedicated to autism research, and that many disparate journals publish additional studies bearing on this multifaceted developmental disorder. Direct telephone contact with technical representatives from pharmaceutical companies was required to ascertain chemical constituents.
- I reviewed the reference lists of all acquired articles and book chapters for potential sources germane to this study, with allowances made for much older works where previous findings illuminate current research.
- Sensitive periods exist throughout all cortical structures and yield to broad modification in pathways governing development of perception, attention, learning, memory, language, rudimentary mathematics, and social engagement. Mirror neurons permeate the cerebral cortex, and since brain regions mature differentially, this work asserts sensitive periods for aspects of mimicry, imitation, and goal emulation are certain.
- Project from the anterior cingulate, extend through layer 6 of the frontoinsular cortex and to prefrontal, orbitofrontal, insular and anterior temporal cortices, the amygdala, hypothalamus, thalamic nuclei, and periaqueductal gray matter. Individuals on the autism spectrum demonstrate significantly reduced, disordered, dysfunction and migration deficits.
- Deficits within the MNS represent a key neurological correlate to impaired social cognition . MNS activates while witnessing another’s actions, producing matching somatosensory and proprioceptive feedback mapped onto the Self. It is modulated by emotion and motivation, provides empathic experience of another, and enables interpretation of facial expressions and other communicative gestures.
- The consequences of early chronic or repeatedly acute stress may produce neuroinflammation similar to illness or injury. These factors contribute to reduction of perceptual, intellectual, and learning capacities, inability to inhibit repetitive or self-destructive behaviours, and gross distortion of communicative, emotional, and social operations.
- The neuroinflammatory cascade leads to apoptosis and aberrant connections between the amygdala, insula, septal nuclei, cingulate gyrus, hippocampus, and neocortex, though mylenation continues . Interconnectivity is nullified as inflammatory metabolites degrade fledgling connections. Hard-wired short-distance connections create a blockade to long-distance neuronal organization.
- Early chronic or repeatedly acute stress produces neuroinflammation and induces similar effects in all primates, and contributes to reduction of perceptual, intellectual, and learning capacities, inability to inhibit repetitive or self-destructive behaviours, and gross distortion of communicative, emotional, and social operations.
- Arachidonic acid plays a role in various cancers through the cyclooxygenase and lipooxygenase pathways, and initiates apoptosis, including tumour necrosis factor. Under great stress, cortisol induces enhanced lipoxygenase expression and free radical-mediated peroxidation which creates AA metabolites, including leukotrienes, which sustain or augment the inflammatory response.
- DHA demonstrates potent antiapoptotic effects through 3 primary routes; enhancement of neuron cell membranes, inhibition of an apoptosis initiator, and is converted into powerful shields against AA dependent inflammation processes.
- DHA is also transformed by an enzyme similar to 15-LOX into neuroprotection D1 (NPD1), which is promoted during return of blood to tissues following ischemia, suppresses Aβ-42-induced toxicity in Alzheimer disease, inhibits apoptosis, blocks leukocyte infiltration, and suppresses proinflammatory gene expression.
- DHA is shunted through the phosphatidylserine synthesis pathway and in turn reduces apoptosis through a variety of genetic mechanisms.
- There is clear in vivo evidence that DHA is vitally important to learning and memory at the component level as deficiency studies reveal smaller neuronal cell bodies in the hippocampus, hypothalamus, and the parietal cortex. DHA also influences Na + , K + , and Ca + channels, promotes synaptic transmission, and enhances long-term potentiation associated with learning.
- Arachidonic acid is also considered essential to infant growth and development as it serves an important function in synaptic transmission and so a careful balance is struck between AA and DHA as both share the same desaturation and elongation pathway when converted from linoleic (LA) and α-linolenic acid (ALN) respectfully.
- Counter to the positive effects, free DHA is regulated in the brain and extreme oxidative stress produces reactive oxygen species capable of generating DHA peroxidation products that induce cell damage. Thus, repeatedly acute stress, or chronic stress in the presence of excess free DHA may result in a tipping point and heighten neuroinflammation.
- Previous studies of infant development linked to breast or bottle feeding, with or without LC-PUFA supplementation, were rife with challenges. Problematic design and contradictory results suggested that no clear evidence exists linking mothers’ orally supplemented breast milk or milk formula to intelligence or vocabulary.
- Typical American diets result in reduced DHA in breast milk compared with the foreign equivalent, due to consumption of foods heavy in AA and its precursors, which contributes to diminished DHA in the developing brain and hinders neurite outgrowth.
- According to several studies, brain DHA to AA ratio measured to be approximately 1.35. Dietary ratios of .56 or less contribute to increased lipid peroxide levels, partly because the increased AA reduces the presence of DHA by decreasing its synthesis and physical replacement within membranes.
- Similac has offered infant formula with a DHA/AA ratio of approximately .37 in 2002, established to replicate American women’s breast milk with a DHA to AA ratio .74 lower than the lowest of the top 10 countries in breast milk worldwide. All others use a DHA to AA ratio at or below .5.
- Excessive supplementation of DHA may also disrupt neuron membrane permeability and enzyme function, and without adequate antioxidant such as vitamin E, may create an accumulation of lipid peroxides that can result in a runaway inflammatory insult to neuronal tissues. Neuroprostanes are generated within the brain through enzyme-independent reactions due to oxidative stress leading to apoptosis
- Further, excessive DHA supplementation, in combination with vitamin E , during sensitive developmental stages may result in premature neuronal hardwiring in genetically or environmentally predisposed infants. Thus, neuroprotection may inhibit needed apoptosis in some regions required for developmental changes, contributing to behaviours diagnostic of developmental disorders.
- It is an unfortunate fact that data exists from foundling homes; infants receiving inadequate nutrition and social isolation until three years of age, often demonstrate at least the minimum behavioural characteristics diagnostic of classical autism ...
- Controlled diets administered to men containing radio-labeled α -linoleic acid (ALN) demonstrated that males cannot convert precursors to DHA above background. Female conversion of ALN into DHA is significant and greatest among participants using an estradiol-based birth control pill. Administration of testosterone with the aromatase inhibitor, anastrozole, blocks the conversion of testosterone to estradiol and inhibits DHA conversion.
- A post-partum surge in sex hormones, much higher than that of puberty, causes testosterone from the testes to flood the brain and convert to estradiol by the aromatase enzyme, encouraging axonal regeneration, synaptogenesis, neurogenesis, dendrititc spine formation and improves cell survival rates secondary to insult or injury, including the MSN and olivary cells which are typically found abnormal in post mortem examinations of autistic children.
- When conversion of testosterone to estradiol does not occur, testosterone accumulates, production of powerful brain antioxidants cease and free radicals increase, neuroblastoma cells undergo apoptosis, aberrant neuronal migration occurs, DHA and AA are converted into toxic inflammatory metabolites, and inflammatory cytokine activity increases.
- That estradiol modulates OXTR explains why OXTR is greatly diminished in autism and yet RNA expression for OXTR remains normal. More importantly, estradiol’s regulation of DHA production provides the final clue to what kinds of genes to look for that can explain (1) autisim’s gender bias, (2) a link between environmental stress and developmental disorders, (3) and the link between testosterone, estradiol, and DHA.
- This method samples DNA from hundreds families with autistic children. Depending on criteria used for diagnosis, those genes that appear most frequently between unrelated families are considered possible candidates for selection. The horizontal reference lines indicate logarithm of odds score = 2.2 suggestive of linkage, and 3.6 = statistically significant for autism spectrum disorder.
- CYP19, the gene at 15q 21.2 cM, encodes for the aromatase enzyme that converts testosterone to estradiol, with 9 regulatory units imparting tissue specificity: endometriosis/ovary/breast cancer, adipose/breast cancer, bone, placenta minor 1, brain, foetal tissues, skin/adipose, placenta minor 2, and placenta major.
- The gene located at 15q21.2 links gender due to the balance between testosterone and estradiol regulation of DHA synthesis. Opportunities for failure at the common splice site, and multiple sites for mutation, methylation, and potential for copy-number alteration suggest 15q21.2 admits potential inhibition or dysfunction.
- In each instance, one of the tissue-specific regions must be copied from the DNA and then spliced onto the copy containing the sequence for the aromatase enzyme, providing tissue-specific expression, but also great potential for transcript level regulation due to psuedogene, miRNA, and ceRNA activity.
- Therefore, this paper asserts that autism is the result of damage to or impairment of one or more components within a system of interconnected processes; the brain’s multi-domain periods of developmental sensitivity, the influence of internal and external environmental stressors on developing neurology, LC-PUFA metabolism, and the genetic mechanisms and metabolic processes of testosterone conversion to estradiol.
- Protein primarily from red meat diminishes DHA to AA dietary ratios, ensuring offspring more ready to take risks and hunt quarry capable of returning the fight, and less likely to “feel the pain” of even very closely related hominid prey. This then represents the healthy functioning of the autistogenesis system.
- The Neanderthal was a powerful hunter throughout the European continent. What some call a bully can also be the child to assume the dominant position in naturalistic settings, without genetic alteration, due to increased risking taking, less empathic connection to competitors, and the ability to react in ways antisocial.
- Neanderthal’s greater tendency for antisocial behaviours, ostensibly adaptive to high risk environments, may have been modulated by the system linking testosterone to estradiol conversion and maintenance of DHA/AA ratios within the brain. Interestingly, the earliest Homo sapiens ancestry lived along the Tsitsikamma coast of South Africa, consuming balanced diets rich in DHA.
- Neuronal maturation occurs throughout the brain in reasonably predictable fashion and this sequence of events can provide a roadmap with mileposts to guide intervention. The younger the child is without competent aromatase expression, or with an inappropriate dietary DHA/AA ratio, in the face of any neuroinflammatory event, the more pan-cerebral the potential damage to sensitive domains.
- New therapies must include activity that provide neurological stimulation targeted to those areas likely damaged so that plasticity may remodel faulty interconnections. Neurologists employing imaging techniques can determine cortical areas with aberrant electrical or BOLD responses to provide neuropsychologists with a plan for therapists to develop brain region-specific intervention and possible dietary LC-PUFA supplementation.