Thursday, January 24, 2008

Auitsm, Valproate and Mania/Psychosis

There is a new open source journal available called Frontiers in Neuroscience , and in the first edition there is an article expounding autism as an Intense world syndrome. It is a very intriguing article that claims amongst other things that autistics have very rich local neural circuitry (perhaps in lieu of sparse global circuitry) and this may be the reason why they have rich modular cognitive abilities like memory etc. I am tempted to contrast this with Schizophrenia/ psychosis where there may be more global processing of information. But before my main thesis an abstract of the paper.

Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems to be triggered by multiple environmental factors during embryonic and/or early postnatal life. While significant advances have been made in identifying the neuronal structures and cells affected, a unifying theory that could explain the manifold autistic symptoms has still not emerged. Based on recent synaptic, cellular, molecular, microcircuit, and behavioral results obtained with the valproic acid (VPA) rat model of autism, we propose here a unifying hypothesis where the core pathology of the autistic brain is hyper-reactivity and hyper-plasticity of local neuronal circuits. Such excessive neuronal processing in circumscribed circuits is suggested to lead to hyper-perception, hyper-attention, and hyper-memory, which may lie at the heart of most autistic symptoms. In this view, the autistic spectrum are disorders of hyper-functionality, which turns debilitating, as opposed to disorders of hypo-functionality, as is often assumed. We discuss how excessive neuronal processing may render the world painfully intense when the neocortex is affected and even aversive when the amygdala is affected, leading to social and environmental withdrawal. Excessive neuronal learning is also hypothesized to rapidly lock down the individual into a small repertoire of secure behavioral routines that are obsessively repeated. We further discuss the key autistic neuropathologies and several of the main theories of autism and re-interpret them in the light of the hypothesized Intense World Syndrome.

The authors use the valproate model of autism for their discussion and it is a well established mouse model of autism. In this model, mother rats are given valproate during pregnancy and the children later had autistic syndromes and were developmentally retarded. There is also some literature documenting a linkage between fetal valproate syndrome and autism.

Rodier et al. have reported that, in a rat model for teratogen exposure, the administration of valproic acid in early development induces morphological brainstem pathology similar to changes sometimes observed in autism. Alterations in the distribution of serotonergic neurons in brain, suggestive of abnormal neuronal differentiation and migration, have also been observed in the animal model. Further work in rats has shown that the prenatal challenge with valproic acid induces behavioral changes, including delayed maturation, decreased social exploration, deficits in sensorimotor gating, and repetitive, stereotyped responses in an open field. In mice, exposure to valproic acid while in utero leads to behavioral retardation and regression during neonatal and juvenile development

Thus from the above discussion it is apparent that exposure to valproic acid has something to do with autism. It is to be noted that valproic acid/ sodium valproate is a well-known anti-convulsant that is also given in bipolar disorder as a mood stabilizer. Now readers of his blog will be familiar with my model of autism , whereby I stress the opposite polarity to schizophrenia/ psychosis. I believe that what we witness in Autism is the converse of what we witness in psychosis. Both are pathological states, but one with too much reality orientation (including not attributing agency to fellow humans/ animals) while other too much fantasy orientation (with tendency towards anthropomorphism). Also while autistics may be the proverbial detail-oriented missing forest for the trees sort of people, schizophrenics are more meaning-and-big-picture-obsessed people with possibly more hyper-active and hyper-plastic global neural circuitry as opposed to what is hypothesized in autistic intense world syndrome.
I also consider bipolar and schizophrenia to be closely related and am not surprised that while lack of valproic acid is used to treat the bipolar psychosis and the bipolar condition; an exposure to the same teratogen during pregnancy ( a critical developmental window ) may have the opposite effect of leading to the opposite disorder like autism. To me this valproic acid linkage proves further that autism and schizophrenia/ psychosis are opposite of each other.

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pasadena therapist said...

I've read and re-read your model of autism and the current thoughts about schizotypy and autism being converse on a single continuum because there is something intuitively fascinating about this relationship. I have a couple of questions though.

1. Introverted anhedonia - couldn't that be attributed to both schizotypy and autism?

2. Could not autism and schizotypy be separate dimensions that happen to appear opposite? Do not some schizophrenics engage in some 'systematizing' as a way of coping with their divergent thinking?

3. I wonder if there's research on the effect of valproate on dopamine, the neurotransmitter that seems to be partially implicated in schizophrenia

Sandy G said...

Hi Pasadena therapist,

Thanks for reading the model with interest. As for your questions,

1) I myself contend that introverted anhedonia is a little uneasy to fit in the model. I believe that it is an affective factor and should not be confused with the remaining primarily cognitive factors. Autism and schizophrenia may be diametrically opposed on cognitively laden factors while may have the same affective course.

2) Again systematizing and empathizing is a dimension that would be different from my cognitive focus. that is more like a male-female dichotomy and such a dichotomy is lacking in autism/ schizophrenia. Some schizophrenics , you are right to point are good systematizers and I do not rely primarily on baron-cohens' that distinction as primary to schizophrenia/ autism difference.

3) There is some research linking neurotrophic effect of VPA on dopamine neurons in the midbrain, although I cannot interpret that finding either way. you can read more here on the VPA dopamine linkages.

Janet Gaspar said...

Hi, this is very interesting! Apparently there is something called a 'normalisation effect' that occurs whem some epileptics are successfully treated with anti-convulsants, that includes psychosis... I have been taking an interest as my daughter has the first stages of juvenile myoclonic epilepsy ( and my son has Asperger's/dyspraxia)and remember it cropping up when I was reading forums.

Perhaps this is related, my son had a strong reaction to antihistamines taken over a period of 2 months which was very similar to an anti-cholinergic poisoning. The JME seems to be related to cholinergic system also, and i think these neurons are also involved in the development of the visual system (through column creation, and these neurons have MHC markers which might indicate an immune type reaction daughter is photosensitive, which is why I was looking at this, I will try to find the link)

So perhaps the cholinergic system plays a part in guiding the formation of the columns during brain development and that is open to influence by the immune debate between the parents genetics?