Well referenced article about the Neurobiology of Autism

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The Intense World Theory – a unifying theory of the neurobiology of autism
Kamila Markram* and Henry Markram

* Laboratory of Neural Microcircuits, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Autism covers a wide spectrum of disorders for which there are many views, hypotheses and theories. Here we propose a unifying theory of autism, the Intense World Theory. The proposed neuropathology is hyper-functioning of local neural microcircuits, best characterized by hyper-reactivity and hyper-plasticity. Such hyper-functional microcircuits are speculated to become autonomous and memory trapped leading to the core cognitive consequences of hyper-perception, hyper-attention, hyper-memory and hyper-emotionality. The theory is centered on the neocortex and the amygdala, but could potentially be applied to all brain regions. The severity on each axis depends on the severity of the molecular syndrome expressed in different brain regions, which could uniquely shape the repertoire of symptoms of an autistic child. The progression of the disorder is proposed to be driven by overly strong reactions to experiences that drive the brain to a hyper-preference and overly selective state, which becomes more extreme with each new experience and may be particularly accelerated by emotionally charged experiences and trauma. This may lead to obsessively detailed information processing of fragments of the world and an involuntarily and systematic decoupling of the autist from what becomes a painfully intense world. The autistic is proposed to become trapped in a limited, but highly secure internal world with minimal extremes and surprises. We present the key studies that support this theory of autism, show how this theory can better explain past findings, and how it could resolve apparently conflicting data and interpretations. The theory also makes further predictions from the molecular to the behavioral levels, provides a treatment strategy and presents its own falsifying hypothesis.
Introduction

The neurobiology of autism has been researched extensively with growing urgency and major strides and insights over the past 30 years (Rubenstein and Merzenich, 2003; Belmonte et al., 2004b; Courchesne, 2004; Casanova, 2007; Minshew and Williams, 2007; Amaral et al., 2008), yet no coherent neurobiologically based theory of autism has yet emerged to explain its entire heterogeneity. A wide range of interpretations, hypotheses, and theories has been put forward, each casting a different light on an important but specific aspect of autism. The central question is whether the spectrum of autism is due to a spectrum of neuropathologies or whether a single common pathology can explain the spectrum. Recently, we put forth a bottom-up hypothesis for autism that is neurobiologically grounded and works its way up from the molecular, cellular, and circuit levels toward the potential cognitive consequences, called the Intense World Syndrome (for extensive review see Markram et al., 2007b). The Intense World Syndrome hypothesis was grounded in original experiments using the valproic acid (VPA) rat model of autism to explore possible alterations across molecular, cellular, synaptic, circuit, and behavioral levels. Such experiments can only be performed using an animal model. This animal model was chosen because VPA intake during pregnancy was linked to an increased risk of giving birth to an autistic child (Moore et al., 2000; Rasalam et al., 2005) and VPA exposure in rats has remarkably similar effects as in humans. The multi-level approach from molecules to behavior, possible only in an animal model, allowed piecing together the different levels of the brain’s organization and up toward its emergent behavior, which revealed a common and coherent theme of alterations and suggested that autism could be explained as an Intense World Syndrome (Markram et al., 2007b). Naturally, there is a vast gap between an animal model and autism that is currently only recognized for humans. In this paper, we therefore explored previous studies, results, hypotheses, and theories in the light of the Intense World hypothesis, and examined whether this hypothesis can stand as a formal and unifying theory of autism.

The original notion of an Intense World Syndrome in autism arose, because VPA-exposed animals exhibited amplified fear processing and memories (Markram et al., 2005, 2008), which indicated that fragments of the world could easily become emotionally aversive and be stored excessively. In strong support of this, we found that on the neural circuit level, VPA-exposed animals exhibited enhanced neuronal reactivity and plasticity across several brain regions, such as the amygdala and neocortex. This provided the potential cellular and circuit explanation for how an autistic brain could be easily trapped in a painfully intense world, potentially explaining a broad range of common autistic symptoms such as sensory sensitivity, withdrawal, repetitive behavior, idiosyncrasies, and even exceptional talents.

The experimentally based and common neuropathology proposed in the Intense World Theory is hyper-functioning of elementary brain modules, called local neural microcircuits, which are characterized by hyper-reactivity and hyper-plasticity, both of which seem to be caused by a tendency for excitatory neurons to dominate their neighbors. Such hyper-functional microcircuits are proposed to easily become autonomous, leading to runaway information processing, over-specialization in tasks and a hyper-preference syndrome. The proposed core cognitive consequences are hyper-perception, hyper-attention, hyper-memory, functions mediated by the neocortex, and hyper-emotionality, mediated by the hyper-functionality of the limbic system. These four dimensions could potentially explain the full spectrum of symptoms in autism, depending on the severity of the microcircuit pathology in different brain regions. The degree of hyper-functionality in different brain regions could vary in each child depending on genetic personality traits, on unique epigenetic conditions, and unique sequence of postnatal experiences.

This article begins by shortly reviewing the validity of the VPA rat model of autism as well as the experimental insights obtained from this model, before delving deeper into an a re-examination and re-interpretation of previous studies on human autism in the light of these experimental results from the animal model. We make the case for a unified Intense World Theory for autism that can potentially explain many of the varied past results and resolve many conflicting findings and views, and by making some falsifiable experimental predictions.

There is a flaw early in the article; it is assumed by the authors that all incidents of autism are identical to that noted in Fetal Anticonvulsant Syndrome, even though it is acknowledged that FAS also includes physical symptoms (facial dysmorphy and ear abnormalities) missing in many autistics.

Further, there is the simple fact that many mothers of autistics did not take VPA or thalidomide during pregnancy; thus, there is no way to "blame" the neurological changes on a brainstem insult caused by exposure to VPA or thalidomide during a crucial stage of pregnancy.