Letters to the Editor
Autism: Multiple Genes Acting on a Distributed Neural Target?
Dear Editor:
Genetic research on the autistic spectrum disorders (ASDs) needs an informative endophenotype (1), that is, a common denominator that would distinguish brain functioning in the ASDs from normal functioning. In physiological functioning, simple reproduction of inputs takes place in primary sensorial areas, and integration of congruent unimodal data into more significative multimodal ones is enacted in associative areas (2). Higher levels of categorization and understanding are progressively reached, and a final choice among many (often emotionally charged) options guides voluntary and adaptive actions. The amount of data to be computed increases exponentially through all those stages. Enlarging webs of neural organizations cooperate for the purpose, continuously and smoothly changing their configuration and distribution of activation. It is difficult to conceive this kind of functioning without the intervention of a modulatory system (3) to integrate and set priorities among incoming and outgoing data. In a recent Positron Emission Tomography study, Hall and others found that individuals with autism are less prone to associate inputs from different sensorial modalities and that they preferentially allocate attentional resources to partial features of stimuli (4). In autism, we clinically detect fragmented mental performances, which tend to be run as isolated processes instead of multiple parallel and interlinked ones. Thus children aged 2 years who have autism and good single-word comprehension tend to concentrate on stereotyped play—probably as a result of the unintegrated hyperfunctioning of discrete brain areas—to the exclusion of parallel and contextually appropriate perceptions and behaviours, such as turning their heads toward a person who is calling them by name. Analogously, a high-functioning and verbal 6-year-old girl with autism avoids scanning the eyes–nose–mouth zone of an interlocutor while trying to express herself verbally, seemingly in the attempt to make mental space available for language processes. In her late teens, the same girl will not be able to maintain multiple mental activities in an activated and easily accessible state—activites such as holding in mind all the meanings of a homograph while reading a phrase in which that homograph is embedded and which would restrict lexical choice to only a single meaning. Theory of mind tasks in a social environment probably exceed the maximum synchronous mental load tolerable by most persons with autism; only a more parsimonious and less efficient piecemeal computing of social inputs in a structured environment is possible. I suggest that reducing the amplitude of synchronously elicitable mental functions with relative preservation of discrete processing is a basic endophenotype of the ASDs, although admittedly a difficult one to use for diagnosis and genetic studies. In ASDs, multiple mutating genes may have cumulative damaging effects on a modulatory circuit similar to that which Andreasen postulated to be altered in schizophrenia (5). The clinical variability of ASDs may derive from the number of altered genes, the distribution of the damage to the integrative network, the degree and prevalence of the consequent hemispheric dysfunction, the presence of comorbidities (the most common being mental retardation), the temperament of the affected individual, and the compensatory mechanisms at work. Neuroplasticity would account for partial reversibility of the above-described dysfunction and explain the improvements that we detect in most individuals with autism as they become older, both spontaneously and under the influence of educational treatments on brain chemistry and structure.
References
1. Nicolson R, Szatmari P. Genetic and neurodevelopmental influences in autistic disorder. Can J Psychiatry 2003;48:526–37.
2. Calvert GA, Brammer MJ, Bullmore ET, Campbell R, Iversen SD, David AS. Response amplification in sensory-specific cortices during crossmodal binding. Neuroreport 1999;10:2619–23.
3. Loddo S. The causes of autism and schizophrenia. [Rapid response to Szatmari: The causes of autistic spectrum disorders.] e-BMJ 2003. Available: http://bmj.com/cgi/eletters/326/7382/173#33854.
4. Hall GB, Szechtman H, Nahmias C. Enhanced salience and emotion recognition in autism: a PET study. Am J Psychiatry 2003;160:1439–41.
5. Andreasen NC. A unitary model of schizophrenia. Bleuler’s “fragmented phrene” as schizencephaly. Arch Gen Psychiatry 1999;56:781–7.
Silvio Loddo, MD
Oristano, Italy
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