Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection

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Although it has long been thought that frontal lobe abnormality must play an important part in generating the severe impairment in higher-order social, emotional and cognitive functions in autism, only recently have studies identified developmentally early frontal lobe defects. At the microscopic level, neuroinflammatory reactions involving glial activation, migration defects and excess cerebral neurogenesis and/or defective apoptosis might generate frontal neural pathology early in development. It is hypothesized that these abnormal processes cause malformation and thus malfunction of frontal minicolumn microcircuitry. It is suggested that connectivity within frontal lobe is excessive, disorganized and inadequately selective, whereas connectivity between frontal cortex and other systems is poorly synchronized, weakly responsive and information impoverished. Increased local but reduced long-distance cortical–cortical reciprocal activity and coupling would impair the fundamental frontal function of integrating information from widespread and diverse systems and providing complex context-rich feedback, guidance and control to lower-level systems.

Introduction

Autism is a disorder of brain development, and yet after 60 years of research, remarkably little is known about the underlying developmental neural defects that cause autistic behavior to emerge during the first years of life. Even more startling is that the least is known about the brain region most likely to be centrally involved: frontal cortex.

The hypothesis that frontal lobe abnormality plays a key part in autism has been espoused by researchers during the past quarter century [1, 2, 3•]. This is not surprising because frontal cortex plays vital roles in higher-order cognitive, language, social and emotion functions [4], each of which is seriously deficient in autism [5]. For example, individuals with autism are typically unable to surmise what another person is thinking [6] or might respond perseveratively once they are taught a particular set of rules [7]. Even within the first years of life, infants with autism show some signs of frontal lobe dysfunction, including abnormalities in social attention and a failure to show the normal trajectory of speech and nonspeech communication development [8, 9, 10, 11, 12, 13].

In the past, support for the frontal lobe hypothesis of autism has depended nearly exclusively on inferential behavioral evidence because there has been a near absence of developmental anatomical and microstructural data.

Here, we review the first studies to provide magnetic resonance imaging (MRI) information about early growth abnormalities in frontal lobes in autism [14, 15••], and new postmortem data that have provided the first quantitative and regional information about minicolumn maldevelopment in frontal cortex [16–17] and have identified the presence of activated glia and neuroinflammatory response in frontal and cerebellar cortices [18••]. Taken together, these new MRI and postmortem anatomical studies — in conjunction with existent neurofunctional, MRI and postmortem results from older autistic patients — suggest that, just as the autistic child is unable to effectively reciprocally interact with his or her social environment, the frontal cortex in autism is deficient in reciprocally interacting with other cortical regions. Instead, it appears that in early development, frontal cortex in autism might be abnormally over-connected with itself.

Section snippets

Macroscopic evidence of early frontal maldevelopment

Recent studies have discovered that although infants who will eventually develop autism are born with normal to slightly smaller than normal brain sizes, soon thereafter the brain grows at an excessive rate, leaving the autistic toddler with an enlarged brain volume [19, 20••, 21]. Excessive rates of brain growth, however, are not maintained and are followed by slowed or arrested growth ([19], see Courchesne and Pierce [22] for a review). Investigations of which brain regions might be driving

Microscopic evidence of frontal maldevelopment in process

In contrast to the clear new MRI evidence of early frontal growth abnormality and a wealth of behavioral and neurofunctional evidence of frontal dysfunction, there remains a glaring gap in our knowledge of the microstructural defects that disarrange frontal neural circuit development, generate the macroscopic overgrowth of frontal gray and white matter and cause abnormal frontal-mediated behavior. New quantitative microscopic studies, in conjunction with clues from older visual inspection-based

Conclusions

For more than two decades it has been clear that frontal lobe abnormality must be an important factor underlying core features of autism, including severe impairment in higher order social and emotional processing and communication, cognitive functions, orienting to and exploring the social and non-social world, and speech. Neuroimaging studies of older children and adults with autism have demonstrated reduced or deviant frontal cortical neural activity. Since first discovered and interpreted

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors were supported by funds from the National Institute of Mental Health (2-ROI-MH36840) and National Institute of Neurological Disorders and Stroke (2-ROI-NS19855) awarded to E Courchesne, and from the National Institute of Mental Health (K01-MH01814) awarded to K Pierce. Thanks also for support from the San Diego Thursday Juniors Club and the Swartz Foundation.

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