Review
Autism as a neural systems disorder: A theory of frontal-posterior underconnectivity

https://doi.org/10.1016/j.neubiorev.2012.02.007Get rights and content

Abstract

The underconnectivity theory of autism attributes the disorder to lower anatomical and functional systems connectivity between frontal and more posterior cortical processing. Here we review evidence for the theory and present a computational model of an executive functioning task (Tower of London) implementing the assumptions of underconnectivity. We make two modifications to a previous computational account of performance and brain activity in typical individuals in the Tower of London task (Newman et al., 2003): (1) the communication bandwidth between frontal and parietal areas was decreased and (2) the posterior centers were endowed with more executive capability (i.e., more autonomy, an adaptation is proposed to arise in response to the lowered frontal-posterior bandwidth). The autism model succeeds in matching the lower frontal-posterior functional connectivity (lower synchronization of activation) seen in fMRI data, as well as providing insight into behavioral response time results. The theory provides a unified account of how a neural dysfunction can produce a neural systems disorder and a psychological disorder with the widespread and diverse symptoms of autism.

Highlights

► Our theory attributes autism to impaired frontal-posterior brain connectivity. ► We present functional and structural brain imaging and behavioral evidence. ► We model underconnectivity with frontal-posterior bandwidth constraints. ► We account for language and social deficits and perceptual sparing in autism. ► We account for individual differences in functional connectivity in autism.

Introduction

Although autism has surely been with mankind for millennia, it was systematically identified only recently by Kanner (1943), and Asperger (1944). Both of these papers were psychiatric case studies of children, and their characterizations of the behaviors in autism remain accurate and insightful to this day. Although neither of these seminal papers provided a scientific account of autism at either the behavioral or neuroscientific level, they both suggested a possible biological origin for the disorder. Despite this identification of the disorder in the 1940s, scientific research into autism (and its funding) remained small in scale in the U.S. until the 1990s, when new methods of cognitive and social neuroscience were developed and began to be applied to autism. Methods including genomics, eye-movement tracking, and electrophysiology held the promise of providing an understanding of the psychological and biological mechanisms that underpin the disorder. Our focus here is on the findings from another new method, neuroimaging of brain structure and of brain activity. In this paper, we propose a formal model of autism that integrates some of the recent neuroimaging findings, instantiating a cortical systems underconnectivity theory of autism.

Autism has long been an enigma in at least three ways: one way is that the symptoms (disorder of social and communicative behaviors, and a restricted range of interests) are diverse and seemingly unrelated; another way is that the syndrome does not bear an obvious correspondence to a particular biological function (such as some forms of blindness being related to damage to the visual cortex); and a third way is that occasionally autism is manifested as a perceptual advantage. However, with the rapid development of new scientific understanding of brain function that has occurred in the past two decades, it is now possible to make sense of these three aspects of the enigma: the diversity of the symptoms of autism can now be understood as a manifestation of a neural systems disorder whose impacts are widespread; the link to a biological substrate is being illuminated by functional and anatomical brain imaging as well as by genomic research; and the understanding of the brain and cognition as a complex system illuminates how a perturbation of the system can have both negative and positive impacts on system functioning. The theory we propose here attempts to provide a detailed scientific account of some aspects of the enigma.

Autism has recently been characterized as a disorder of neurological origin with abnormalities found in the coordinated functioning of brain regions. This theoretical view, the cortical underconnectivity theory, first emerged from fMRI (functional magnetic resonance imaging) measurements of cortical activation in several types of thinking tasks. These studies showed that the degree of synchronization of the activation (or functional connectivity) between frontal and posterior brain regions was lower in autism. The observation was first made in a language comprehension task (Just et al., 2004), and undersynchronization of activation during task performance has since been found between the frontal lobe and more posterior regions in a wide variety of other tasks (Damarla et al., 2010, Just et al., 2004, Just et al., 2007, Kana et al., 2006, Kana et al., 2007, Kana et al., 2009, Koshino et al., 2005, Koshino et al., 2008, Mason et al., 2008, Mizuno et al., 2011, Schipul et al., 2011; see Schipul et al., in press for a recent review). We propose that the lower synchronization arises because the communication bandwidth between frontal and posterior cortical areas is lower in autism than in the typical population. We use the term bandwidth to refer to the maximal rate of data transfer supported by a communication channel, taking into account the impact of noise, consistent with Shannon's (1949) usage.

Decreased bandwidth would clearly impact system performance when the interregional communication needs were high enough. Some of the central questions that emerge from examining underconnectivity in autism are: (1) How would a bandwidth constraint in autism affect the communication transfer between frontal and posterior regions? (2) How might a brain with autism adapt to or compensate for such an impairment? (3) Does the physical or anatomical distance between cortical areas play a key role in information transfer in autism? (4) Are there underlying structural and developmental bases for the underconnectivity? and (5) Can computational modeling of fMRI data account for the variation in synchronization (functional connectivity) in terms of variation in several structural and functional attributes of the brain? In this paper, we attempt to address these questions using a formal theory accompanied by a computational model.

This article is organized into several sections below: a brief summary of previous findings, a description of underconnectivity theory and of its implementation as a computational model, and a discussion of the theory and its relation to other theories.

Section snippets

Previous biological findings

Several types of previous background findings concerning brain biology lend plausibility to underconnectivity theory, although they are not a part of the theory proper.

Convergence of the brain imaging evidence implicating disrupted connectivity in autism

Aside from the lower-level biological mechanisms cited above that could underpin cortical connectivity disruption, four recent brain imaging findings more directly implicate aberrant cortical connectivity in autism, and they do so in a tightly convergent way.

First, the synchronization of activation (or functional connectivity) between frontal and posterior regions of the cortex is lower in autism than in control groups during task performance across a number of different domains of thought,

Underconnectivity theory

The cortical underconnectivity theory that we have previously proposed in the context of specific tasks (Just et al., 2004, Just et al., 2007) posits that inter-regional (systems level) connective circuitry in the brain is disrupted in autism, and that patterns of thought that are particularly dependent on integration of frontal and more posterior contributions are disrupted. Furthermore, the theory attributes disruptions in psychological functions such as Theory of Mind and executive

Computational modeling of brain function and cognition

As functional imaging is increasingly providing finer detail about brain activation, computational modeling provides a theory-building workspace where the new pieces of information about underlying mechanisms can be brought together and their co-functioning can be examined (Just and Varma, 2007). In this workspace, the component mechanisms can be specified in detail, and their ability to account for the observed phenomena can be tested, as a few initial attempts have shown (Anderson et al., 2004

The 4CAPS model of frontal-posterior underconnectivity in autism

The new model takes as its point of departure the 4CAPS model of TOL problem-solving in healthy adults (Newman et al., 2003), and modifies it to account for the fMRI findings of lower functional connectivity in autism in this task (Just et al., 2007). The first modification is the enforcement of bandwidth constraints on communication between frontal and posterior centers. The second modification, which is assumed to arise as an adaptation to the bandwidth constraints, is increased autonomy of

Modeling results

The control and autism models were run on several blocks of the stimuli used in the Just et al. (2007) study. The models solved the problems making the same moves as the human participants (using the shortest solution path), generating a predicted fMRI time series for each model center. Correlations between these time series were computed for pairs of model centers in each model, corresponding to the functional connectivity measures of the human data.

Discussion of the model

Formal modeling of a complex process constitutes a theoretical account to provide added value beyond a verbal description of the underlying mechanism. A verbal description of a dynamic process cannot capture the detail of the processing or the unfolding of events over time. Modeling enforces a specific, precise computational implementation of the theory, shedding light on both the sufficiency and necessity of its proposals. The ability of the models to solve TOL problems also demonstrates the

Relation to other theories of autism

The concreteness of the computational model facilitates the comparison between underconnectivity theory and predecessor approaches to autism, such as the theories of weak central coherence (Frith, 1989), impaired complex information processing (Minshew et al., 1997), enhanced perceptual functioning (Mottron et al., 2006), mindblindness (Baron-Cohen, 1995), impaired social processing and motivation (Dawson et al., 2002), and longer-distance cortical communication. All of these theories capture

Questions raised by the theory

Although the underconnectivity perspective provides a useful theoretical framework for investigating autism, the theory does not currently provide the answers to some remaining central questions about autism. We view the current form of the underconnectivity theory as preliminary, and anticipate that future research will result in considerable refinement, expansion, and modification. Below we raise some of the key questions that are currently framed by the theory but which have not yet been

Summary

Underconnectivity theory proposes that autism be characterized as a neural systems disorder marked by frontal-posterior connectivity abnormalities. Because of lowered bandwidth between frontal and posterior brain networks in autism, the flow of information between frontal and posterior areas is impaired, resulting in deficits in tasks that require substantial frontal contribution and in increased reliance on posterior regions. This increased dependence on more posterior regions could become

Acknowledgements

This research was supported by the Autism Centers of Excellence Grant HD055748 from the National Institute of Child Health and Human Development and the Office of Naval Research Grant N00014-07-1-0041.

References (148)

  • M.K. Chung et al.

    Less white matter concentration in autism: 2D voxel-based morphometry

    NeuroImage

    (2004)
  • R. Coben et al.

    EEG power and coherence in autistic spectrum disorder

    Clininical Neurophysiology

    (2008)
  • I.L. Cohen

    An artificial neural network analogue of learning in autism

    Biological Psychiatry

    (1994)
  • E. Courchesne et al.

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

    Current Opinion in Neurobiology

    (2005)
  • E. Courchesne et al.

    Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity

    International Journal of Developmental Neuroscience

    (2005)
  • G.K. Deutsch et al.

    Children's reading performance is correlated with white matter structure measured by diffusion tensor imaging

    Cortex

    (2005)
  • M. Dranias et al.

    Dopaminergic and non-dopaminergic value systems in conditioning and outcome-specific revaluation

    Brain Research

    (2008)
  • P.T. Fletcher et al.

    Microstructural connectivity of the arcuate fasciculus in adolescents with high-functioning autism

    NeuroImage

    (2010)
  • D.H. Geschwind et al.

    Autism spectrum disorders: developmental disconnection syndromes

    Current Opinion in Neurobiology

    (2007)
  • S. Grossberg

    The link between brain learning, attention, and consciousness

    Consciousness and Cognition

    (1999)
  • L. Gustafsson

    Inadequate cortical feature maps: a neural circuit theory of autism

    Biological Psychiatry

    (1997)
  • D.K. Hartline et al.

    Rapid conduction and the evolution of giant axons and myelinated fibers

    Current Biology

    (2007)
  • C. Hughes et al.

    Evidence for executive dysfunction in autism

    Neuropsychologia

    (1994)
  • P.R. Huttenlocher

    Morphometric study of human cerebral cortex development

    Neuropsychologia

    (1990)
  • T.B. Jones et al.

    Sources of group differences in functional connectivity: an investigation applied to autism spectrum disorder

    NeuroImage

    (2010)
  • J.H. Kaas

    Topographic maps are fundamental to sensory processing

    Brain Research Bulletin

    (1997)
  • R.K. Kana et al.

    Inhibitory control in high-functioning autism: decreased activation and underconnectivity in inhibition networks

    Biological Psychiatry

    (2007)
  • T.A. Keller et al.

    Altering cortical connectivity: remediation-induced changes in the white matter of poor readers

    Neuron

    (2009)
  • D.P. Kennedy et al.

    The intrinsic functional organization of the brain is altered in autism

    NeuroImage

    (2008)
  • T.A. Knaus et al.

    Language laterality in autism spectrum disorder and typical controls: a functional, volumetric, and diffusion tensor MRI study

    Brain and Language

    (2010)
  • H. Koshino et al.

    Functional connectivity in an fMRI working memory task in high-functioning autism

    NeuroImage

    (2005)
  • J.E. Lee et al.

    Diffusion tensor imaging of white matter in the superior temporal gyrus and temporal stem in autism

    Neuroscience Letters

    (2007)
  • J.L. Marin-Teva et al.

    Microglia promote the death of developing Purkinje cells

    Neuron

    (2004)
  • R.A. Mason et al.

    Theory of Mind disruption and recruitment of the right hemisphere during narrative comprehension in autism

    Neuropsychologia

    (2008)
  • J.R. Anderson et al.

    An integrated theory of the mind

    Psychological Review

    (2004)
  • Asperger, H., 1944. Autistic Psychopathy in Childhood. Translated in Autism and Asperger'sSyndrome, Frith, U., 1991....
  • Aylward, E.H., Minshew, N.J., Field, K., Sparks, B.F., Singh, N., 2002. Effects of age on brain volume and head...
  • A. Bailey et al.

    A clinicopathological study of autism

    Brain

    (1998)
  • S. Baron-Cohen

    Are autistic children ‘behaviorists’?

    Journal of Autism and Developmental Disorders

    (1989)
  • S. Baron-Cohen

    Mindblindness: An Essay on Autism and Theory of Mind

    (1995)
  • Baslow, M.H., 2003. N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochemical Research 28,...
  • M. Bauman et al.

    Histoanatomic observations of the brain in early infantile autism

    Neurology

    (1985)
  • Belmonte, M.K., Allen, G., Beckel-Mitchener, A., Boulanger, L.M., Carper, R.A., Webb, S.J., 2004. Autism and abnormal...
  • J. Boucher et al.

    Unfamiliar face recognition in relatively able autistic children

    Journal of Child Psychology and Psychiatry and Allied Disciplines

    (1992)
  • G.M. Boynton et al.

    Linear systems analysis of functional magnetic resonance imaging in human V1

    The Journal of Neuroscience

    (1996)
  • J. Brock et al.

    The temporal binding deficit hypothesis of autism

    Developmental Psychopathology

    (2002)
  • M.L. Carlsson

    Hypothesis: Is infantile autism a hypoglutamatergic disorder? Relevance of glutamate–serotonin interactions for pharmacotherapy

    Journal of Neural Transmission

    (1998)
  • Casanova, M.F., van Kooten, I.A., Switala, A.E., van Engeland, H., Heinsen, H., Steinbusch, H.W., Hof, P.R., Trippe,...
  • F. Castelli et al.

    Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes

    Brain

    (2002)
  • J.-P. Changeux et al.

    Selective stabilization of developing synapses as a mechanism for the specification of neuronal networks

    Nature

    (1976)
  • Cited by (418)

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