Matthew K. Belmonte

Autism and Abnormal Development of Brain Connectivity

It has been said that people with autism suffer from a lack of “central coherence,” the cognitive ability to bind together a jumble of separate features into a single, coherent object or concept ([Frith, 1989][1]). Ironically, the same can be said of the field of autism research, which all too

Autism as a disorder of neural information processing: Directions for research and targets for therapy.

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.

Fragile X syndrome and autism at the intersection of genetic and neural networks.

Autism, an entirely behavioral diagnosis with no largely understood etiologies and no population-wide biomarkers, contrasts with fragile X syndrome (FXS), a single-gene disorder with definite alterations of gene expression and neuronal morphology. Nevertheless, the behavioral overlap between autism and FXS suggests some overlapping mechanisms. Understanding how the single-gene alteration in FXS plays out within complex genetic and neural network processes may suggest targets for autism research and illustrate strategies for relating autism to more singular genetic syndromes.

Functional anatomy of impaired selective attention and compensatory processing in autism

In autism, physiological indices of selective attention have been shown to be abnormal even in situations where behaviour is intact. This divergence between behaviour and physiology suggests the action of some compensatory process of attention, one which may hold clues to the aetiology of autisms characteristic cognitive phenotype. Six subjects with autism spectrum disorders and six normal control subjects were studied with functional magnetic resonance imaging while performing a bilateral visual spatial attention task. In normal subjects, the task evoked activation in a network of cortical regions including the superior parietal lobe (P<0.001), left middle temporal gyrus (P=0.002), left inferior (P<0.001) and middle (P<0.02) frontal gyri, and medial frontal gyrus (P<0.02). Autistic subjects, in contrast, showed activation in the bilateral ventral occipital cortex (P<0.03) and striate cortex (P<0.05). Within the task condition, a region-of-interest comparison of attend-left versus attend-right conditions indicated that modulation of activation in the autistic brain as a function of the lateral focus of spatial attention was abnormally decreased in the left ventral occipital cortex (P<0.03), abnormally increased in the left intraparietal sulcus (P<0.01), and abnormally variable in the superior parietal lobe (P<0.03). These results are discussed in terms of a model of autism in which a pervasive defect of neural and synaptic development produces over-connected neural systems prone to noise and crosstalk, resulting in hyper-arousal and reduced selectivity. These low-level attentional traits may be the developmental basis for higher-order cognitive styles such as weak central coherence.

Visual attention in autism families: ‘unaffected’ sibs share atypical frontal activation

BACKGROUND In addition to their more clinically evident abnormalities of social cognition, people with autism spectrum conditions (ASC) manifest perturbations of attention and sensory perception which may offer insights into the underlying neural abnormalities. Similar autistic traits in ASC relatives without a diagnosis suggest a continuity between clinically affected and unaffected family members. METHODS We applied fMRI in the context of a non-social task of visual attention in order to determine whether this continuity persists at the level of brain physiology. RESULTS Both boys with ASC and clinically unaffected brothers of people with ASC were impaired at a visual divided-attention task demanding conjunction of attributes from rapidly and simultaneously presented, spatially disjoint stimuli and suppression of spatially intervening distractors. In addition, both groups in comparison to controls manifested atypical fronto-cerebellar activation as a function of distractor congruence, and the degree of this frontal atypicality correlated with psychometric measures of autistic traits in ASC and sibs. Despite these resemblances between the ASC and sib groups, an exploratory, hypothesis-generating analysis of correlations across brain regions revealed a decrease in overall functional correlation only in the ASC group and not in the sibs. CONCLUSIONS These results establish a neurophysiological correlate of familial susceptibility to ASC, and suggest that whilst abnormal time courses of frontal activation may reflect processes permissive of autistic brain development, abnormal patterns of functional correlation across a wider array of brain regions may relate more closely to autisms determinants.

Abnormal Attention in Autism Shown by Steady-State Visual Evoked Potentials

This study examined brain electrical responses as a physiological measure of speed and specificity of attentional shifting in eight adult males with autism. Subjects were required to shift attention between rapidly flashed targets alternating between left and right visual hemifields. When targets were separated by less than 700 ms, steady- state brain electrical response in both hemispheres was augmented and background EEG decreased for rightward shifts as compared with leftward shifts. At longer separations, persons with autism showed no modulation of background EEG, and high variability in steady-state response. These results contrast with those in normal controls, where in each hemisphere separately steady-state response increased and background EEG descreased for shifts directed contralaterally to that hemisphere. Group differences were significant at p < 0.04 for the steady-state response and p < 0.0001 for the background EEG. Lack of hemispherically independent modulation in autism may reflect the operation of a non-specific mechanism of sensory gating.

More than maths and mindreading: Sex differences in empathizing/systemizing covariance

Empathizing–Systemizing theory posits a continuum of cognitive traits extending from autism into normal cognitive variation. Covariance data on empathizing and systemizing traits have alternately suggested inversely dependent, independent, and sex‐dependent (one sex dependent, the other independent) structures. A total of 144 normal undergraduates (65 men, 79 women) completed the Reading the Mind in the Eyes, Embedded Figures, and Benton face recognition tests, the Autism Spectrum Quotient, and measures of digit length ratio and field of study; some also completed tests of motion coherence threshold (64) and go/no‐go motor inhibition (128). Empathizing and systemizing traits were independent in women, but largely dependent in men. In men, level of systemizing skill required by field of study was directly related to social interactive and mindreading deficits; mens social impairments correlated with prolonged go/no‐go response times, and men tended to apply systemizing strategies to solve problems of empathizing or global processing: rapid perceptual disembedding predicted heightened sensitivity to facial emotion. In women, level of systemizing in field was related to male‐typical digit ratios and autistic superiorities in detail orientation, but not to autistic social and communicative impairments; and perceptual disembedding was related to social interactive skills but independent of facial emotion and visual motion perception.

Permutation testing made practical for functional magnetic resonance image analysis

We describe an efficient algorithm for the step-down permutation test, applied to the analysis of functional magnetic resonance images. The algorithms time bound is nearly linear, making it feasible as an interactive tool. Results of the permutation test algorithm applied to data from a cognitive activation paradigm are compared with those of a standard parametric test corrected for multiple comparisons. The permutation test identifies more weakly activated voxels than the parametric test, always activates a superset of the voxels activated by this parametric method, almost always yields significance levels greater than or equal to those produced by the parametric method, and tends to enlarge activated clusters rather than adding isolated voxels. Our implementation of the permutation test is freely available as part of a widely distributed software package for analysis of functional brain images.

Shifts of visual spatial attention modulate a steady-state visual evoked potential

Although the effects of static allocations of visual spatial attention have been investigated using event-related potentials, most studies of shifts in visual spatial attention have been limited to behavioural measures. This study applied electroencephalographic measures to shifts in visual spatial attention in an effort to elucidate the time courses of such shifts. Using a custom-developed steady-state evoked potential analysis system, we analysed amplitude changes in EEG responses to rapid, periodic visual stimulation during a behavioural task that required rapid, repetitive shifts in visual spatial attention. Both stimulus-evoked oscillations (that is, those signals whose phases matched the phase of the steady-state stimulus) and ongoing, background (non-phase-locked) oscillations were measured. This analysis revealed a transient increase in phase-locked amplitude, in the interval 0-300-ms post-stimulus, contralateral to the visual hemifield in which an attended target appeared. The magnitude of this increase varied with the length of the interval since the previous shift. In addition, by about 600-ms post-stimulus, phase-locked amplitude increased in the hemisphere contralateral to the newly-attended visual hemifield and decreased in the ipsilateral hemisphere. In the case of long inter-target intervals, phase-locked amplitude increased in the right hemisphere regardless of the laterality of the target. Non-phase-locked amplitude exhibited a complementary pattern of modulation: it decreased contralaterally to the newly-attended visual hemifield and increased ipsilaterally. These components may be electrophysiological concomitants of both transient and long-lasting alterations in neural function that implement shifts in visual spatial attention. In particular, we suggest that they may reflect orienting to a target stimulus, and reorienting to a cued location.

Anatomic dissociation of selective and suppressive processes in visual attention

Visual spatial attention is associated with activation in parietal regions as well as with modulation of visual activity in ventral occipital cortex. Within the parietal lobe, localisation of activity has been hampered by variation in individual anatomy. Using fMRI within regions of interest derived from individual functional maps, we examined the response of superior parietal lobule, intraparietal sulcus, and ventral occipital cortex in 11 normal adults as attention was directed to the left and right visual hemifields during bilateral visual stimulation. Activation in ventral occipital cortex was augmented contralateral to the attended hemifield (P < 0.006), while intraparietal activation was augmented ipsilaterally (P < 0.009), and superior parietal lobule showed no modulation of activity as a function of attended hemifield. These findings suggest that spatial enhancement of relevant stimuli in ventral occipital cortex is complemented by an intraparietal response associated with suppression of, or preparation of a reflexive shift of attention toward, irrelevant stimuli. The spatial attention system in superior parietal cortex, in contrast, may be driven to equal degrees by currently attended stimuli and by stimuli that are potential targets of attention.