Imaging data in autism: From structure to malfunction

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During the last two decades, neuroimaging studies have improved our knowledge of brain development and contributed to our understanding of disorders involving the developing brain. Differences in cerebral anatomy have been determined in autism spectrum disorder (ASD). Morphological studies by magnetic resonance imaging have provided evidence of structural differences in ASD compared with the normal population. This has enhanced our view of autism as a neurobiological disorder corresponding with different stages and events in brain development. Alterations in volume of the total brain and specifically the cerebellum, frontal lobe, and limbic system have been identified. There appears to be a pattern of increased and then decreased rate of brain growth over time. We integrate these observations with neurobehavioral findings to provide a developmental hypothesis of the pathophysiology of autism.

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Nosology

Whether autism should be considered a single syndrome with highly variable severity (ie, ASD) or an aggregate of specific disorders that share common features is an unresolved issue. It is clear that autism is a syndrome with multiple etiologies. Recently, enormous advances in genetics, neuroimaging, and neurotransmitter studies have advanced our knowledge of the pathophysiology of autism, although much uncertainty remains. There is an effort to develop a validated typology related to

Total brain volume

Several studies have reported an increase in the overall size and weight of the brain in individuals with autism compared with age-matched controls.21, 22 Brain size in children with autism appears to be normal at birth.14, 23 This conclusion is based on measurements of head circumference with an index that has been shown to be highly predictive of computed tomography (CT)- and MRI-based brain volume.8 By age 2 to 4 years, however, 90% of autistic patients have larger than average brain

Developmental perspective: abnormal brain growth

Early brain development involves two overlapping processes: progressive events and regressive events. Progressive events include neurogenesis, axon guidance, and formation of synapses and neurotransmitter development.27 The vast majority of neurons are present in the prenatal period. In contrast, the growth of synapses, fiber bundles, and dendritic arborization largely occur during early postnatal development. Regressive events include apoptosis, axonal pruning, and synapse elimination.

White matter alterations

Enlarged brain volume has preferentially involved white matter.8, 26, 33 This may correlate with the clinical impression of impaired information processing in autism. Recent studies have addressed compartmentalized areas of white matter: radial, sagittal, and bridging.34 The radial compartment corresponds to the corona radiata and U-fibers. The sagittal compartment consists in ipsilateral association fibers, that is, projection fibers linking the cortex, amygdala, thalamus, basal ganglia, and

Cerebellum

Although the cerebellum has traditionally been associated with motor integration, neuropathologic studies demonstrating decreased Purkinge and granular cells have been followed by intense scrutiny of the cerebellum in imaging studies of autism.46 Furthermore, studies in animals and humans with cerebellar lesions have demonstrated behavioral and cognitive sequelae.47, 48, 49, 50 Converging evidence indicates that the cerebellum is implicated in the regulation of language, cognition, and emotion.

Cerebral cortex and the theory of mind

The frontal lobe and its connections with the limbic system have been implicated in the theory of mind; that is, the core deficit in autism being the inability to normally intuit what is on another person’s mind. Carper et al26 described regions of gray and white matter hyperplasia in 2- to 3-year-old boys with autism (as much as 20% enlargement), with an anteroposterior gradient emphasizing frontal lobe involvement. These differences were not found in the older age group of children with

Limbic system

A developmental defect has been hypothesized in the limbic system, given its mediation of memory, social, and affective functions. Neuropathologic studies have demonstrated small, compact neurons in the amygdala, hippocampus, entorhinal cortex, and mamillary body.10, 46, 51, 53 Raymond et al11 described in an autopsy study that cell bodies of the CA4 neurons in an 8-year-old autistic patient were smaller than those of an age-matched control. There was also decreased branching of the CA4 and CA1

Conclusion

Neuroimaging has provided rich supportive evidence that autism is a neurodevelopmental disorder. In general, there is an early increase in brain volume, preferentially affecting white matter, with later “normalization” in total size. Changes reported in size of cerebellar and limbic systems structures have been variable. From morphometric to functional MRI studies, there is clear evidence that brain dysfunction in autism is associated with abnormal patterns of development affecting whole brain

Acknowledgment

We thank Dr. Gilbert Vezina for his careful review of the manuscript.

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