Cerebellar contributions to autism spectrum disorders

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Abstract

The pathophysiology of autism appears to encompass a number of different brain structures and systems. However, the most consistent site of neural abnormality in autism is the cerebellum. Postmortem investigations have reported a variety of anomalies, most notably a reduction in the number of Purkinje neurons. Additionally, structural neuroimaging studies have shown volumetric changes in the cerebellum, including decreases in gray matter and increases in white matter. Emerging evidence for cerebellar abnormality in autism was paralleled by a revolution in our understanding of normal cerebellar function and cerebellar connectivity, such that the importance of elucidating the contributions of the cerebellum to autism is now clear. In fact, recent brain-behavior correlation studies suggest that cerebellar abnormality may play a more central role in autism than previously thought. At present, it is crucial that we increase our understanding of cerebellar functioning in autism, and functional neuroimaging studies are just beginning to reveal the possible role(s) of cerebellar dysfunction in this disorder. In this review, evidence for cerebellar anatomic and functional abnormality in autism will be delineated. This will be followed by consideration of the implications of cerebellar abnormality in autism. Two major questions will be addressed: (1) how might dysfunction of the cerebellum impact the development of connectivity between the cerebellum and other brain systems, and (2) how might cerebellar dysfunction impact behavior and the symptoms of autism. The paper concludes with a discussion of how cerebellar abnormalities might inform our understanding of the etiology of autism spectrum disorders.

Introduction

A crucial step in determining the cause of autism is to understand its underlying neurobiology. Abnormalities in a variety of brain regions and systems have been proposed to contribute to the pathophysiology of this disorder (e.g., [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]), and there are data to support involvement of a number of these regions. However, this review will focus on one of the most consistent sites of neuroanatomic abnormality in autism – the cerebellum. Emerging evidence for cerebellar abnormality in autism has been paralleled by a revolution in our understanding of normal cerebellar function, such that the importance of elucidating the contributions of the cerebellum to autism is now clear. The purpose of this review is to delineate cerebellar findings in autism and discuss their implications for understanding the disorder.

Section snippets

Cerebellar anatomic abnormality in autism: postmortem evidence

In postmortem studies of the brains of individuals with autism, the cerebellum has been the most consistently observed site of pathology. The most frequently reported pathology in these studies is a reduction in the normal number of Purkinje neurons (Fig. 1), which has been reported in nearly every case in which the cerebellum was examined [10], [12], [13], [14], [15], [16], [17], [18]. The extent of Purkinje neuron reduction may vary from case to case, but one recent study showed an overall

Cerebellar abnormality in autism: when does it emerge?

Postmortem studies have provided some clues regarding the time during development when Purkinje cell reduction occurs. The absence of reactive gliosis in early reports [14], [15], [18] and the lack of empty basket cells, which normally ensheath the Purkinje neuron cell bodies [12], have provided perhaps the strongest evidence for an early developmental (i.e., prenatal) reduction of Purkinje neurons. This is also supported by the lack of neuronal loss in the inferior olive [14]. However, Bailey

Cerebellar anatomic abnormality in autism: in vivo evidence

The anatomic study of the cerebellum in vivo using magnetic resonance imaging (MRI) has provided a wealth of evidence for cerebellar abnormality in autism spectrum disorders. In very young individuals with autism (2–3 years of age), gray matter volumes in the whole cerebellum did not differ significantly from normal [37], but cerebellar white matter volumes were significantly and substantially (i.e., nearly 40%) increased [37]. Studies that did not separate gray and white matter also reported

Imaging cerebellar function in autism

Functional neuroimaging data on the cerebellum in individuals with autism are relatively limited, with few studies designed specifically to address cerebellar function. Early investigations using positron emission tomography (PET) to measure resting glucose metabolism showed no difference from normal in the cerebellar vermis and hemispheres [72], [73]. In contrast, serotonergic abnormalities in the cerebella of boys with autism were revealed using PET [74], and activation studies using the PET

The implications of cerebellar pathology in autism

When considering the implications of cerebellar pathology in a developmental disorder such as autism, it is necessary to consider two separate questions about cerebellar dysfunction: (1) how might dysfunction of the cerebellum in the context of a developing central nervous system impact connectivity between the cerebellum and other brain systems? and (2) how might cerebellar dysfunction impact behavior and the symptoms of autism?

The implications of cerebellar pathology for understanding the etiology of autism

The etiology of autism is unknown. Family and twin studies suggest a strong yet complex genetic component [155], and linkage and association studies have pointed to an extensive list of candidate genes [156]. The confluence of evidence for cerebellar abnormality in autism suggests that investigators attempting to determine the genetic basis of autism might consider genes that are involved in cerebellar development. Mouse studies have identified a number of such genes [157], one of which is

Conclusion

The cerebellum is one of the most common sites of anatomic abnormality in autism. In recent years, neurofunctional investigations have revealed a pattern of cerebellar dysfunction that is compatible with previously observed anatomic defects. Cerebellar pathology in the context of a developing brain may influence the behaviors and symptoms of autism via at least two paths. Through a direct route, the pathology will lead to cerebellar dysfunction, which, due to the cerebellar role in diverse

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