Introduction

While autism has been recognized as a clinical disorder since 1943, only in the two past decades have we gained a significant understanding of the neurobiological underpinnings of the disorder. The cerebellum, in particular, is among those most consistently reported structures to be affected in autism; however, our understanding of how abnormalities in the cerebellum may contribute to the core and associated clinical symptoms of autism is only beginning to emerge. This chapter will provide an overview of cerebellar function and discuss possible contributions of cerebellar dysfunction to the clinical presentation of autism. In the Diagnostic and Statistical Manual (Fourth Edition-TR) (DSM-IV-TR) (American Psychiatric Association 2000), Autistic Disorder (autism), Asperger’s Disorder (AD), and Pervasive Developmental Disorder Not Otherwise Specified are classified as discrete disorders under the category of Pervasive Developmental Disorders. The pervasive developmental disorders are often referred to as autism spectrum disorders (ASD). AD is differentially diagnosed from autism by the absence of delayed language acquisition or intellectual disability. Although a single autism spectrum disorder category has been proposed for the DSM-V, a valuable body of research now exists that has investigated these PDD subtypes separately, with particular reference to differential involvement of the cerebellum in autistic disorder versus Asperger’s disorder. To illustrate the possible influence of the cerebellum on the characteristic features associated with autism, comparisons between individuals with high-functioning autism (classic autism with language delay but IQ > 80) and those with AD will be used.

Overview of the Cerebellum

The cerebellum is located in the hindbrain, tucked beneath the cerebral hemispheres. It consists of a tightly folded and crumpled layer of cortex (cerebellar cortex), with white matter underneath, and several deep nuclei embedded in the white matter. The cerebellum is divided into two hemispheres and a midline region known as the cerebellar vermis. The folding of the cerebellum is highly consistent, with folds conventionally used to anatomically divide the cerebellum into ten smaller lobules (Fig. 1). The laminar arrangement of neural circuitry across the cerebellar cortex is remarkably homogenous, implying that information processing is consistent across the cerebellum. As the cellular arrangement of cerebellar cortices are functionally analogous across the cerebellum, it is the distinct, parallel afferent and efferent projections of each of the lobules with higher cortical structures that give rise to the functional diversity of the cerebellum (Fig. 2). Rather than receiving afferents directly from the cerebral cortex, the cerebellum receives cortical input via pontine nuclei and inferior olive in the brainstem (Fig. 3). The outer cortex of the cerebellum consists of three layers: the molecular layer, Purkinje cell layer, and granular layer (Fig. 4). Fundamental to the function of the cerebellum are the Purkinje cells, the primary computational units which integrate information from approximately 150,000 to 200,000 synaptic inputs. Projections to the cerebellum ultimately converge on the Purkinje cells, which in turn project to the deep cerebellar nuclei. Three deep cerebellar structures, the fastigial, dentate, and interposed nuclei, have excitatory projections to the thalamus and can be conceived in simple terms as cerebellar output structures.

Fig. 1
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Schematic diagram of the flattened cerebellum illustrating the lobes, lobules, and deep cerebellar nuclei

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Fig. 2
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Overview of the parallel loops between the cerebellum and cerebral cortices, via the thalamus and brainstem, that control motor, language, and cognition

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Fig. 3
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Sagittal view of the brainstem and cerebellum, demonstrating input to the cerebellar cortical layers from the brainstem

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Fig. 4
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A portion of cerebellar cortical lobule, illustrating the microstructural organization of the cerebellum including input and output structures

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The inputs from motor and premotor areas to the cerebellum that subserve motor function and learning have been widely characterized. However the cerebellum also receives inputs from frontal, prefrontal, temporal, and posterior parietal cortices, via brainstem nuclei, which underpin a range of cognitive functions including working memory, visuospatial perception, attention, emotion, and language. Correspondingly, information from the deep cerebellar nuclei is sent back to these regions. The fastigial nucleus has been shown to modulate functions such as working memory and emotion regulation, while output of the dentate nucleus is split between cognitive and motor functions. The interposed nuclei are predominantly responsible for gait and posture control as well as other motor functions. It is this way that higher-order brain structures and the cerebellum form reciprocal, anatomic loops (Middleton and Strick 1998, 2000). Output from the right cerebellar hemisphere projects to the left cerebral hemisphere, while output of the left cerebellar hemisphere projects to the right cerebral hemisphere, crossing over at the thalamus and brainstem.

For over a century our understanding of the cerebellum has focussed predominantly on motor learning and control, with classic clinical descriptions of cerebellar damage including ataxic gait, tremor, and abnormal eye movements. However, only recently has there been an appreciation of cerebellar contributions to higher-order processes, such as executive function, socialization, and language development. Following the observation that the cerebellum made projections to the prefrontal cortex, an area classically associated with decision making and higher-order thought, Leiner et al. (1986) proposed that the cerebellum may also play a role in cognition and reasoning. It was suggested that the cerebellum may contribute to refining cognitive skills in an analogous way to how the cerebellum contributes to motor dexterity and motor learning (Leiner et al. 1986). The broader clinical implications of cerebellar lesions were demonstrated in the seminal work of Schmahmann and Sherman (1998) who characterized “cerebellar cognitive affective syndrome” in 20 patients with localized cerebellar regions. They described deficits that included multiple impairments across language, executive functions, mood, affect, and visuospatial abilities. Further clinical evidence for cerebellar contributions to cognition and language arose from children who had undergone surgical removal of cerebellar tumors. It was found that left cerebellar lesions caused spatial deficits, while lesions in the right cerebellar hemisphere resulted in verbal dysfluency and mutism (Levisohn et al. 2000; Riva and Giorgi 2000); spatial and linguistic functions are classically attributed to the right and left cerebral hemispheres, respectively. The range of cognitive functions reported to be affected as a consequence of cerebellar lesions includes planning and sequencing, visuospatial performance, expressive language, verbal memory, emotion regulation, and modulation of affect (Gerschcovich et al. 2011; Gottwald et al. 2004; Levisohn et al. 2000; Riva and Giorgi 2000; Schmahmann and Sherman 1998; Tavano et al. 2007).

To gether these clinical findings have reinforced the importance of the cerebellum in the reciprocal neural loops that subserve motor, linguistic, and cognitive functions. However, the precise contributions of the cerebellum to motor, linguistic, and cognitive processes and mechanisms underpinning this modulation are the source of ongoing debate. Current models encompass a complementary role of the cerebellum in both online error monitoring and developing and enhancing internal models of motor and cognitive tasks based on prior experience. Error is evaluated by comparing the difference between expected and actual outcomes. For example, if performing a motor task such as throwing a ball: did the ball hit the target? Or in working memory-related functions such as writing, is the order of letters and words correct (Ito 2008)? The concept of “internal models,” which evolved from models of cerebellar motor learning, suggests that the cerebellum creates and stores a model of how an action is performed, thereby reducing dependence on feedback in order to precisely perform an action (Ito 2008). The cerebellum is proposed to form representations of internal (relating to the body) and external (our environment and objects within it) performances, with feedback from trial-by-trial errors leading to optimization of these models, thereby improving performance over time. This model of adaptive learning is now proposed to extend to cognitive functions, based in part on neuroimaging studies that have shown coupling of prefrontal and cerebellar regions during cognitive tasks (Stoodley and Schmahmann 2009; Stoodley et al. 2012). Extension of internal models to non-motor tasks may help address how we draw on prior experience to rehearse future events and predict outcomes, such as social interactions or playing a game of chess (Szpunar et al. 2007).

Neuroanatomical Investigations of the Cerebellum in Autism and AD

Autistic Disorder

The work of Eric Courchesne and colleagues since the late 1980s was the first to implicate the cerebellum in the core symptoms of autism (Allen and Courchesne 2003; Courchesne 1997; Courchesne et al. 1994b, 1988). Cerebellar abnormalities in individuals with autism were first reported by Courchesne et al. (1988), and since then approximately 90 % of postmortem examinations have revealed cerebellar pathology in individuals with autism (Allen and Courchesne 2003). Numerous neurohistological examinations have identified multiple organizational and morphological abnormalities at the cellular level of the cerebellum. Purkinje cells have been found to be fewer in number, smaller in size, and less density packed (Bauman and Kemper 1985, 1996; Ritvo et al. 1986; Fatemi et al. 2002; Lee et al. 2002). Cells of the inferior olive, one of the two major input structures of the cerebellum which provide the climbing fibers to Purkinje cells (Fig. 2), have been shown to be small in size but comparable in number to control groups (Bauman and Kemper 1985). The Bergman glia, which guide neuronal migration during development and later insulate, maintain, and regulate Purkinje cell structure and function (Yamada and Watanabe 2002), have also been reported to be greater in number (Bailey et al. 1998).

A range of neuroimaging studies have revealed more global morphologic and structural abnormalities in the cerebellum in autism. Anatomic investigation of the cerebellum using magnetic resonance imaging (MRI) has demonstrated different cerebellar growth trajectories in children with autism compared to typically developing children (Hashimoto et al. 1995; Herbert et al. 2003; Palmen et al. 2005; Sparks 2002). At ages 2–3, total cerebellar size is reportedly 39 % larger in autistic children compared to typically developing children; however, after this age, total cerebellar volume remains relatively largely unchanged (Courchesne et al. 2001). Enlarged total cerebellar volume appears to be consistent across all ages in prepubescent development (Courchesne et al. 2001). Not only is the total size of the cerebellum larger, but the rate of development is also more rapid in individuals with autism, with the most rapid development occurring during infancy. Both cerebellar size and rate of development do not normalize in autism until early adolescence (Hashimoto et al. 1995; Courchesne et al. 2001).

There has been considerable discussion within the literature over changes to the cerebellar vermis in autism (Stanfield et al. 2008), a region important for the coordination of ocular motor functions, verbal working memory, and coordinating speech (Stoodley and Schmahmann 2009). During the first 1–4 years of life, cerebellar vermian lobules I–V and VI–VII develop significantly more rapidly in children with autism compared to typically developing children, followed by “halted development” (Hashimoto et al. 1995; Courchesne 2004; Courchesne et al. 1994a, 1988; Levitt et al. 1999). Conversely, in older children, the cerebellar vermian lobules VI–VII and VIII–X are generally shown to be smaller in children with autism, although with considerable heterogeneity (Stanfield et al. 2008).

Asperger’s Disorder

There have been fewer investigations of cerebellar abnormalities in AD as much of the current research has focussed exclusively on autism or has used combined autism spectrum disorder groups. Of the handful of studies that have reported on neuroanatomic abnormalities in AD specifically, the overall profile suggests that, in contrast to autism, not only are there fewer cerebellar regions affected in AD (Yu et al. 2011), but the disturbance is less severe on both a morphological and neuroanatomical level (Bauman and Kemper 2005; Yu et al. 2011). Although there is consensus within the limited literature that the degree of cerebellar disruption is more limited than that observed in autism (Bauman 1991; Catani et al. 2008; Kwon et al. 2004; Yu et al. 2011), agreement on the extent of cellular abnormalities and regions of the cerebellum affected in AD is yet to be achieved.

In a preliminary study of AD, Bauman and Kemper (1996) found evidence of a minor reduction in the number of Purkinje cells in the cerebellar hemispheres but no cellular abnormalities of the deep cerebellar nuclei or the inferior olivary nucleus, unlike in HFA groups (Bauman and Kemper 1996). Unlike children with autism, cerebellar enlargement has not been observed in AD (McAlonan et al. 2002; Kwon et al. 2004). Limited autopsy data available on AD suggests only minor, localized differences (Bauman and Kemper 1996). While there is some evidence of structural changes, including reduced cerebellar volume (Hallahan et al. 2009), this has not been consistently demonstrated (McAlonan et al. 2002). McAlonan et al. (2002) found reduced grey matter in the cerebellum of AD subjects; however, the authors concluded that these cerebellar abnormalities may be secondary to abnormalities in fronto-striatal pathways (McAlonan et al. 2002). Of key interest is that a recent meta-analysis of neuroimaging studies comparing autism and AD found grey matter deficits occurred bilaterally in the autistic cerebellum, but only in the right cerebellar hemisphere in AD (Yu et al. 2011).

Although the vermian lobules VI and VII abnormalities are widely reported to be affected in autism, this region is not implicated in AD (Catani et al. 2008; Lincoln et al. 1998). In comparison across autism, AD, and control groups, cross-sectional areas of the cerebellar vermian lobules VI and VII were found to be significantly reduced in those with HFA, but there was no difference between AD and controls (Lincoln et al. 1998).

Functional Consequences of Cerebellar Impairment

Overall, the findings from neuroimaging studies indicate significant cerebellar changes in autism spectrum disorders, with significantly greater cerebellar pathology in autism compared to AD (Bauman and Kemper 2005; Fatemi et al. 2012; McAlonan et al. 2009; Yu et al. 2011). Functionally, these changes may give rise to impairments in integration of information entering the cerebellum. Furthermore, breakdown in connectivity resulting from disruption to output structures of the cerebellum may result in impaired feedback from the cerebellum to higher-order brain regions that subserve executive, social, and motor functions (Catani et al. 2008; Stoodley and Schmahmann 2009). The following section discusses how such neuropathological changes may contribute to the motor, cognitive, and behavioral features of autism spectrum disorders.

Some of the most compelling evidence for cerebellar contributions to the psychopathology in autism derives studies of children with congenital cerebellar malformations (Tavano et al. 2007) and in children with resected (surgically removed) cerebellar tumors (Riva and Giorgi 2000). Children who had vermian lesions demonstrated classic autistic symptoms, such as expressive and receptive language disturbance, flat facial affect, impaired attention and verbal memory, and avoidance of eye contact, and met DSM-IV criteria for autistic disorder (Riva and Giorgi 2000). Accordingly, functional magnetic resonance imaging (fMRI) studies have revealed differential patterns of activation in the cerebellum of individuals with autism compared to controls on both motor and non-motor tasks, suggesting a role for this region in their cognitive and motor presentation (Allen and Courchesne 2003; Allen et al. 2004; Mostofsky et al. 2009). While cerebellar deficits may be more pronounced in autism than AD, Rinehart and colleagues have subsequently proposed that fronto-striatal motor deficits may be common to both disorders (Nayate et al. 2005). This will be discussed here in terms of motor dysfunction, language, and cognition.

Motor Impairment

As the role of the cerebellum in motor control is more extensively delineated than its role in higher-order cognitive processes, studies of motor performance in autism and AD may provide a useful means by which to investigate functional impairment of cerebellar networks in this population. The types of motor impairment associated with autism and AD are more subtle than the motor symptoms classically associated with cerebellar damage, such as ataxia and tremor. Broader motor deficits are now becoming more widely recognized as a central feature of autism and AD (see Fournier et al. 2010 for a recent review) and may manifest as clumsiness, rigidity, abnormal posture and gait, stereotyped movement and tics, dystonia, hyperkinesias, and difficulty with motor planning and sequencing (Damasio and Maurer 1978; Fabbri-Destro et al. 2009; Fournier et al. 2010; Green et al. 2002; Leary and Hill 1996).

One of the defining characteristics of autism and Asperger’s disorder is the presence of repetitive and stereotyped motor behaviors. These types of behaviors have been found to arise from a range of conditions that are generally associated with the frontal cortex and basal ganglia. However, repetitive and stereotyped behaviors, including rocking, echolalia, and complex hand mannerisms that are typical in autism, have been reported following both congenital abnormalities (Tavano et al. 2007) and surgical removal of the inferior vermis (Riva and Giorgi 2000). Rates of repetitive and stereotyped behaviors have been found to be significantly negatively correlated with the size of cerebellar vermis lobules VI–VII (Pierce and Courchesne 2001). Supporting evidence from mouse models with reduced Purkinje cell numbers has also shown increased incidence of repetitive behaviors, such as strict adherence to spatial paths during exploration. It is likely that there is a breakdown of the functional loops that exist between the cerebellum and frontal lobes that control inhibition of behavioral responses (Schmahmann et al. 2007).

Broader motor abnormalities have been documented across all domains of movement, including posture and gait, upper limb movements, manual dexterity, and eye movements. Indeed, in the original descriptions of both autism (Kanner 1943) and Asperger’s disorder (Asperger 1944), there are records of abnormal posture, clumsiness, and difficulties with fine motor control. However, young people with HFA are found to be more impaired than those with AD on clinical tests of manual dexterity, ball skills, and static and dynamic balance (Ben-Itzchaka and Zachorb 2007). One of the consistent findings across these motor domains, indicative of cerebellar involvement in motor dysfunction, is greater variability of movement, which has been observed in kinematic studies of gait (Jansiewicz et al. 2006; Rinehart et al. 2006a, b; Vilensky et al. 1981), posture (Gepner and Mestre 2002), upper limb movements (Papadopoulos et al. 2011), and ocular motor function (Stanley-Cary et al. 2011; Takarae et al. 2004). While mean measures of motor performance in autism and AD appear comparable to controls, variability in movement end points is greater in individuals with autism and AD (Ben-Itzchaka and Zachorb 2007; Nayate et al. 2011; Takarae et al. 2004, 2008).

Cerebellar-like motor deficits have been observed in two studies of gait in children with autism: specifically, greater difficulty walking along a straight line and the coexistence of variable stride length and duration (Rinehart et al. 2006c, d). Interestingly, quantitative gait deficits observed in AD were intermediate relative to individuals with autism and control participants. Greater variability of movement end points has been observed in HFA but not in AD (Papadopoulos et al. 2011). Furthermore, upper body kinematics in autism and AD (Rinehart et al. 2006a) are similar to cerebellar patients who have difficulty modulating movement gain; those with HFA, but not AD, have been found to spend more time in the decelerative phase of movement in which the final adjustments to movement are made to ensure target acquisition. Structural imaging of the cerebellum in adults with AD has also revealed that there are significant impairments in the output structures of the cerebellum, but not input structures (Catani et al. 2008). This suggests that while cerebellar function is relatively intact, impaired feedback into the cerebello-cortico-thalamic network may underpin motor dysfunction in AD.

In the early phases of motor learning, cortical regions such as the visual and premotor cortices and the basal ganglia are engaged. With habituation and learning, there is a shift away from dependence on visual feedback and the cerebellum becomes more heavily engaged during later learning phases (Swett et al. 2010). Neuroimaging studies of motor learning in autism (Gidley-Larson et al. 2008; Mostofsky et al. 2009) suggest that cerebellar networks are underactivated during motor learning and during motor execution, but there is sustained activation of cortical regions in later motor learning phases. Impaired motor learning may result from an impaired ability to shift motor execution from cortical regions associated with active, effortful motor control to regions associated with automated and habitual motor control (Mostofsky et al. 2009).

Studies of ocular motor performance are particularly sensitive for identifying cerebellar dysfunction. The ocular motor network is well characterized, based on studies of congenital and acquired abnormalities, studies of nonhuman primates, and functional neuroimaging studies in humans. Similar to its role in movement control more generally, the cerebellum is essential to optimizing ocular motor learning and accuracy of eye movements over both short- and long-term time frames as well as stabilization of the eye while the head and body is in motion (vestibular-ocular reflex). Where the functional integrity of the cerebellum is compromised, characteristic abnormalities include alteration to the velocity profile of movement, greater trial-by-trial variability, and impaired adaptation of amplitude to changed visual demands. A number of ocular motor studies have now characterized such abnormalities in both saccadic and pursuit eye movements in autism suggesting functional disturbance of the cerebellum (Nowinski et al. 2005; Stanley-Cary et al. 2011; Takarae et al. 2004).

While both reflexive and voluntary eye movements appear normal at first glance in autism, with mean eye movement variables such as latency, accuracy, duration, and peak velocity, comparable to that of control participants, variability of eye movement metrics is greater in these individuals (Nowinski et al. 2005; Stanley-Cary et al. 2011; Takarae et al. 2004). Dysmetric eye movements (overshooting and undershooting) are generally associated with the pathology of the cerebellar vermis (Takagi et al. 1998). Recent findings by Johnson et al. (under review) examined the integrity of cerebellar-dependent ocular motor learning using a classical double-step saccade adaptation paradigm. In this task, the pause in visual processing that occurs as a saccade is being made is exploited; the visual target is displaced during the saccade, which creates a perceived visual error. With repeated trials, saccade amplitude reduces over time to correct for the error. It was found that children with autism, but not Asperger’s disorder, were slower to adapt the amplitude and velocity profile of their saccades. Although there is no supporting evidence from neuroimaging techniques as yet that these deficits are solely attributable to cerebellar changes, these are indicative of dysfunction across the cerebello-cortico-thalamic network that regulates eye movements.

Language

Language impairment is often associated with impairment of frontal or temporal lobe damages; however, more recently, lesions of the cerebellum have also been found to result in linguistic deficits. The cerebellar vermis and posterior cerebellum have been identified as the key language centers of the cerebellum, and there is lateralization of language processes in the cerebellum, consistent with their reciprocal counterparts in the frontal, temporal, and parietal cortices (Stoodley and Schmahmann 2009; Stoodley et al. 2012). The profile of right cerebellar language deficits manifests as “linguistic in coordination” such as reduced verbal fluency or agrammatism, inflection and intonation, grammatical use, phonological and semantic rules, and word generation (Gebhart et al. 2002; Riva and Giorgi 2000). By contrast, left cerebellar damage can result in difficulty forming word associations, generalizing language across contexts, as well as difficulties with articulation and motor control during speech (Stoodley and Schmahmann 2009; Stoodley et al. 2012).

Children with autism have delayed language development, defined by the absence of single words by age 24 months and lack of communicative phrases by 36 months (American Psychiatric Association 2000). Once language develops in a child with high-functioning autism, they often continue to have difficulty initiating and sustaining conversation and show impaired pragmatics and grammatical rules and communication (Howlin 2003). By contrast, children with AD do not experience language delays and may indeed have precocious language (Table 1). They also tend to have fewer problems with initiating conversation (Howlin 2003). Their language is often verbose and pedantic, and they show difficulty with modulating volume and intonation when expressing emotion, often described as having a flat or monotonous tone (Howlin 2003). While cerebellar contributions to language dysfunction in AD have not been investigated, findings comparing groups with specific language impairment to those with autism found language performance test scores were correlated with anterior vermis volume (Hodge et al. 2010). As early neuroanatomical findings suggest that the cerebellum is less severely affected in AD, this may in some way explain the diversity in language ability across autism and AD.

Table 1 Summary of diagnostic criteria relating to spoken language in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised
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The types of language deficits that are characteristic in ASDs (Spiers et al. 2011) are also common to other conditions that affect the cerebellar vermis, such as congenital vermian lobule abnormalities, fragile X, and specific language impairment (Hodge et al. 2010). These disorders may offer insight into language deficits in ASDs. For example, children who underwent surgical removal of posterior cerebellar tumors were found postsurgically to have language impairments, including lack of spontaneity in communicative language, despite preserved ability to fluently repeat complicated sentences, impaired verbal fluency, and reduced vocal intonation (Riva and Giorgi 2000). These language traits are similar to the language deficits seen in children with autism (Tables 1 and 2). It is conceivable based on preliminary investigations in autism and insight from other early childhood disorders of the cerebellum that those differences in language development and impairments between autism and AD (and perhaps even differences in verbal IQ profiles) may be related to the degree of cerebellar abnormality in these disorders. Future studies in this field should address the mechanisms by which the cerebellum modulates language and further, the relationship between the cerebellum, age of language development, and language impairments in autism spectrum disorders.

Table 2 Summary of diagnostic criteria relating to spoken language in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition
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Cognition

The contribution of the cerebellum to cognitive processes such as attention, working memory, planning, or Theory of Mind (ToM) is only now beginning to be understood in healthy adults. One of the core diagnostic symptoms of autism, but not Asperger’s disorder, is delay in cognitive development (American Psychiatric Association 2000). Approximately 75 % of individuals diagnosed with autism have cognitive impairment, with the degree of cognitive impairment significantly correlated with the severity of their autistic symptoms (Ben-Itzchaka and Zachorb 2007). Studies of cerebellar activity during cognitive tasks in individuals with autism and AD tasks are limited.

One of the core characteristics of autism and AD is lack of cognitive flexibility, which can be seen in symptoms such as repetitive and stereotyped behavior, insistence on sameness within the environment and perseveration. Together these difficulties reflect impairments in shifting attention. When investigating the relationship between the cerebellum and cognition in autism and AD, attention has been the most widely investigated cognitive function: A number of links have been established between cerebellar anatomic abnormalities and deficits in attention (Allen and Courchesne 2003; Allen et al. 2004; Courchesne et al. 1994b; Townsend et al. 1996, 2000). In an fMRI study of selective attention to visually presented stimuli, there was significantly decreased activation bilaterally across the posterior cerebellum in autism, whereas cerebellar activity increased with task complexity in controls (Allen and Courchesne 2003). Impairments in shifting attention in individuals with autism were also found to be correlated to the size of cerebellar vermis lobules VI–VII (Townsend et al. 2000), with attention shifting ability that is comparable to individuals who had cerebellar lesions (Courchesne et al. 1994b). There has been no study of the relationship between the cerebellum and attention monitoring in individuals with AD. Additionally, how the cerebellum modulates attentional processes is unknown (Ito 2008).

Random number generation tasks are also often used as a measure of executive functioning. In these tasks, participants are typically instructed to type a string of numbers on a keyboard, using the keys 1–9, in a randomized order, while avoiding repeated single numbers (e.g., 2,2,2), consecutive numbers (e.g., 4,5,6) or cycling strings of numbers (3,5,3,5). Therefore, the ability to generate random numbers requires inhibition of these prepotent responses, changing number retrieval plans and actively monitoring previous responses (Towse and Valentine 1997). Neuroimaging studies have revealed that random number generation is associated with significantly greater activation of the dentate nucleus and portions of both the right and left cerebellar hemispheres, coupled with activation in the prefrontal cortex (Daniels et al. 2003; Jahanshahi et al. 2000). While the prefrontal cortex is specialized for response selection and inhibition of inappropriate responses, it is proposed that the cerebellum may be associated with response monitoring, for example, monitoring recent key presses to avoid contravening the rules of randomness in this task (i.e., cycling, repeating single numbers) (Jahanshahi et al. 2000). In a comparison of random number generation in groups of children with high-functioning autism and AD, differential errors in random number generation emerged. While both groups of children were successfully able to generate random number patterns, children with autism were more likely to produce repeated single numbers, whereas those with AD showed more cycling of strings of numbers (Rinehart et al. 2006a). Therefore, while all participants understood the task rules, it appears that the neural loops that inhibit and monitor response errors during random number-generating tasks may be differentially impaired in these groups. While there is a considerable body of work in prefrontal deficits underpinning executive function, how cerebellar disruption may be involved in error monitoring and inhibition of prepotent responses is yet to be elucidated.

Impairments in ToM have been proposed as a framework by which to understand the social deficits seen in autism and AD (Happé et al. 1996). ToM is a metacognitive strategy that describes our ability to attribute mental states such as intentions, goals, and beliefs in ourselves and others. Like other higher-order cognitive strategies, ToM is controlled primarily by the prefrontal cortex, and neuroimaging studies have revealed impaired ToM performance associated with reduced prefrontal activation in individuals with AD (Happé et al. 1996). Yet there has been more recent reporting of significant activation of the cerebellum in healthy adults during ToM tasks (Gallagher et al. 2000), and ToM deficits have also been reported following lesions to the posterior cerebellum (Gerschcovich et al. 2011). Although ToM was not explicitly examined, severity of social impairment, as measured by the Autistic Diagnostic Interview, has also been negatively correlated with diffusion anisotropy in the fibers of the left superior cerebellar peduncle (Catani et al. 2008). There has been no neuroimaging study of Theory of Mind performance in autism to date. It has been proposed that impaired social interactions in children with autism may arise from an inability to generate internal models of others’ experiences, based on previous experiences of their own; consequently, the ability to predict the outcome of future social interactions is also impeded (Ito 2004).

Summary

Cerebellar pathology is one of the most consistent findings in autism and AD. Differences in language development trajectories and a range of motor and cognitive findings support the neuroanatomical evidence for greater cerebellar disruption in individuals with autism. Yet, the differences in language development trajectory also emphasize the importance of longitudinal investigations of cerebellar development and language catch up in these groups. The links presented here between cerebellar pathology and symptoms characteristic of ASDs are largely hypothetical extensions from work in congenital and acquired cerebellar lesions in children. Further work is required to fully characterize the neuroanatomical abnormalities, connectivity between the cerebellum and the cerebral cortex, and the functional impairment associated with cerebellar pathology in these individuals. Likewise, further work is required to investigate the complex relationship between cerebellar pathology and the presentation of social, linguistic, and motor symptoms seen across autism and AD. The recent understanding of the cerebellum as playing a complimentary role to the cerebral cortex in a broad range of cognitive and motor behaviors further emphasizes the need to conceptualize behavior in terms of functional circuits rather than discrete regions of control. Conceptualizing the neurobiological underpinnings of autism and AD in this way may help us to understand the heterogeneity of the presentation of core symptoms in autism and AD. This is necessary not only for a fuller and more complete understanding of autism and AD but also for developing appropriate therapeutic options for individuals with these disorders.

Key Terms

  • Agrammatism. An impaired ability to talk in a grammatically correct sequence.

  • Cerebellar cortex. The outermost layer of the cerebellum.

  • Cerebral cortex. The outermost layer of the largest part of the brain (the cerebrum). This structure can be divided into many smaller subregions, such as the prefrontal cortex, temporal cortex, and parietal cortex, which are responsible for cognition, memory, emotion, motor, and sensory processing.

  • Executive function. An umbrella term referring to a collection of higher-order cognitive processes that include inhibition and impulse control, attention, problem solving, planning, reasoning, task switching, and working memory.

  • Hindbrain. The area of the brain that collectively includes the cerebellum, brainstem, and upper part of the spinal cord.

  • Morphology. The study of form and structure of body parts.

  • Neurohistology. The study of microscopic anatomy of brain cells.

  • Ocular motor. The movement of our eyes.

  • Saccade. The rapid movements our eyes make from one target to another.

  • Theory of mind. Is a cognitive strategy that describes our ability to attribute mental states such as intentions, goals, and beliefs to ourselves and others.

  • Prepotent response. A response that is automatic, either by reflex or learned habit.

  • Working memory. The process by which we temporarily store and manipulate information in the mind. Information stored in working memory can be made available to other systems to integrate multiple pieces of information, for example, during planning or reasoning tasks.

Key Facts

  • The cerebellum is the most consistently reported site of neural abnormality in autism spectrum disorders.

  • Children who have lesions of the cerebellar vermis, one of the most commonly reported sites of abnormality in autism, often develop classic autistic symptoms.

  • Early neuroimaging evidence suggests children with Asperger’s disorder show fewer cerebellar abnormalities than those with autism.

  • Impaired motor function is a common feature of both autism and Asperger’s disorder and cerebellar abnormalities in these disorders may contribute to these deficits.

  • The cerebellum may modulate and refine cognitive and linguistic skills in a parallel manner to which it refines motor performance.

  • Differences in cerebellar abnormalities across autism and Asperger’s disorder may account for differences in language development trajectories.

Summary Points

  • The cerebellum is the most consistently reported site of neural abnormality in autism spectrum disorders.

  • Traditional understanding of the cerebellum has focussed on motor learning and control; however, recent evidence has implicated the cerebellum in cognitive and language functions.

  • It is understood that the cerebellum refines motor performance in primates. It is possible that the cerebellum also modulates and refines cognitive and linguistic skills in a parallel fashion.

  • Neuroanatomical abnormalities of the cerebellum appear less pronounced in Asperger’s disorder relative to autistic disorder with only minor reductions in Purkinje cell numbers but no abnormalities of the deep cerebellar structures.

  • Neurobehavioral evidence from motor function studies also suggests less pronounced cerebellar disruption in Asperger’s disorder relative to autism.

  • Differences in cerebellar abnormalities across autism and Asperger’s disorder may account for differences in language development trajectories.

  • Further investigation of the contribution of the cerebellum to cognitive processes such as executive function, socialization. and language in autism and Asperger’s disorder is warranted.