Cerebellum In Autism Spectrum Disorders Research Articles

Neuroanatomy of autism: what is the role of the cerebellum?

Autism (or autism spectrum disorder) was initially defined as a psychiatric disorder, with the likely cause maternal behavior (the very destructive "refrigerator mother" theory). It took several decades for research into brain mechanisms to become established. Both neuropathological and imaging studies found differences in the cerebellum in autism spectrum disorder, the most widely documented being a decreased density of Purkinje cells in the cerebellar cortex. The popular interpretation of these results is that cerebellar neuropathology is a critical cause of autism spectrum disorder. We challenge that view by arguing that if fewer Purkinje cells are critical for autism spectrum disorder, then any condition that causes the loss of Purkinje cells should also cause autism spectrum disorder. We will review data on damage to the cerebellum from cerebellar lesions, tumors, and several syndromes (Joubert syndrome, Fragile X, and tuberous sclerosis). Collectively, these studies raise the question of whether the cerebellum really has a role in autism spectrum disorder. Autism spectrum disorder is now recognized as a genetically caused developmental disorder. A better understanding of the genes that underlie the differences in brain development that result in autism spectrum disorder is likely to show that these genes affect the development of the cerebellum in parallel with the development of the structures that do underlie autism spectrum disorder.

Functional connectivity of the sensorimotor cerebellum in autism: associations with sensory over-responsivity.

The cerebellum has been consistently shown to be atypical in autism spectrum disorder (ASD). However, despite its known role in sensorimotor function, there is limited research on its association with sensory over-responsivity (SOR), a common and impairing feature of ASD. Thus, this study sought to examine functional connectivity of the sensorimotor cerebellum in ASD compared to typically developing (TD) youth and investigate whether cerebellar connectivity is associated with SOR. Resting-state functional connectivity of the sensorimotor cerebellum was examined in 54 ASD and 43 TD youth aged 8-18 years. Using a seed-based approach, connectivity of each sensorimotor cerebellar region (defined as lobules I-IV, V-VI and VIIIA&B) with the whole brain was examined in ASD compared to TD youth, and correlated with parent-reported SOR severity. Across all participants, the sensorimotor cerebellum was functionally connected with sensorimotor and visual regions, though the three seed regions showed distinct connectivity with limbic and higher-order sensory regions. ASD youth showed differences in connectivity including atypical connectivity within the cerebellum and increased connectivity with hippocampus and thalamus compared to TD youth. More severe SOR was associated with stronger connectivity with cortical regions involved in sensory and motor processes and weaker connectivity with cognitive and socio-emotional regions, particularly prefrontal cortex. These results suggest that atypical cerebellum function in ASD may play a role in sensory challenges in autism.

Knockdown of the Non-canonical Wnt Gene Prickle2 Leads to Cerebellar Purkinje Cell Abnormalities While Cerebellar-Mediated Behaviors Remain Intact.

Autism spectrum disorders (ASD) involve brain wide abnormalities that contribute to a constellation of symptoms including behavioral inflexibility, cognitive dysfunction, learning impairments, altered social interactions, and perceptive time difficulties. Although a single genetic variation does not cause ASD, genetic variations such as one involving a non-canonical Wnt signaling gene, Prickle2, has been found in individuals with ASD. Previous work looking into phenotypes of Prickle2 knock-out (Prickle2-/-) and heterozygous mice (Prickle2-/+) suggest patterns of behavior similar to individuals with ASD including altered social interaction and behavioral inflexibility. Growing evidence implicates the cerebellum in ASD. As Prickle2 is expressed in the cerebellum, this animal model presents a unique opportunity to investigate the cerebellar contribution to autism-like phenotypes. Here, we explore cerebellar structural and physiological abnormalities in animals with Prickle2 knockdown using immunohistochemistry, whole-cell patch clamp electrophysiology, and several cerebellar-associated motor and timing tasks, including interval timing and eyeblink conditioning. Histologically, Prickle2-/- mice have significantly more empty spaces or gaps between Purkinje cells in the posterior lobules and a decreased propensity for Purkinje cells to fire action potentials. These structural cerebellar abnormalities did not impair cerebellar-associated behaviors as eyeblink conditioning and interval timing remained intact. Therefore, although Prickle-/- mice show classic phenotypes of ASD, they do not recapitulate the involvement of the adult cerebellum and may not represent the pathophysiological heterogeneity of the disorder.

Deficits in cerebellum-dependent learning and cerebellar morphology in male and female BTBR autism model mice.

Recently, there has been increased interest in the role of the cerebellum in autism spectrum disorders (ASD). To better understand the pathophysiological role of the cerebellum in ASD, it is necessary to have a variety of mouse models that have face validity for cerebellar disruption in humans. Here, we add to the literature on the cerebellum transgenic and induced mouse models of autism with the characterization of the cerebellum in the BTBR T+Itpr3tf/J (BTBR) inbred mouse strain, which has behavioral phenotypes that are suggestive of ASD in patients. When we examined both male and female BTBR mice in comparison to C57BL/6J (C57) controls, we noted that both sexes of BTBR mice showed motor coordination deficits characteristic of cerebellar dysfunction, but only the male mice showed differences in delay eyeblink conditioning, a cerebellum-dependent learning task that is also disrupted in ASD patients. Both male and female BTBR mice showed considerable expansion of and abnormal foliation in the cerebellum vermis--including significant expansion of specific lobules in the anterior cerebellum. In addition, we found a slight but significant decrease in Purkinje cell density in both male and female BTBR mice, irrespective of lobule. Furthermore, there was a marked reduction of Purkinje cell dendritic spines density in both male and female BTBR mice. These findings suggest that, for the most part, the BTBR mouse model successfully phenocopies many of the characteristics of the subpopulation of ASD patients that have a hypertrophic cerebellum. We discuss the significance of strain differences in the cerebellum as well as the importance of this first effort to identify both concordances and difference between male and female BTBR mice with regard to the cerebellum.

Diffusion Kurtosis Imaging of the Cerebellum in Autism Spectrum Disorder

Diffusion Kurtosis Imaging of the Cerebellum in Autism Spectrum Disorder

Sex Differences in Resting-State Functional Connectivity of the Cerebellum in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is more prevalent in males than females, but the underlying neurobiology of this sex bias remains unclear. Given its involvement in ASD, its role in sensorimotor, cognitive, and socio-affective processes, and its developmental sensitivity to sex hormones, the cerebellum is a candidate for understanding this sex difference. The current study used resting-state functional magnetic resonance imaging (fMRI) to investigate sex-dependent differences in cortico-cerebellar organization in ASD. We collected resting-state fMRI scans from 47 females (23 ASD, 24 controls) and 120 males (56 ASD, 65 controls). Using a measure of global functional connectivity (FC), we ran a linear mixed effects analysis to determine whether there was a sex-by-diagnosis interaction in resting-state FC. Subsequent seed-based analyses from the resulting clusters were run to clarify the global connectivity effects. Two clusters in the bilateral cerebellum exhibited a diagnosis-by-sex interaction in global connectivity. These cerebellar clusters further showed a pattern of interaction with regions in the cortex, including bilateral fusiform, middle occipital, middle frontal, and precentral gyri, cingulate cortex, and precuneus. Post hoc tests revealed a pattern of cortico-cerebellar hyperconnectivity in ASD females and a pattern of hypoconnectivity in ASD males. Furthermore, cortico-cerebellar FC in females more closely resembled that of control males than that of control females. These results shed light on the sex-specific pathophysiology of ASD and are indicative of potentially divergent neurodevelopmental trajectories for each sex. This sex-dependent, aberrant cerebellar connectivity in ASD might also underlie some of the motor and/or socio-affective difficulties experienced by members of this population, but the symptomatic correlate(s) of these brain findings remain unknown.Clinical Trial Registration: www.ClinicalTrials.gov, NIH Clinical Study Protocol 10-M-0027 (ZIA MH002920-09) identifier #NCT01031407

Reduced Cerebellar Volume in Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) affects 1 in 59 children in the U.S., and considerable efforts are being made to understand specific effects on the brain. The cerebellum has a complex role in cognition, behavior, language, and motor function, with these functions being affected in many individuals with ASD. Recent studies of the cerebellum in ASD have conflicting results, potentially based on variation in age, gender, and method of study. Importantly, boys are four times more likely to be identified with ASD than girls. The purpose of this study is to determine whether cerebellar volume in adolescent and young adult males with ASD differs from typically‐developing individuals.We obtained magnetic resonance images (MRI) from male subjects with ASD (N=19) and age‐matched, typically‐developing controls (N=12) recruited through the Thompson Center for Autism and Neurodevelopmental Disorders in Columbia, MO (mean age 15.3 years). We manually segmented whole cerebellar volume from the MRIs using Amira©. Measures of inter‐rater error showed differences of less than 2%. We then compared the two groups using ANCOVA, with age and whole brain volume as covariates. All data collection and recruitment protocols followed IRB approval.Total cerebellar volume is reduced in the males with ASD, by approximately 7% on average, with a strong trend toward statistical significance (p=0.071). These results lend support to the hypothesis that symptoms in some individuals with ASD may be due to cerebellar effects. Given the involvement of the cerebellum in motor coordination and cognitive aspects of language and other behaviors, it logically follows that these functions are affected in many individuals with ASD.Future work will address this hypothesis directly through assessment of the relationship between these structural measures and neurodevelopmental outcomes. Ultimately, our findings may be used as biomarkers for future risk‐factor analysis of co‐morbidities for those with an ASD diagnosis, allowing for early intervention and preventative care.Support or Funding InformationThis project was supported by funding from the IMSD EXPRESS program (NIH R25GM056901), the MU Department of Pathology & Anatomical Sciences, and the Autism Speaks Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hyperexcitability and Hyperplasticity Disrupt Cerebellar Signal Transfer in the IB2 KO Mouse Model of Autism.

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASDs has been suggested, but the underlying functional alterations remained obscure. We investigated single-neuron and microcircuit properties in IB2 (Islet Brain-2) KO mice of either sex. The IB2 gene (chr22q13.3 terminal region) deletion occurs in virtually all cases of Phelan-McDermid syndrome, causing autistic symptoms and a severe delay in motor skill acquisition. IB2 KO granule cells showed a larger NMDA receptor-mediated current and enhanced intrinsic excitability, raising the excitatory/inhibitory balance. Furthermore, the spatial organization of granular layer responses to mossy fibers shifted from a "Mexican hat" to a "stovepipe hat" profile, with stronger excitation in the core and weaker inhibition in the surround. Finally, the size and extension of long-term synaptic plasticity were remarkably increased. These results show for the first time that hyperexcitability and hyperplasticity disrupt signal transfer in the granular layer of IB2 KO mice, supporting cerebellar involvement in the pathogenesis of ASD.SIGNIFICANCE STATEMENT This article shows for the first time a complex set of alterations in the cerebellum granular layer of a mouse model [IB2 (Islet Brain-2) KO] of autism spectrum disorders. The IB2 KO in mice mimics the deletion of the corresponding gene in the Phelan-McDermid syndrome in humans. The changes reported here are centered on NMDA receptor hyperactivity, hyperplasticity, and hyperexcitability. These, in turn, increase the excitatory/inhibitory balance and alter the shape of center/surround structures that emerge in the granular layer in response to mossy fiber activity. These results support recent theories suggesting the involvement of cerebellum in autism spectrum disorders.

Alterations in white matter microstructure and regional volume are related to motor functions in boys with autism spectrum disorder

BackgroundAltered inter-regional structural connectivity related to higher cognitive functions has been commonly reported in individuals with autism spectrum disorder (ASD). However, whether these alterations similarly involve cortico-cerebellar motor circuitries remains largely elusive. MethodsUsing a cross-modality approach accounting for in-scanner motion levels, we investigated white matter (WM) properties in motor circuits of 55 boys with ASD (aged 8–18 years) and 68 age-matched typically developing boys. Regional WM volumes in the primary motor, supplementary motor, somatosensory, and cerebellar areas were investigated using voxel-based morphometry. Diffusion spectrum imaging tractography was used to estimate WM integrity of the corticospinal, cortico-ponto-cerebellar (including fronto-ponto-cerebellar and parieto-ponto-cerebellar), and dentato-rubro-thalamo-cortical tracts. The reaction time test in the Cambridge Neuropsychological Test Automated Battery was used to assess motor performances. ResultsBoys with ASD had shorter movement time, increased WM volumes in the left somatosensory area, but decreased generalized fractional anisotropy value in the left parieto-ponto-cerebellar tract, compared to controls. A positive correlation between movement time and microstructural properties of the left parieto-ponto-cerebellar tract was found in boys with ASD. ConclusionsAs the first study to demonstrate altered WM properties in the left somatosensory area, and its descending pathway connecting to the cerebellum in ASD, current results may highlight a potential new target of interventions for motor performance in ASD.

Lobular patterns of cerebellar resting-state connectivity in adults with Autism Spectrum Disorder.

Autism spectrum disorder is a neurodevelopmental disorder characterized by core deficits in social functioning. Core autistics traits refer to poor social and imagination skills, poor attention-switching/strong focus of attention, exceptional attention to detail, as expressed by the autism-spectrum quotient. Over the years, the importance of the cerebellum in the aetiology of autism spectrum disorder has been acknowledged. Neuroimaging studies have provided a strong support to this view, showing both structural and functional connectivity alterations to affect the cerebellum in autism spectrum disorder. According to the underconnectivity theory, disrupted connectivity within cerebello-cerebral networks has been specifically implicated in the aetiology of autism spectrum disorder. However, inconsistent results have been generated across studies. In this study, an integrated approach has been used in a selected population of adults with autism spectrum disorder to analyse both cerebellar morphometry and functional connectivity. In individuals with autism spectrum disorder, a decreased cerebellar grey matter volume affected the right Crus II, a region showing extensive connections with cerebral areas related to social functions. This grey matter reduction correlates with the degree of autistic traits as measured by autism-spectrum quotient. Interestingly, altered functional connectivity was found between the reduced cerebellar Crus II and contralateral cerebral regions, such as frontal and temporal areas. Overall, the present data suggest that adults with autism spectrum disorder present with specific cerebellar structural alterations that may affect functional connectivity within cerebello-cerebral modules relevant to social processing and account for core autistics traits.

A Proton Magnetic Resonance Spectroscopic Study in Autism Spectrum Disorder Using a 3-Tesla Clinical Magnetic Resonance Imaging (MRI) System: The Anterior Cingulate Cortex and the Left Cerebellum.

The pathophysiology of autism spectrum disorder (ASD) is not fully understood. We used proton magnetic resonance spectroscopy to investigate metabolite concentration ratios in the anterior cingulate cortex and left cerebellum in ASD. In the ACC and left cerebellum studies, the ASD group and intelligence quotient- and age-matched control group consisted of 112 and 114 subjects and 65 and 45 subjects, respectively. In the ASD group, γ-aminobutyric acid (GABA)+/ creatine/phosphocreatine (Cr) was significantly decreased in the anterior cingulate cortex, and glutamate (Glu)/Cr was significantly increased and GABA+/Cr was significantly decreased in the left cerebellum compared to those in the control group. In addition, both groups showed negative correlations between Glu/Cr and GABA+/Cr in the left cerebellum, and positive correlations between GABA+/Cr in the anterior cingulate cortex and left cerebellum. ASD subjects have hypoGABAergic alterations in the anterior cingulate cortex and hyperglutamatergic/hypoGABAergic alterations in the left cerebellum.

Saccadic eye movement abnormalities in autism spectrum disorder indicate dysfunctions in cerebellum and brainstem.

BackgroundIndividuals with autism spectrum disorder (ASD) show atypical scan paths during social interaction and when viewing faces, and recent evidence suggests that they also show abnormal saccadic eye movement dynamics and accuracy when viewing less complex and non-social stimuli. Eye movements are a uniquely promising target for studies of ASD as their spatial and temporal characteristics can be measured precisely and the brain circuits supporting them are well-defined. Control of saccade metrics is supported by discrete circuits within the cerebellum and brainstem - two brain regions implicated in magnetic resonance (MR) morphometry and histopathological studies of ASD. The functional integrity of these distinct brain systems can be examined by evaluating different parameters of visually-guided saccades.MethodsA total of 65 participants with ASD and 43 healthy controls, matched on age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to peripheral targets. To examine the influence of attentional processes, blocked gap and overlap trials were presented. We examined saccade latency, accuracy and dynamics, as well as the trial-to-trial variability of participants’ performance.ResultsSaccades of individuals with ASD were characterized by reduced accuracy, elevated variability in accuracy across trials, and reduced peak velocity and prolonged duration. In addition, their saccades took longer to accelerate to peak velocity, with no alteration in the duration of saccade deceleration. Gap/overlap effects on saccade latencies were similar across groups, suggesting that visual orienting and attention systems are relatively spared in ASD. Age-related changes did not differ across groups.ConclusionsDeficits precisely and consistently directing eye movements suggest impairment in the error-reducing function of the cerebellum in ASD. Atypical increases in the duration of movement acceleration combined with lower peak saccade velocities implicate pontine nuclei, specifically suggesting reduced excitatory activity in burst cells that drive saccades relative to inhibitory activity in omnipause cells that maintain stable fixation. Thus, our findings suggest that both cerebellar and brainstem abnormalities contribute to altered sensorimotor control in ASD.Electronic supplementary materialThe online version of this article (doi:10.1186/2040-2392-5-47) contains supplementary material, which is available to authorized users.

Distinct regions of the cerebellum show gray matter decreases in autism, ADHD, and developmental dyslexia.

Differences in cerebellar structure have been identified in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and developmental dyslexia. However, it is not clear if different cerebellar regions are involved in each disorder, and thus whether cerebellar anatomical differences reflect a generic developmental vulnerability or disorder-specific characteristics. To clarify this, we conducted an anatomic likelihood estimate (ALE) meta-analysis on voxel-based morphometry (VBM) studies which compared ASD (17 studies), ADHD (10 studies), and dyslexic (10 studies) participants with age-matched typically-developing (TD) controls. A second ALE analysis included studies in which the cerebellum was a region of interest (ROI). There were no regions of significantly increased gray matter (GM) in the cerebellum in ASD, ADHD, or dyslexia. Data from ASD studies revealed reduced GM in the inferior cerebellar vermis (lobule IX), left lobule VIIIB, and right Crus I. In ADHD, significantly decreased GM was found bilaterally in lobule IX, whereas participants with developmental dyslexia showed GM decreases in left lobule VI. There was no overlap between the cerebellar clusters identified in each disorder. We evaluated the functional significance of the regions revealed in both whole-brain and cerebellar ROI ALE analyses using Buckner and colleagues' 7-network functional connectivity map available in the SUIT cerebellar atlas. The cerebellar regions identified in ASD showed functional connectivity with frontoparietal, default mode, somatomotor, and limbic networks; in ADHD, the clusters were part of dorsal and ventral attention networks; and in dyslexia, the clusters involved ventral attention, frontoparietal, and default mode networks. The results suggest that different cerebellar regions are affected in ASD, ADHD, and dyslexia, and these cerebellar regions participate in functional networks that are consistent with the characteristic symptoms of each disorder.

The Cerebellum in Autism: Pathogenic or an Anatomical Beacon?

To The Editor: In the September 2012 issue of The Cerebellum, Fatemi et al. presented a comprehensive literature analysis of the putative role of the cerebellum in autism pathogenesis [1]. While this is an important work, which synthesizes the main findings of cerebellar research in autism spectrum disorders (ASD), we believe there is an alternative hypothesis to the role of the cerebellum in autism that is more parsimonious. The conclusion that the cerebellum is pathogenic in ASD is predicated on the notion that the cerebellum functions in the cognitive processes disrupted in autism, although such pathways remain undiscovered. While the cerebellar contribution to higher cognition has been debated for decades [2], a clear mechanistic understanding of how the cerebellum may integrate with processes affected in autism, such as theory of mind, is not well established—as Fatemi et al. noted. Human studies that have consistently implicated the cerebellum in ASD do so mostly on the basis of volumetric imaging studies, or postmortem histologic and molecular changes, including our own work [3]. However, as opposed to the notion that these changes are pathogenic—which would require an as yet undiscovered mechanism for the cerebellum in the higher cognitive functions affected in ASD—we propose instead that the unique anatomy, physiology, and development of the cerebellum may result in an exaggerated manifestation of the brain-wide pathologic changes that underlie autism, without being causal for the clinical phenotype. In this sense, then, the cerebellum in autism may be acting as an “anatomical beacon” of more subtle changes in other brain regions where the functional pathology actually rests. The unique anatomy, physiology, and development of the cerebellum make it a distinct part of the human brain. The cerebellum has the highest cell density of any brain area, approximately four times that of the neocortex [4, 5], and cerebellar Purkinje cells have more synapses than any other cell type by orders of magnitude [6]. As building synapses requires the appropriate molecular “toolkit,” the cerebellum's molecular complexity of transcripts [7, 8] and proteins [9, 10] rivals that of the cerebral cortex. Underlying the heightened synaptogenesis of the cerebellum is the need for energy to carry out this process, resulting in oxidative metabolic demand that is similar to the cerebral cortex as well [11]. The implications of these well-recognized cerebellar properties to autism are profound. The ASD phenotype is considered to ultimately result from synaptic dysfunction [12], which derives from underlying genetic changes that manifest in aberrant RNA and protein production [13, 14]. Additionally, autism has a strong and growing association with related problems in oxidative metabolism [15]. Is it possible that cerebellar pathology in ASD is more evident than other brain areas purely because the cerebellum contains more of the components that are disrupted in autism? If the molecular and cellular processes that are abnormal in ASD are dysfunctional throughout the brain, then these observations suggest that the cerebellum may have properties that result in an exaggerated manifestation of ASD pathology compared to other brain regions. Therefore, we hypothesize that the cerebellum may not be etiological in the pathogenesis of autism spectrum disorders; rather its unique anatomic and physiologic properties may accentuate the mechanisms that are aberrant throughout the autistic brain. Consequently, investigations into autism pathology may be more readily observed in the cerebellum because the changes are more obvious than the concomitant changes in other brain areas responsible for the clinical phenotype. This hypothesis does not diminish the potential importance of the cerebellum to autism research. Harnessing this unique property has serious implications in diagnostic testing, for example with neuroimaging. Diagnostic tests may be able to identify biological changes in ASD patients earlier in life, which is known to correlate with improved patient outcomes [16, 17], by focusing on the cerebellum. While cerebellar changes may not directly cause the cognitive deficits of ASD, they could serve as an “internal biomarker” for the more subtle alterations that must therefore be ongoing in other brain areas but would require more sensitive techniques to detect. Until it is understood how the cerebellum functions in the higher cognitive processes that are abnormal in autism, the field must consider the alternative hypothesis that changes found in the cerebellum of autistic patients are not pathogenic, but rather are collateral manifestations of the cellular and molecular deficits that are present throughout the autistic brain. The distinctive nature of the cerebellum may exaggerate changes that are more subtle in other brain areas, without being causal of the ASD phenotype. However, such an interpretation does not diminish the importance of cerebellar research in autism, as this unique characteristic may make the cerebellum an ideal diagnostic target.