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Abstract

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 etiology 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 etiology of Autism Spectrum Disorder. However, inconsistent results have been generated across studies. In the present study an integrated approach has been used in a selected population of adults with Autism Spectrum Disorder to analyze 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.

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... The alterations include decreased number and size of Purkinje cells (Ritvo et al., 1986;Fatemi et al., 2002), hyper-or hypo-plasia of cerebellar vermis (Hashimoto et al., 1995;Courchesne et al., 2001), and abnormal size of the cerebellum (Hardan et al., 2001 Third, abnormal cerebellar development and function lead to the defects in not only motor behaviors but also cognitive and emotional tasks in ASD patients. For example, the reduction in cerebellar gray matter volume is correlated with poor social interaction abilities (D'Mello et al., 2015); the cerebellum is activated during motor and cognitive tasks (Allen and Courchesne, 2003;Allen et al., 2004); and cerebellar functional connectivity is altered during the resting-state in ASD patients (Khan et al., 2015;Olivito et al., 2016;Igelstro¨m et al., 2017;Olivito et al., 2017;Oldehinkel et al., 2019). We here extend the discussion on these issues with more recent studies on the connection between cerebellar dysfunction and ASD. ...
... This type of studies highlights that the cerebellum is a coprocessor or modulator of general information processing to impact broad functions through its connectivity with other brain regions (Ito, 2008;D'Angelo and Casali, 2013;Van Overwalle and Marie¨n, 2016). Clinical observations using functional MRI (fMRI) demonstrate abnormal and inconsistent changes in the cerebrocerebellar connectivity in ASD patients (Khan et al., 2015;Olivito et al., 2016Olivito et al., , 2017Igelstro¨m et al., 2017;Oldehinkel et al., 2019). The cerebellum is hyperconnected with sensorimotor cortex but hypoconnected with supramodal regions in ASD patients (Khan et al., 2015). ...
... Moreover, a hyperconnectivity is found between left dentate nucleus and supramodal regions of the cerebellum in ASD (Olivito et al., 2016). Finally, a study shows significant decrease in the volume of right Crus II and in the connectivity between right Crus II and frontal, temporal, and parietal regions in ASD patients (Olivito et al., 2017). From different aspects, these studies show the cerebrocerebellar connectivity that contributes to higher-order and supramodal functions in ASD patients (Khan et al., 2015;Olivito et al., 2016;Igelstro¨m et al., 2017;Olivito et al., 2017), and establish an altered cerebro-cerebellar connectivity in ASD. ...
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The cerebellum has long been conceptualized to control motor learning and motor coordination. However, increasing evidence suggests its roles in cognition and emotion behaviors. In particular, the cerebellum has been recognized as one of key brain regions affected in autism spectrum disorder (ASD). To better understand the contribution of the cerebellum in ASD pathogenesis, we here discuss recent behavioral, genetic, and molecular studies from the human and mouse models. In addition, we raise several questions that need to be investigated in future studies from the point view of cerebellar dysfunction, cerebro-cerebellar connectivity and ASD.
... In line with this theory, structural and functional alterations within cerebello-cortical networks that are involved in different aspects of social interactions have been described in patients affected by cerebellar damage [21,38,[77][78][79]. Further details are reported in the contribution on "Connectivity within the cerebello-cerebral mentalizing network and clinical implications" by Olivito et al. ...
... Impaired sequencing and prediction mechanisms are thought to affect social abilities in several neuropsychiatric and neurodevelopmental pathologies characterized by cerebello-cerebral dysfunctions [20,21,38,77,79]. Within this framework, to give a few examples, in schizophrenia, alterations in forward modeling are considered to be the cause of hallucinations because of the inability to distinguish between internal states and external events [80,81]. ...
... Interestingly, together with this clinical evidence of social impairment, increasingly more neuroimaging studies have shown structural and functional alterations in the regions of the "social cerebellum" and in the cerebello-cerebral mentalizing networks in neuropsychiatric populations [77,79,[189][190][191][192][193][194]. Indeed, in schizophrenia, evidence demonstrated microstructural disruption of cerebro-cerebellar pathways [195] and intracerebellar white matter [192]. ...
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The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social “mirroring”) which is very close to its original role in motor learning, as well as in social understanding of other individuals’ mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social “mentalizing”). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions.
... It includes both affective and cognitive components and implies the capacity to recognize emotions, intentions, and thoughts (state of mind) of another person in or out of a social context (Meltzoff & Moore, 1989).Anatomically, brain alterations have been described that involve frontal, temporal, and parietal areas (Abell et al., 1999;Carper et al., 2002;Hazlett et al., 2006;Minshew & Williams, 2007) as well as subcortical structures (Amaral et al., 2008;Cauda et al., 2011;Sparks et al., 2002). Recent studies have demonstrated cerebellar involvement in this condition since post-mortem studies have shown Purkinje cell loss in ASD individuals, and neuroimaging data have shown structural and functional cerebellar alterations in these individuals (Anteraper et al., 2020;Fatemi et al., 2012;Olivito et al., 2017Olivito et al., , 2018. Cerebellar abnormalities have emerged as biomarkers to discriminate individuals with ASD from typically developing individuals (Ecker et al., 2010). ...
... It has been shown that social mentalizing recruits closed-loop circuitry between the posterior cerebellar Crus II and the temporoparietal junction (TPJ) and medial prefrontal cortex, two key areas of the mentalizing network (Van Overwalle et al., 2020; Van Overwalle, Van de Steen, & Mariën, 2019). In addition, in lobules Crus I and II decreased gray matter (GM) has been found in ASD Olivito et al., 2018) correlating with the severity of social, communication, and repetitive behaviors on autism diagnostic scales . ...
... The Wechsler Adult Intelligence Scale-Revised (WAIS-R; Wechsler, 1981;Orsini & Laicardi, 1997) and the Raven progressive matrices test (Raven, 1949) were administered in the two studied cohorts and in the HP group to verify the presence of an average intellectual level. The Cerebellar Cognitive Affective Syndrome (CCAS) (Hoche et al., 2018) scale was not performed since the present study involved ASD individuals and CB individuals who were previously enrolled in other studies from our group (Clausi et al., 2019, b;Olivito et al., 2017Olivito et al., , 2018 that occurred when the CCAS scale was not yet available. The presence of autism traits was evaluated using the Autism Spectrum Quotient (Ruta et al., 2012). ...
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In recent years, structural and functional alterations in the cerebellum have been reported in autism spectrum disorder (ASD). Intriguingly, recent studies demonstrated that the social behavioral profile of individuals with cerebellar pathologies is characterized by a theory of mind (ToM) impairment, one of the main behavioral hallmarks of ASD. The aim of the present study was to compare ToM abilities and underlying cerebello-cortical structural patterns between ASD individuals and individuals with cerebellar atrophy to further specify the cerebellar role in mentalizing alterations in ASD. Twenty-one adults with ASD without language and intellectual impairments (based on DSM-5), 36 individuals affected by degenerative cerebellar damage (CB), and 67 healthy participants were enrolled in the study. ToM abilities were assessed using the reading the mind in the eyes test and the faux pas test. One-way ANCOVA was conducted to compare the performances between the two cohorts. Three-dimensional T1-weighted magnetic resonance scans were collected, and a voxel-based morphometry analysis was performed to characterize the brain structural alterations in the two cohorts. ASD and CB participants had comparable ToM performance with similar difficulties in both the tests. CB and ASD participants showed an overlapping pattern of gray matter (GM) reduction in a specific cerebellar portion (Crus-II). Our study provides the first direct comparison of ToM abilities between ASD and CB individuals, boosting the idea that specific cerebellar structural alterations impact the mentalizing process. The present findings open a new perspective for considering the cerebellum as a potential target for treatment implementation. The present work will critically advance current knowledge about the cerebellar role in ToM alterations of ASD, in particular, elucidating the presence of common cerebellar structural abnormalities in ASD and cerebellar individuals that may underlie specific mentalizing alterations. These findings may pave the way for alternative therapeutic indications, such as cerebellar neuromodulation, with a strong clinical impact. Lay Summary The present work will critically advance current knowledge about the cerebellar role in theory of mind alterations of autism spectrum disorder (ASD), in particular, elucidating the presence of common cerebellar structural abnormalities in ASD and cerebellar individuals that may underlie specific mentalizing alterations. These findings may pave the way for alternative therapeutic indications, such as cerebellar neuromodulation, with a strong clinical impact.
... A recent study with ASD adults analyzing anatomical and structural changes in the cerebellum [58] provided evidence for the social role of the cerebellum in ASD dysfunctions. The results showed decreased cerebellar grey matter volume in the right Crus II, a region showing extensive connections with cerebral areas related to social functions. ...
... This grey matter reduction was correlated with the degree of autistic traits as measured by the autism-spectrum quotient [59]. Interestingly, altered functional connectivity was found between the reduced cerebellar Crus II and contralateral cerebral regions, such as frontal and temporal areas [58]. These data suggested that adults with autism spectrum disorder suffer from specific cerebellar structural alterations that may affect functional connectivity within cerebello-cerebral modules relevant to social processing, and this may account for their autistic traits [58]. ...
... Interestingly, altered functional connectivity was found between the reduced cerebellar Crus II and contralateral cerebral regions, such as frontal and temporal areas [58]. These data suggested that adults with autism spectrum disorder suffer from specific cerebellar structural alterations that may affect functional connectivity within cerebello-cerebral modules relevant to social processing, and this may account for their autistic traits [58]. ...
... For instance, reduced cerebellar gray matter volumes in individuals with ASD have been shown to be correlated with poorer social interaction abilities and more severe stereotyped behaviors . Additionally, functional neuroimaging has revealed altered cerebellar activation during motor and cognitive tasks (Allen et al. 2004;Allen and Courchesne 2003), as well as altered cerebellar functional connectivity during resting-state (Igelström et al. 2017;Khan et al. 2015;Oldehinkel et al. 2019;Olivito et al. 2016Olivito et al. , 2017 in individuals with ASD. Thus, there is evidence of cerebellar abnormalities in ASD at the genetic, structural, and functional levels. ...
... Recently, several studies have directly investigated connectivity between the cerebellum and regions of the cortex in ASD using resting-state functional MRI (fMRI; Igelström et al. 2017;Khan et al. 2015;Oldehinkel et al. 2019;Olivito et al. 2016Olivito et al. , 2017. Specifically, Khan et al. (2015) divided the cortex into regions involved primarily in sensorimotor or supramodal (i.e., higher-order cognitive) functions and examined seed-to-voxel functional connectivity between regions of the cortex and the cerebellum among children and adolescents (8-17 years). ...
... Additionally, overconnectivity was observed between the left dentate nucleus and supramodal regions of the cerebellum in ASD (Olivito et al. 2016). Another study observed decreased grey matter volume of right Crus II in ASD and also found decreased connectivity in ASD between the right Crus II and frontal, temporal, and parietal regions (Olivito et al. 2017). Overall, the majority of studies have observed decreased connectivity in ASD between the cerebellum and cortical regions that contribute to higher-order, supramodal functions (e.g., TPJ, regions part of ToM/DMN networks, frontal regions) (Igelström et al. 2017;Khan et al. 2015;Olivito et al. 2016Olivito et al. , 2017. ...
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There is growing evidence of altered connectivity in autism spectrum disorders (ASD) between the cerebellum and cortex. Three intrinsic connectivity networks (ICNs) are especially important to cognitive processing in ASD: the default mode network (DMN), executive control network (ECN), and salience networks (SNs). The goal of this study was to compare resting-state functional connectivity between the cerebellum and the DMN, ECN, and SN in ASD and typically developing children (n = 74, ages 7–12 years). Children with ASD showed stronger connectivity between the ventral DMN and left cerebellar lobules I–IV. No meaningful relationships were observed between ICN-cerebellar functional connectivity and ASD symptoms. These results suggest that the cerebellum contributes to altered network connectivity in ASD.
... A popular theory is that injury to the cerebellum, either congenital or acquired via sex-dependent hormonal or environmental factors, interrupts closed-loop cerebellar-cortical circuits while the brain's functional architecture is still fragile. With compromised structural integrity, the cerebellum acts ''upstream'' (Wang et al., 2014) to reshape the brain's functional organization, and this ultimately leads to the ''downstream'' cortical and behavioral abnormalities seen in ASD (Olivito et al., 2018). Although studies are inconsistent with respect to directionality, there do appear to be sustained changes in cerebellar-cortical functional connectivity (FC) in ASD (Noonan et al., 2009;Khan et al., 2015;Olivito et al., 2018), but whether these changes manifest differently in ASD males and ASD females remains unknown. ...
... With compromised structural integrity, the cerebellum acts ''upstream'' (Wang et al., 2014) to reshape the brain's functional organization, and this ultimately leads to the ''downstream'' cortical and behavioral abnormalities seen in ASD (Olivito et al., 2018). Although studies are inconsistent with respect to directionality, there do appear to be sustained changes in cerebellar-cortical functional connectivity (FC) in ASD (Noonan et al., 2009;Khan et al., 2015;Olivito et al., 2018), but whether these changes manifest differently in ASD males and ASD females remains unknown. ...
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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, we ran a linear mixed effects analysis to determine whether there was a sex-by-diagnosis interaction in resting-state functional connectivity. 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 functional connectivity 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.
... Further evidence has been provided by RS-fMRI studies in subjects with autism spectrum disorders (ASD) [19][20][21][22], who typically experience social dysfunctions, showing altered FC within cerebello-cerebral mentalizing networks. Through these circuits, cerebellar dysfunction may affect key social brain regions and impact the social functioning. ...
... Disrupted cerebello-cerebral functional connectivity has been previously demonstrated in people with ASD [19][20][21], a group consistently reported to show cerebellar structural alterations [41][42][43][44][45]. These observations suggested that a dysfunction of cerebello-cerebral interaction could impact core ASD symptoms, including social and communication deficits and repetitive and stereotyped behaviours. ...
Article
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In recent years, increasing evidence of the cerebellar role in social cognition has emerged. The cerebellum has been shown to modulate cortical activity of social brain regions serving as a regulator of function-specific mentalizing and mirroring processes. In particular, a mentalizing area in the posterior cerebellum, specifically Crus II, is preferentially recruited for more complex and abstract forms of social processing, together with mentalizing cerebral areas including the dorsal medial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), and the precuneus. In the present study, the network-based statistics approach was used to assess functional connectivity (FC) differences within this mentalizing cerebello-cerebral network associated with a specific cerebellar damage. To this aim, patients affected by spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease specifically affecting regions of the cerebellar cortex, and age-matched healthy subjects have been enrolled. The dmPFC, left and right TPJ, the precuneus, and the cerebellar Crus II were used as regions of interest to construct the mentalizing network to be analyzed and evaluate pairwise functional relations between them. When compared with controls, SCA2 patients showed altered internodal connectivity between dmPFC, left (L-) and right (R-) TPJ, and right posterior cerebellar Crus II. The present results indicate that FC changes affect a function-specific mentalizing network in patients affected by cerebellar damage. In particular, they allow to better clarify functional alteration mechanisms driven by the cerebellar damage associated with SCA2 suggesting that selective cortico-cerebellar functional disconnections may underlie patients’ social impairment in domain-specific complex and abstract forms of social functioning.
... In this special issue, Freedman and Foxe and Bozzi et al. provide reviews of the pathophysiology of two comorbid symptoms that have been strongly associated with ASD, namely deficits in oculomotor plasticity and epilepsy (Bozzi et al., 2018;Freedman & Foxe, 2018). Oculomotor plasticity or saccadic eye movement adaptation is controlled in part by the cerebellum, a brain region often implicated in ASD [see (Olivito et al., 2018) in this volume (Hampson & Blatt, 2015) but also see (Traut et al., 2018)]. In their review, Freedman and Foxe explore the link between saccadic eye movement adaptation and ASD. ...
... The lack of consistency in neuroimaging findings regarding cerebellar pathology in ASD may well be related to the heterogeneity of this disorder, and they make the case that re-examining cerebellar pathology through the lens of eye movement deficits may help to clarify this situation and identify a sub-phenotype within ASD. In keeping with this theme of possible cerebellar dysfunction in ASD, Olivito et al. (2018) show decreased cerebellar grey matter in the right Crus II in a small cohort of adults with ASD, and in turn, show reduced functional connectivity between this region and multiple distributed cortical regions. It will be of significant interest in future work to determine whether eye movement deficits in ASD can be related directly to cerebellar structural and functional measures. ...
... In contrast, a recent large-scale analysis by Guell et al. (G2018;787 participants) reported about equal recruitment of Crus I and Crus II, but their analysis involved only social animations and no other mentalizing tasks, which seriously limits this finding. Moreover, as noted in the introduction, the high incidence of mentalizing in Crus II is consistent with recent fMRI studies focusing on the connectivity of the cerebellum with the cerebral cortex among healthy adults ( Van Overwalle et al., 2019c, 2020 or individuals with autism (Olivito et al., 2018), and the cerebellar network structure proposed by several authors . ...
... First, with respect to diagnosis, this offers tools to predict impairments in specific social mentalizing functions that might be too easily ignored, given the important motoric dysfunctions that are clinically very apparent (D 'Mello et al., 2015;Stoodley et al., 2017). To illustrate, a recent study with autistic adults, analyzing anatomical and structural changes in the cerebellum (Olivito et al., 2018), provided evidence for the mentalizing role of the cerebellum in ASD dysfunctions. The results showed decreased cerebellar grey matter volume in the right Crus II with peak voxel (MNI 29 −73 −43) centered very close to the present 'sequencing' ROIs, and this reduced volume was correlated with the degree of autistic traits. ...
Article
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This meta-analysis explores the role of the posterior cerebellum Crus I/II in social mentalizing. We identified over 200 fMRI studies via NeuroSynth that met our inclusion criteria and fell within bilateral Crus II areas related to "sequencing" during mentalizing (coordinates ±24 -76 -40; from earlier studies) and mere social "mentalizing" or self-related emotional cognition (coordinates ±26 -84 -34; from NeuroSynth), located in the cerebellar mentalizing network of Buckner et al. (2011). A large majority of these studies (74%) involved mentalizing or self-related emotional cognition. Other functions formed small minorities. This high incidence in Crus II compares very favorably against the lower base-rate for mentalizing and self-related emotions (around 35%) across the whole brain as revealed in NeuroSynth. In contrast, there was much less support for a similar role of Crus I (coordinates -40 -70 -40 from earlier "sequencing" studies) as only 35% of the studies were related to mentalizing or self-related emotions. The present findings show that a domain-specific social mentalizing functionality is supported in the cerebellar Crus II. This has important implications for theories of the social cerebellum focusing on sequencing of social actions, and for cerebellar neurostimulation treatments.
... Our behavior imaging correlation analysis suggested that the rsFC of the cerebellum was related to the emotional recognition ability in ALT individuals. For instance, fMRI studies showed that the posterior cerebellum (especially the Crus I/II) participates in emotional and social processing through the corticocerebellar connection to the pSTS [46,47]. Further, a TMS study found that excitatory stimulation of the left cerebellum reduced the accuracy of processing facial emotions [48]. ...
Article
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Individuals with autism-like traits (ALT) belong to a subclinical group with similar social deficits as autism spectrum disorders (ASD). Their main social deficits include atypical eye contact and difficulty in understanding facial expressions, both of which are associated with an abnormality of the right posterior superior temporal sulcus (rpSTS). It is still undetermined whether it is possible to improve the social function of ALT individuals through noninvasive neural modulation. To this end, we randomly assigned ALT individuals into the real (n=16) and sham (n=16) stimulation groups. All subjects received five consecutive days of intermittent theta burst stimulation (iTBS) on the rpSTS. Eye tracking data and functional magnetic resonance imaging (fMRI) data were acquired on the first and sixth days. The real group showed significant improvement in emotion recognition accuracy after iTBS, but the change was not significantly larger than that in the sham group. Resting-state functional connectivity (rsFC) between the rpSTS and the left cerebellum significantly decreased in the real group than the sham group after iTBS. At baseline, rsFC in the left cerebellum was negatively correlated with emotion recognition accuracy. Our findings indicated that iTBS of the rpSTS could improve emotion perception of ALT individuals by modulating associated neural networks. This stimulation protocol could be a vital therapeutic strategy for the treatment of ASD.
... Interestingly, fMRI studies on people with ASD have shown abnormal FC between regions of the DMN comprising the temporoparietal junction and the medial prefrontal cortex and posterior lobules of the cerebellum, such as Crus-I/II, involved in the mentalizing process (D'Mello and Stoodley, 2015;Olivito et al., 2018). Thus, we hypothesize that atypical interplay between these lobules and supra-modal cortices might impede explicit emotional processing when context complexity increases and that further social effort is required for the conscious attribution of emotions and intentions (Saxe and Powell, 2006). ...
... Numerous studies have suggested that autism spectrum disorders (ASDs) involve a disruption of cortical connectivity that results in a reduction of synchronized and coordinated brain activity between regions (Dinstein et al., 2011). This fundamental network change may underlie the behavioral symptomology seen in the disorder (Cherkassky et al., 2006;D'Mello and Stoodley, 2015;Just, 2004;Just et al., 2012;Olivito et al., 2018). Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) studies support this claim in a number of specific cognitive domains that include language comprehension (Gao et al., 2019;Just, 2004), visuospatial processing (Damarla et al., 2010), theory of mind abilities (Kana et al., 2009), working memory (Koshino et al., 2008(Koshino et al., , 2005, and the recognition of emotional faces (Mennella et al., 2017). ...
Article
Autism spectrum disorders (ASDs) involve alterations to cortical connectivity that manifest as reduced coordinated activity between cortical regions. The neurons of the cortical subplate are a major contributor to establishing thalamocortical, corticothalamic and corticocortical long-range connections and only a subset of this cell population survives into adulthood. Previous reports of an indistinct gray-white matter boundary in subjects with ASD suggest that the adjacent subplate may also show organizational abnormalities. Frozen human postmortem tissue samples from the parietal lobe (BA7) were used to evaluate white-matter neuron densities adjacent to layer VI with an antibody to NeuN. In addition, fixed postmortem tissue samples from frontal (BA9), parietal (BA7) and temporal lobe (BA21) locations, were stained with a Golgi-Kopsch procedure, and used to examine the morphology of these neuronal profiles. Relative to control cases, ASD subjects showed a large average density increase of NeuN-positive profiles of 44.7 percent. The morphologies of these neurons were consistent with subplate cells of the fusiform, polymorphic and pyramidal cell types. Lower ratios of fusiform to other cell types are found early in development and although adult ASD subjects showed consistently lower ratios, these differences were not significant. The increased number of retained subplate profiles, along with cell type ratios redolent of earlier developmental stages, suggests either an abnormal initial population or a partial failure of the apoptosis seen in neurotypical development. These results indicate abnormalities within a neuron population that plays multiple roles in the developing and mature cerebral cortex, including the establishment of long-range cortical connections.
... This observation is in contrast to a previous study reporting left, but not right, DN functional dysconnectivity in ASD (Olivito et al., 2017). However, a voxel-based morphometry analysis by the same research group revealed structural differences in the regional cerebellar gray matter volume (GMV), specifically in right Crus II (Olivito et al., 2018). More recently, Hanaie and colleagues (2018) have reported reduced RsFc of the right DN in ASD. ...
Article
Cerebellar abnormalities are commonly reported in autism spectrum disorder (ASD). Dentate nuclei (DN) is a key structure in the anatomical circuits linking the cerebellum to the extracerebellum. Previous resting-state functional connectivity (RsFc) analyses reported DN abnormalities in high-functioning ASD (HF-ASD). This study examined the RsFc of the DN in young adults with HF-ASD compared to healthy controls (HC) with the aim to expand upon previous findings of DN in a dataset using advanced imaging acquisition methods that optimize spatiotemporal resolution and statistical power. Additional seed-to-voxel analyses were carried out using motor and non-motor DN coordinates reported in previous studies as seeds. We report abnormal dentato-cerebral and dentato-cerebellar functional connectivity in ASD. Our results expand and in part replicate previous descriptions of DN RsFc abnormalities in this disorder, and reveal correlations between DN-cerebral RsFc and ASD symptom severity.
... Recent resting-state fMRI studies in ASD reveal altered functional connectivity between the dentate nucleus and the cerebral cortex [119] and decreased volume in right Crus II that correlates with the degree of autistic traits. Right Crus II is interconnected with contralateral frontal and temporal areas related to social cognition, and altered functional connectivity has been reported between the smaller Crus II and these cerebral areas [277]. In the Tsc1 (tuberous sclerosis) mouse model of ASD, neuromodulation of right Crus I (hemispheric extension of lobule VIIA) rescued social deficits, consistent with the suggestion that the dysfunction of cerebro-CB circuits underlies selected aspects of disrupted behavior in ASD [278]. ...
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Sporadically advocated over the last two centuries, a cerebellar role in cognition and affect has been rigorously established in the past few decades. In the clinical domain, such progress is epitomized by the “cerebellar cognitive affective syndrome” (“CCAS”) or “Schmahmann syndrome.” Introduced in the late 1990s, CCAS reflects a constellation of cerebellar-induced sequelae, comprising deficits in executive function, visuospatial cognition, emotion–affect, and language, over and above speech. The CCAS thus offers excellent grounds to investigate the functional topography of the cerebellum, and, ultimately, illustrate the precise mechanisms by which the cerebellum modulates cognition and affect. The primary objective of this task force paper is thus to stimulate further research in this area. After providing an up-to-date overview of the fundamental findings on cerebellar neurocognition, the paper substantiates the concept of CCAS with recent evidence from different scientific angles, promotes awareness of the CCAS as a clinical entity, and examines our current insight into the therapeutic options available. The paper finally identifies topics of divergence and outstanding questions for further research.
... Evidence suggests that crus II plays a particularly influential role in mentalizing processes [8]. Consistent with their roles in social cognition, crus I and II have been implicated in autism spectrum disorder [9][10][11][12]. ...
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Emerging evidence suggests that the cerebellum may contribute to variety of cognitive capacities, including social cognition. Nonverbal learning disability (NVLD) is characterized by visual-spatial and social impairment. Recent functional neuroimaging studies have shown that children with NVLD have altered cerebellar resting-state functional connectivity, which is associated with various symptom domains. However, little is known about cerebellar white matter microstructure in NVLD and whether it contributes to social deficits. Twenty-seven children (12 with NVLD, 15 typically developing (TD)) contributed useable diffusion tensor imaging data. Tract-based spatial statistics (TBSS) were used to quantify fractional anisotropy (FA) in the cerebellar peduncles. Parents completed the Child Behavior Checklist, providing a measure of social difficulty. Children with NVLD had greater fractional anisotropy in the left and right inferior cerebellar peduncle. Furthermore, right inferior cerebellar peduncle FA was associated with social impairment as measured by the Child Behavior Checklist Social Problems subscale. Finally, the association between NVLD diagnosis and greater social impairment was mediated by right inferior cerebellar peduncle FA. These findings provide additional evidence that the cerebellum contributes both to social cognition and to the pathophysiology of NVLD.
... The copyright holder for this preprint this version posted July 30, 2021. ; https://doi.org/10.1101/2021.07.27.21261165 doi: medRxiv preprint (Olivito et al., 2018) 0.01 0.08 8 x x 4. (Hong et al., 2017) 0.01 0.1 5 x x x 5. (Wang et al., 2017) 0.01 0.1 6 x x x x 6. (Shou et al., 2017) 0.01 0.08 8 x x x x 7. (Guo et al., 2016) 0.01 0.08 8 x x x x x 8. (Shen et al., 2016) 0.008 0.08 6 x x x x x 9. (Green et al., 2016) 0.01 0.1 5 x x x x 10. (Olivito et al., 2017) 0.01 0.08 8 x x 11. (Zhou et al., 2016) 0.01 0.08 8 x x x 12. (Rausch et al., 2016) 0.01 -6 ...
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Many studies investigate the alterations in resting state functional connectivity in autism. Most of these studies focus on different regions of the brain to find the connectivity differ- ences between autism spectrum disorder and typically developing populations. The present review quantitatively extracts this data from all the seed based studies on autism spectrum disorder and uses it to build, for the first time, an Autism Altered Functional Connectome (AAFC) which summarizes the alterations in functional connectivity consistently reported in the literature. The data extracted from all the studies matching the inclusion criteria are presented at one place in human as well as a machine-readable format for further interpretation and analysis. Systematically reviewing 41 publications on 2818 subjects comprising 1459 typically developing and 1359 subjects with autism spectrum disorder, a total of 932 altered functional connectivity links were employed to construct an AAFC. The AAL atlas mapping of these links resulted in 71 replicated links of which 49 were consistent, and 574 unreplicated links that were reported just once. Out of 49, 38 were replicated across different non overlapping datasets. Majority of the studies analyzed the functional connectivity of the Default Mode Network (DMN) and its regions. Two important DMN regions, namely precuneus and posterior cingulate cortex were reported to exhibit different connectivity profiles with former majorly underconnected and later majorly overconnected consistently reported across multiple studies. After mapping the AAFLs to an atlas of brain networks, poor integration within DMN regions, and poor segregation of DMN regions with extra-DMN regions was observed. Keywords: Connectome, Autism Spectrum Disorder, Brain, Magnetic Resonance Imaging
... Cerebellar contributions to autism spectrum disorder, posttraumatic stress disorder, and personality disorders reveal alterations in the cerebellum as part of the disruption/aberration in cerebrocerebellar circuits, and recent investigations demonstrate changes in morphology or connectivity in manifest or premanifest schizophrenia (Moberget et al. 2018) and in bipolar disorder (Shinn et al. 2017). Differences in cerebellar structure and function are among the most common neuroanatomical findings in autism (Bauman & Kemper 1985;Schmahmann 1994;Fatemi et al. 2012;Olivito et al. 2017bOlivito et al. , 2018Arnold Anteraper et al. 2018; for a review, see D 'Mello & Stoodley 2015), and evidence from animal models suggests that cerebellar disruption is sufficient to produce restricted/repetitive behaviors and autism-like impairments in social behavior (see, e.g., Tsai et al. 2012. ...
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... More importantly, we further suggest that the posterior cerebellum may play a central role in social dysfunctions observed in many clinical pathologies. Indeed, deficits in mentalizing at large, and in the posterior cerebellum in particular, may play a crucial role in the onset and maintenance of psychiatric disorders related to limited mentalizing and emotion recognition, such as autism spectrum disorder [12][13][14], depression [15,16], bipolar disorder [17], obsessive compulsive disorder [18][19][20][21], addiction [22][23][24][25], and schizophrenia [26][27][28][29][30]. ...
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... Future studies could optimize recovery timings further in the experimental protocol in order to analyze these novel concepts in greater detail. Given the emerging involvement of the cerebellum in several neurological and neuropsychiatric disorders, one could envisage the use of this simple protocol to assess mechanisms of cognitive alterations in pathologies such as Alzheimer's disease, Multiple Sclerosis and autism, just to name a few (Castellazzi et al., 2014;d'Ambrosio et al., 2017;Olivito et al., 2018). ...
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... In fact, of the 32 studies discussed which included neuroimaging results, 26 (81%) reported differences in the posterior cerebellar hemispheres.The preferential distribution of differences in the posterior cerebellar hemispheres is also very reminiscent of data obtained from individuals diagnosed with ASD. Most of the functional abnormalities described in the cerebella of these patients also preferentially involve the posterior cerebellar hemispheres(Riva et al., 2013; D'Mello et al., 2015;Olivito et al., 2018). It is also remarkable that similar to the frontal cortices, the posterior zone of the cerebellum is one of the areas to have evolved more recently from a phylogenetic point of view(Weaver, 2005). ...
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Differences in cerebellar structure, function, and connectivity are well documented in autism spectrum disorder, and developmental cerebellar damage significantly elevates the risk for an autism diagnosis. Here we discuss the evidence for specific regional cerebellar disruption in autism, with a broader consideration of the impact of these regional differences on the modulation of cerebro-cerebellar circuits supporting autism-relevant behaviors. Further, we consider whether cerebellar contributions to these networks could disrupt predictive processing in autism, leading to the range of behavioral and neural patterns that characterize this complex neurodevelopmental disorder. Finally, we propose that the cerebellum could offer a potential therapeutic target for modulating autism-relevant circuits and behaviors.
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The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD.
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This meta-analytic connectivity modeling (MACM) study explores the functional connectivity of the cerebellum with the cerebrum in social cognitive processes. In a recent meta-analysis, Van Overwalle, Baetens, Mariën, and Vandekerckhove () documented that the cerebellum is implicated in social processes of "body" reading (mirroring; e.g., understanding other persons' intentions from observing their movements) and "mind" reading (mentalizing, e.g., inferring other persons' beliefs, intentions or personality traits, reconstructing persons' past, future, or hypothetical events). In a recent functional connectivity study, Buckner et al. () offered a novel parcellation of cerebellar topography that substantially overlaps with the cerebellar meta-analytic findings of Van Overwalle et al. (). This overlap suggests that the involvement of the cerebellum in social reasoning depends on its functional connectivity with the cerebrum. To test this hypothesis, we explored the meta-analytic co-activations as indices of functional connectivity between the cerebellum and the cerebrum during social cognition. The MACM results confirm substantial and distinct connectivity with respect to the functions of (a) action understanding ("body" reading) and (b) mentalizing ("mind" reading). The consistent and strong connectivity findings of this analysis suggest that cerebellar activity during social judgments reflects distinct mirroring and mentalizing functionality, and that these cerebellar functions are connected with corresponding functional networks in the cerebrum. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
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Summary Ten able adults with autism or Asperger syndrome and 10 normal volunteers were PET scanned while watching animated sequences. The animations depicted two triangles moving about on a screen in three different conditions: moving randomly, moving in a goal-directed fashion (chasing, fighting), and moving interactively with implied intentions (coaxing, tricking). The last condition frequently elicited descriptions in terms of mental states that viewers attributed to the triangles (mentalizing). The autism group gave fewer and less accurate descriptions of these latter animations, but equally accurate descriptions of the other animations compared with controls. While viewing animations that elicited mentalizing, in contrast to randomly moving shapes, the normal group showed increased activation in a previously identified mentalizing network (medial prefrontal cortex, superior temporal sulcus at the temporoparietal junction and temporal poles). The autism group showed less activation than the normal group in all these regions. However, one additional region, extrastriate cortex, which was highly active when watching animations that elicited mentalizing, showed the same amount of increased activation in both groups. In the autism group this extrastriate region showed reduced functional connectivity with the superior temporal sulcus at the temporo-parietal junction, an area associated with the processing of biological motion as well as with mentalizing. This finding suggests a physiological cause for the mentalizing dysfunction in autism: a bottleneck in the interaction between higher order and lower order perceptual processes.
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The cerebellum plays important roles in sensori-motor and supramodal cognitive functions. Cellular, volumetric, and functional abnormalities of the cerebellum have been found in autism spectrum disorders (ASD), but no comprehensive investigation of cerebro-cerebellar connectivity in ASD is available. We used resting-state functional connectivity magnetic resonance imaging in 56 children and adolescents (28 subjects with ASD, 28 typically developing subjects) 8-17 years old. Partial and total correlation analyses were performed for unilateral regions of interest (ROIs), distinguished in two broad domains as sensori-motor (premotor/primary motor, somatosensory, superior temporal, and occipital) and supramodal (prefrontal, posterior parietal, and inferior and middle temporal). There were three main findings: 1) Total correlation analyses showed predominant cerebro-cerebellar functional overconnectivity in the ASD group; 2) partial correlation analyses that emphasized domain specificity (sensori-motor vs. supramodal) indicated a pattern of robustly increased connectivity in the ASD group (compared with the typically developing group) for sensori-motor ROIs but predominantly reduced connectivity for supramodal ROIs; and 3) this atypical pattern of connectivity was supported by significantly increased noncanonical connections (between sensori-motor cerebral and supramodal cerebellar ROIs and vice versa) in the ASD group. Our findings indicate that sensori-motor intrinsic functional connectivity is atypically increased in ASD, at the expense of connectivity supporting cerebellar participation in supramodal cognition. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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A recent meta-analysis explored the role of the cerebellum in social cognition and documented that this part of the brain is critically implicated in social cognition, especially in more abstract and complex forms of mentalizing. The authors found an overlap with clusters involved in sensorimotor (during mirror and self-judgment tasks) as well as in executive processes (across all tasks) documented in earlier nonsocial cerebellar meta-analyses, and hence interpreted their results in terms of a domain-general function of the cerebellum. However, these meta-analytic results might be interpreted in a different, complementary way. Indeed, the results reveal a striking overlap with the parcellation of cerebellar topography offered by a recent functional connectivity analysis. In particular, the majority of social cognitive activity in the cerebellum can also be explained as located within the boundaries of a default/mentalizing network of the cerebellum, with the exception of the involvement of primary and integrative somatomotor networks for self-related and mirror tasks, respectively. Given the substantial overlap, a novel interpretation of the meta-analytic findings is put forward suggesting that cerebellar activity during social judgments might reflect a more domain-specific mentalizing functionality in some areas of the cerebellum than assumed before.
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Neuroanatomical differences in the cerebellum are among the most consistent findings in autism spectrum disorder (ASD), but little is known about the relationship between cerebellar dysfunction and core ASD symptoms. The newly-emerging existence of cerebellar sensorimotor and cognitive subregions provides a new framework for interpreting the functional significance of cerebellar findings in ASD. Here we use two complementary analyses — whole-brain voxel-based morphometry (VBM) and the SUIT cerebellar atlas — to investigate cerebellar regional gray matter (GM) and volumetric lobular measurements in 35 children with ASD and 35 typically-developing (TD) children (mean age 10.4 ± 1.6 years; range 8-13 years). To examine the relationships between cerebellar structure and core ASD symptoms, correlations were calculated between scores on the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview (ADI) and the VBM and volumetric data. Both VBM and the SUIT analyses revealed reduced GM in ASD children in cerebellar lobule VII (Crus I/II). The degree of regional and lobular gray matter reductions in different cerebellar subregions correlated with the severity of symptoms in social interaction, communication, and repetitive behaviors. Structural differences and behavioral correlations converged on cerebellar Crus I/II, a region which shows structural and functional connectivity with fronto-parietal and default mode networks. These results emphasize the importance of the location within the cerebellum to the potential functional impact of structural differences in ASD, and suggest that GM differences in cerebellar right Crus I/II are associated with the core ASD profile.
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Objective The relationship between sex/gender differences and autism has attracted a variety of research ranging from clinical, neurobiological to etiological, stimulated by the male bias in autism prevalence. Findings are complex and do not always relate to each other in a straightforward manner. Distinct but interlinked questions on the relationship between sex/gender differences and autism remain under addressed. To better understand the implications from existing research and to help design future studies, we propose a four-level conceptual framework to clarify the embedded themes. Method We searched PubMed for publications before September 2014 using search terms “‘sex OR gender OR females’ AND autism.” 1,906 citations were screened for relevance, along with publications identified via additional literature reviews, resulting in 329 reports that were reviewed. Results Level 1 “Nosological and diagnostic challenges” concerns the question “How should autism be defined and diagnosed in males and females?” Level 2 “Sex/gender-independent and sex/gender-dependent characteristics” addresses the question “What are the similarities and differences between males and females with autism?” Level 3 “General models of etiology: liability and threshold” asks the question “How is the liability for developing autism linked to sex/gender?” Level 4 “Specific etiological-developmental mechanisms” focuses on the question “What etiological-developmental mechanisms of autism are implicated by sex/gender and/or sexual/gender differentiation?” Conclusions Using this conceptual framework, findings can be more clearly summarized, and the implications of the links between findings from different levels can become clearer. Based on this four-level framework, we suggest future research directions, methodology, and specific topics in sex/gender differences and autism.
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Differences in cerebellar structure have been identified in autism spectrum disorders (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 morphometric (VBM) studies which compared ASD (17 studies), ADHD (10 studies), and dyslexic (10 studies) participants with age-matched typically-developing controls. A second ALE analysis included studies in which the cerebellum was a region of interest (ROI). There were no regions of significantly increased grey 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.
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Converging theories and data suggest that atypical patterns of functional and structural connectivity are a hallmark neurobiological feature of autism. However, empirical studies of functional connectivity, or, the correlation of MRI signal between brain regions, have largely been conducted during task performance and/or focused on group differences within one network [e.g., the default mode network (DMN)]. This narrow focus on task-based connectivity and single network analyses precludes investigation of whole-brain intrinsic network organization in autism. To assess whole-brain network properties in adolescents with autism, we collected resting-state functional connectivity MRI (rs-fcMRI) data from neurotypical (NT) adolescents and adolescents with autism spectrum disorder (ASD). We used graph theory metrics on rs-fcMRI data with 34 regions of interest (i.e., nodes) that encompass four different functionally defined networks: cingulo-opercular, cerebellar, fronto-parietal, and DMN (Fair etal., 2009). Contrary to our hypotheses, network analyses revealed minimal differences between groups with one exception. Betweenness centrality, which indicates the degree to which a seed (or node) functions as a hub within and between networks, was greater for participants with autism for the right lateral parietal (RLatP) region of the DMN. Follow-up seed-based analyses demonstrated greater functional connectivity in ASD than NT groups between the RLatP seed and another region of the DMN, the anterior medial prefrontal cortex. Greater connectivity between these regions was related to lower ADOS (Autism Diagnostic Observation Schedule) scores (i.e., lower impairment) in autism. These findings do not support current theories of underconnectivity in autism, but, rather, underscore the need for future studies to systematically examine factors that can influence patterns of intrinsic connectivity such as autism severity, age, and head motion.
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Voxel-based morphometry (VBM) studies have reported abnormalities in brain regions involved in functions that are commonly impaired in autism spectrum disorders (ASD). However, little is known about brain structure anomalies in low-functioning (LF) young children with ASD. A VBM analysis was carried out to assess brain regions involved in ASD LF children, and a multiple regression analysis was used to examine the relationship between regional volume changes and autism symptom measures. Twenty-six LF ASD children (2-10 years) were compared with 21 controls. A VBM-Diffeomorphic Anatomical Registration analysis using Exponentiated Lie algebra (DARTEL) was used to evaluate gray matter (GM) and white matter alterations, covaried with Intelligence Quotient, age, and total brain volume. The resulting altered regions were correlated with Autism Diagnostic Interview (ADI)-Revised and Autism Diagnostic Observation Schedule (ADOS)-Generic scores. GM bilateral reduction was noted in the cerebellum (Crus II and vermis) and in the hippocampi in ASD group. GM reduction was also detected in the inferior and superior frontal gyri, in the occipital medial and superior gyri, and in the inferior temporal gyrus of the left cerebral hemisphere. In the right hemisphere, GM reduction was found in the post-central cortex and in the occipital inferior gyrus. Multiple regression analysis showed a correlation between alterations in GM volume in the cerebellum (Crus II and vermis) and ADI-communication and ADOS-total (communication and interaction) scores. These findings seem to confirm that the cerebellum is involved in integrating and regulating emotional and cognitive functions which are impaired in ASD.
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Two hypotheses of autism spectrum disorder (ASD) propose that this condition is characterized by deficits in Theory of Mind and by hypoconnectivity between remote cortical regions with hyperconnectivity locally. The default mode network (DMN) is a set of remote, functionally connected cortical nodes less active during executive tasks than at rest and is implicated in Theory of Mind, episodic memory, and other self-reflective processes. We show that children with ASD have reduced connectivity between DMN nodes and increased local connectivity within DMN nodes and the visual and motor resting-state networks. We show that, like the trajectory of synaptogenesis, internodal DMN functional connectivity increased as a quadratic function of age in typically developing children, peaking between, 11 and 13 years. In children with ASD, these long-distance connections fail to develop during adolescence. These findings support the "developmental disconnection model" of ASD, provide a possible mechanistic explanation for the Theory-of-Mind hypothesis of ASD, and show that the window for effectively treating ASD could be wider than previously thought. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
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The cerebellum plays a role in a wide variety of complex behaviors. In order to better understand the role of the cerebellum in human behavior, it is important to know how this structure interacts with cortical and other subcortical regions of the brain. To date, several studies have investigated the cerebellum using resting-state functional connectivity magnetic resonance imaging (fcMRI; Krienen and Buckner, 2009; O'Reilly et al., 2010; Buckner et al., 2011). However, none of this work has taken an anatomically-driven lobular approach. Furthermore, though detailed maps of cerebral cortex and cerebellum networks have been proposed using different network solutions based on the cerebral cortex (Buckner et al., 2011), it remains unknown whether or not an anatomical lobular breakdown best encompasses the networks of the cerebellum. Here, we used fcMRI to create an anatomically-driven connectivity atlas of the cerebellar lobules. Timecourses were extracted from the lobules of the right hemisphere and vermis. We found distinct networks for the individual lobules with a clear division into "motor" and "non-motor" regions. We also used a self-organizing map (SOM) algorithm to parcellate the cerebellum. This allowed us to investigate redundancy and independence of the anatomically identified cerebellar networks. We found that while anatomical boundaries in the anterior cerebellum provide functional subdivisions of a larger motor grouping defined using our SOM algorithm, in the posterior cerebellum, the lobules were made up of sub-regions associated with distinct functional networks. Together, our results indicate that the lobular boundaries of the human cerebellum are not necessarily indicative of functional boundaries, though anatomical divisions can be useful. Additionally, driving the analyses from the cerebellum is key to determining the complete picture of functional connectivity within the structure.
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Currently there are no brief, self-administered instruments for measuring the degree to which an adult with normal intelligence has the traits associated with the autistic spectrum. In this paper, we report on a new instrument to assess this: the Autism-Spectrum Quotient (AQ). Individuals score in the range 0–50. Four groups of subjects were assessed: Group 1: 58 adults with Asperger syndrome (AS) or high-functioning autism (HFA); Group 2: 174 randomly selected controls. Group 3: 840 students in Cambridge University; and Group 4: 16 winners of the UK Mathematics Olympiad. The adults with AS/HFA had a mean AQ score of 35.8 (SD = 6.5), significantly higher than Group 2 controls (M = 16.4, SD = 6.3). 80% of the adults with AS/HFA scored 32+, versus 2% of controls. Among the controls, men scored slightly but significantly higher than women. No women scored extremely highly (AQ score 34+) whereas 4% of men did so. Twice as many men (40%) as women (21%) scored at intermediate levels (AQ score 20+). Among the AS/HFA group, male and female scores did not differ significantly. The students in Cambridge University did not differ from the randomly selected control group, but scientists (including mathematicians) scored significantly higher than both humanities and social sciences students, confirming an earlier study that autistic conditions are associated with scientific skills. Within the sciences, mathematicians scored highest. This was replicated in Group 4, the Mathematics Olympiad winners scoring significantly higher than the male Cambridge humanities students. 6% of the student sample scored 327plus; on the AQ. On interview, 11 out of 11 of these met three or more DSM-IV criteria for AS/HFA, and all were studying sciences/mathematics, and 7 of the 11 met threshold on these criteria. Test—retest and interrater reliability of the AQ was good. The AQ is thus a valuable instrument for rapidly quantifying where any given individual is situated on the continuum from autism to normality. Its potential for screening for autism spectrum conditions in adults of normal intelligence remains to be fully explored.
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Controversy surrounds the role of the temporoparietal junction (TPJ) area of the human brain. Although TPJ has been implicated both in reorienting of attention and social cognition, it is still unclear whether these functions have the same neural basis. Indeed, whether TPJ is a precisely identifiable cortical region or a cluster of subregions with separate functions is still a matter of debate. Here, we examined the structural and functional connectivity of TPJ, testing whether TPJ is a unitary area with a heterogeneous functional connectivity profile or a conglomerate of regions with distinctive connectivity. Diffusion-weighted imaging tractrography–based parcellation identified 3 separate regions in TPJ. Resting-state functional connectivity was then used to establish which cortical networks each of these subregions participates in. A dorsal cluster in the middle part of the inferior parietal lobule showed resting-state functional connectivity with, among other areas, lateral anterior prefrontal cortex. Ventrally, an anterior TPJ cluster interacted with ventral prefrontal cortex and anterior insula, while a posterior TPJ cluster interacted with posterior cingulate, temporal pole, and anterior medial prefrontal cortex. These results indicate that TPJ can be subdivided into subregions on the basis of its structural and functional connectivity.
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This study used fMRI to investigate the functioning of the Theory of Mind (ToM) cortical network in autism during the viewing of animations that in some conditions entailed the attribution of a mental state to animated geometric figures. At the cortical level, mentalizing (attribution of metal states) is underpinned by the coordination and integration of the components of the ToM network, which include the medial frontal gyrus, the anterior paracingulate, and the right temporoparietal junction. The pivotal new finding was a functional underconnectivity (a lower degree of synchronization) in autism, especially in the connections between frontal and posterior areas during the attribution of mental states. In addition, the frontal ToM regions activated less in participants with autism relative to control participants. In the autism group, an independent psychometric assessment of ToM ability and the activation in the right temporoparietal junction were reliably correlated. The results together provide new evidence for the biological basis of atypical processing of ToM in autism, implicating the underconnectivity between frontal regions and more posterior areas.
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Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males.
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In children with autism spectrum disorders, previous studies have shown high rates of psychiatric comorbidity. To date, studies on adults have been scarce. The aim of the present study was to investigate psychiatric comorbidity in young adults with Asperger syndrome. Participants were 26 men and 28 women (mean age 27 years) with a clinical diagnosis of Asperger syndrome. Psychiatric comorbidity was assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders. IQ was measured using the Wechsler Adult Intelligence Scale, Third Edition. Autism spectrum diagnoses were confirmed using the DIagnostic Interview for Social and Communication Disorders. In our study group, 70% had experienced at least one episode of major depression, and 50% had suffered from recurrent depressive episodes. Anxiety disorders were seen in about 50%. Psychotic disorders and substance-induced disorders were uncommon. In conclusion, young adults with autism spectrum disorders are at high risk for mood and anxiety disorders. To identify these conditions and offer treatment, elevated vigilance is needed in clinical practice.
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Growing consensus suggests that autism spectrum disorders (ASD) are associated with atypical brain networks, thus shifting the focus to the study of connectivity. Many functional connectivity studies have reported underconnectivity in ASD, but results in others have been divergent. We conducted a survey of 32 functional connectivity magnetic resonance imaging studies of ASD for numerous methodological variables to distinguish studies supporting general underconnectivity (GU) from those not consistent with this hypothesis (NGU). Distinguishing patterns were apparent for several data analysis choices. The study types differed significantly with respect to low-pass filtering, task regression, and whole-brain field of view. GU studies were more likely to examine task-driven time series in regions of interest, without the use of low-pass filtering. Conversely, NGU studies mostly applied task regression (for removal of activation effects) and low-pass filtering, testing for correlations across the whole brain. Results thus suggest that underconnectivity findings may be contingent on specific methodological choices. Whereas underconnectivity reflects reduced efficiency of within-network communication in ASD, diffusely increased functional connectivity can be attributed to impaired experience-driven mechanisms (e.g., synaptic pruning). Both GU and NGU findings reflect important aspects of network dysfunction associated with sociocommunicative, cognitive, and sensorimotor impairments in ASD.
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The cerebellum processes information from functionally diverse regions of the cerebral cortex. Cerebellar input and output nuclei have connections with prefrontal, parietal, and sensory cortex as well as motor and premotor cortex. However, the topography of the connections between the cerebellar and cerebral cortices remains largely unmapped, as it is relatively unamenable to anatomical methods. We used resting-state functional magnetic resonance imaging to define subregions within the cerebellar cortex based on their functional connectivity with the cerebral cortex. We mapped resting-state functional connectivity voxel-wise across the cerebellar cortex, for cerebral-cortical masks covering prefrontal, motor, somatosensory, posterior parietal, visual, and auditory cortices. We found that the cerebellum can be divided into at least 2 zones: 1) a primary sensorimotor zone (Lobules V, VI, and VIII), which contains overlapping functional connectivity maps for domain-specific motor, somatosensory, visual, and auditory cortices; and 2) a supramodal zone (Lobules VIIa, Crus I, and II), which contains overlapping functional connectivity maps for prefrontal and posterior-parietal cortex. The cortical connectivity of the supramodal zone was driven by regions of frontal and parietal cortex which are not directly involved in sensory or motor processing, including dorsolateral prefrontal cortex and the frontal pole, and the inferior parietal lobule.
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Convergent data from various scientific approaches strongly implicate cerebellar systems in nonmotor functions. The functional anatomy of these systems has been pieced together from disparate sources, such as animal studies, lesion studies in humans, and structural and functional imaging studies in humans. To better define this distinct functional anatomy, in the current study we delineate the role of the cerebellum in several nonmotor systems simultaneously and in the same subjects using resting state functional connectivity MRI. Independent component analysis was applied to resting state data from two independent datasets to identify common cerebellar contributions to several previously identified intrinsic connectivity networks (ICNs) involved in executive control, episodic memory/self-reflection, salience detection, and sensorimotor function. We found distinct cerebellar contributions to each of these ICNs. The neocerebellum participates in (1) the right and left executive control networks (especially crus I and II), (2) the salience network (lobule VI), and (3) the default-mode network (lobule IX). Little to no overlap was detected between these cerebellar regions and the sensorimotor cerebellum (lobules V-VI). Clusters were also located in pontine and dentate nuclei, prominent points of convergence for cerebellar input and output, respectively. The results suggest that the most phylogenetically recent part of the cerebellum, particularly crus I and II, make contributions to parallel cortico-cerebellar loops involved in executive control, salience detection, and episodic memory/self-reflection. The largest portions of the neocerebellum take part in the executive control network implicated in higher cognitive functions such as working memory.
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Does the cerebellum influence nonmotor behavior? Recent anatomical studies demonstrate that the output of the cerebellum targets multiple nonmotor areas in the prefrontal and posterior parietal cortex, as well as the cortical motor areas. The projections to different cortical areas originate from distinct output channels within the cerebellar nuclei. The cerebral cortical area that is the main target of each output channel is a major source of input to the channel. Thus, a closed-loop circuit represents the major architectural unit of cerebro-cerebellar interactions. The outputs of these loops provide the cerebellum with the anatomical substrate to influence the control of movement and cognition. Neuroimaging and neuropsychological data supply compelling support for this view. The range of tasks associated with cerebellar activation is remarkable and includes tasks designed to assess attention, executive control, language, working memory, learning, pain, emotion, and addiction. These data, along with the revelations about cerebro-cerebellar circuitry, provide a new framework for exploring the contribution of the cerebellum to diverse aspects of behavior.
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Individuals with autism spectrum disorders (ASDs) often display symptoms from other diagnostic categories. Studies of clinical and psychosocial outcome in adult patients with ASDs without concomitant intellectual disability are few. The objective of this paper is to describe the clinical psychiatric presentation and important outcome measures of a large group of normal-intelligence adult patients with ASDs. Autistic symptomatology according to the DSM-IV-criteria and the Gillberg & Gillberg research criteria, patterns of comorbid psychopathology and psychosocial outcome were assessed in 122 consecutively referred adults with normal intelligence ASDs. The subjects consisted of 5 patients with autistic disorder (AD), 67 with Asperger's disorder (AS) and 50 with pervasive developmental disorder not otherwise specified (PDD NOS). This study group consists of subjects pooled from two studies with highly similar protocols, all seen on an outpatient basis by one of three clinicians. Core autistic symptoms were highly prevalent in all ASD subgroups. Though AD subjects had the most pervasive problems, restrictions in non-verbal communication were common across all three subgroups and, contrary to current DSM criteria, so were verbal communication deficits. Lifetime psychiatric axis I comorbidity was very common, most notably mood and anxiety disorders, but also ADHD and psychotic disorders. The frequency of these diagnoses did not differ between the ASD subgroups or between males and females. Antisocial personality disorder and substance abuse were more common in the PDD NOS group. Of all subjects, few led an independent life and very few had ever had a long-term relationship. Female subjects more often reported having been bullied at school than male subjects. ASDs are clinical syndromes characterized by impaired social interaction and non-verbal communication in adulthood as well as in childhood. They also carry a high risk for co-existing mental health problems from a broad spectrum of disorders and for unfavourable psychosocial life circumstances. For the next revision of DSM, our findings especially stress the importance of careful examination of the exclusion criterion for adult patients with ASDs.
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This multi-study analysis (6 fMRI studies; 142 participants) explores the functional activation and connectivity of the cerebellum with the cerebrum during repeated behavioral information uptake informing about personality traits of different persons. The results suggest that trait repetition recruits activity in areas belonging to the mentalizing and executive control networks in the cerebrum, and the executive control areas in the cerebellum. Cerebral activation was observed in the executive control network including the posterior medial frontal cortex (pmFC), the bilateral prefrontal cortex (PFC) and bilateral inferior parietal cortex (IPC), in the mentalizing network including the bilateral middle temporal cortex (MTC) extending to the right superior temporal cortex (STC), as well as in the visual network including the left cuneus (Cun) and the left inferior occipital cortex. Moreover, cerebellar activation was found bilaterally in lobules VI and VII belonging to the executive control network. Importantly, significant patterns of functional connectivity were found linking these cerebellar executive areas with cerebral executive areas in the medial pmFC, the left PFC and the left IPC, and mentalizing areas in the left MTC. In addition, connectivity was found through links between the cerebral areas in the left hemisphere involved in the executive and mentalizing networks, as well as with their homologue areas in the right hemisphere. The discussion centers on the role of these cerebello-cerebral connections in matching internal predictions generated by the cerebellum with external information from the cerebrum, presumably involving the sequencing of behaviors.
Conference Paper
Emotion attribution (EA) from faces is key to social cognition, and deficits in perception of emotions from faces underlie neuropsychiatric disorders in which cerebellar pathology is reported. Here, we test the hypothesis that the cerebellum contributes to social cognition through EA from faces. We examined 57 patients with cerebellar disorders and 57 healthy controls. Thirty-one patients had complex cerebrocerebellar disease (complex cerebrocerebellar disease group (CD)); 26 had disease isolated to cerebellum (isolated cerebellar disease group (ID)). EA was measured with the Reading the Mind in the Eyes test (RMET), and informants were administered a novel questionnaire, the Cerebellar Neuropsychiatric Rating Scale (CNRS). EA was impaired in all patients (CD p < 0.001, ID p < 0.001). When analyzed for valence categories, both CD and ID missed more positive and negative stimuli. Positive targets produced the highest deficit (CD p < 0.001, ID p = 0.004). EA impairments correlated with CNRS measures of deficient social skills (p < 0.05) and autism spectrum behaviors (p < 0.005). Patients had difficulties with emotion regulation (CD p < 0.001, ID p < 0.001), autism spectrum behaviors (CD p < 0.049, ID p < 0.001), and psychosis spectrum symptoms (CD p < 0.021, ID p < 0.002). ID informants endorsed deficient social skills (CD p < 0.746, ID p < 0.003) and impaired attention regulation (CD p < 0.144, ID p < 0.001). Within the psychosis spectrum domain, CD patients were worse than controls for lack of empathy (CD p = 0.05; ID p = 0.49). Thus, patients with cerebellar damage were impaired on an EA task associated with deficient social skills and autism spectrum behaviors and experienced psychosocial difficulties on the CNRS. This has relevance for ataxias, the cerebellar cognitive affective/Schmahmann syndrome, and neuropsychiatric disorders with cerebellar pathology.
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To examine differences by sex in the timing of identification of individuals with autism spectrum disorders (ASD), survey data were collected in the Netherlands from 2,275 males and females with autistic disorder, Asperger’s syndrome and PDD-NOS. Among participants <18 years of age, females with Asperger’s syndrome were identified later than males. Among participants ≥18 years of age, females with autistic disorder were identified later than males. In more recent years, girls with Asperger’s syndrome are diagnosed later than boys, confirming earlier findings. In adults, the delayed timing of diagnosis in females with autistic disorder may be related to changing practices in diagnosis over time. Strategies for changing clinician behaviour to improve recognition of ASD in females are needed.
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This meta-analysis explores the role of the cerebellum in social cognition. Recent meta-analyses of neuroimaging studies since 2008 demonstrate that the cerebellum is only marginally involved in social cognition and emotionality, with a few meta-analyses pointing to an involvement of at most 54% of the individual studies. In this study, novel meta-analyses of over 350 fMRI studies, dividing up the domain of social cognition in homogeneous subdomains, confirmed this low involvement of the cerebellum in conditions that trigger the mirror network (e.g., when familiar movements of body parts are observed) and the mentalizing network (when no moving body parts or unfamiliar movements are present). There is, however, one set of mentalizing conditions that strongly involve the cerebellum in 50-100% of the individual studies. In particular, when the level of abstraction is high, such as when behaviors are described in terms of traits or permanent characteristics, in terms of groups rather than individuals, in terms of the past (episodic autobiographic memory) or the future rather than the present, or in terms of hypothetical events that may happen. An activation likelihood estimation (ALE) meta-analysis conducted in this study reveals that the cerebellum is critically implicated in social cognition and that the areas of the cerebellum which are consistently involved in social cognitive processes show extensive overlap with the areas involved in sensorimotor (during mirror and self-judgments tasks) as well as in executive functioning (across all tasks). We discuss the role of the cerebellum in social cognition in general and in higher abstraction mentalizing in particular. We also point out a number of methodological limitations of some available studies on the social brain that hamper the detection of cerebellar activity.
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Clinical, experimental and neuroimaging studies indicate that the cerebellum is involved in neural processes beyond the motor domain. Cerebellar somatotopy has been shown for motor control, but topographic organization of higher-order functions has not yet been established. To determine whether existing literature supports the hypothesis of functional topography in the human cerebellum, we conducted an activation likelihood estimate (ALE) meta-analysis of neuroimaging studies reporting cerebellar activation in selected task categories: motor (n = 7 studies), somatosensory (n = 2), language (n = 11), verbal working memory (n = 8), spatial (n = 8), executive function (n = 8) and emotional processing (n = 9). In agreement with previous investigations, sensorimotor tasks activated anterior lobe (lobule V) and adjacent lobule VI, with additional foci in lobule VIII. Motor activation was in VIIIA/B; somatosensory activation was confined to VIIIB. The posterior lobe was involved in higher-level tasks. ALE peaks were identified in lobule VI and Crus I for language and verbal working memory; lobule VI for spatial tasks; lobules VI, Crus I and VIIB for executive functions; and lobules VI, Crus I and medial VII for emotional processing. Language was heavily right-lateralized and spatial peaks left-lateralized, reflecting crossed cerebro-cerebellar projections. Language and executive tasks activated regions of Crus I and lobule VII proposed to be involved in prefrontal-cerebellar loops. Emotional processing involved vermal lobule VII, implicated in cerebellar-limbic circuitry. These data provide support for an anterior sensorimotor vs. posterior cognitive/emotional dichotomy in the human cerebellum. Prospective studies of multiple domains within single individuals are necessary to better elucidate neurobehavioral structure–function correlations in the cerebellar posterior lobe.
Article
Autistic spectrum disorder (ASD) is accompanied by subtle and spatially distributed differences in brain anatomy that are difficult to detect using conventional mass-univariate methods (e.g., VBM). These require correction for multiple comparisons and hence need relatively large samples to attain sufficient statistical power. Reports of neuroanatomical differences from relatively small studies are thus highly variable. Also, VBM does not provide predictive value, limiting its diagnostic value.Here, we examined neuroanatomical networks implicated in ASD using a whole-brain classification approach employing a support vector machine (SVM) and investigated the predictive value of structural MRI scans in adults with ASD. Subsequently, results were compared between SVM and VBM. We included 44 male adults; 22 diagnosed with ASD using “gold-standard” research interviews and 22 healthy matched controls.SVM identified spatially distributed networks discriminating between ASD and controls. These included the limbic, frontal-striatal, fronto-temporal, fronto-parietal and cerebellar systems. SVM applied to gray matter scans correctly classified ASD individuals at a specificity of 86.0% and a sensitivity of 88.0%. Cases (68.0%) were correctly classified using white matter anatomy. The distance from the separating hyperplane (i.e., the test margin) was significantly related to current symptom severity. In contrast, VBM revealed few significant between-group differences at conventional levels of statistical stringency.We therefore suggest that SVM can detect subtle and spatially distributed differences in brain networks between adults with ASD and controls. Also, these differences provide significant predictive power for group membership, which is related to symptom severity.
Article
The cerebral cortex communicates with the cerebellum via polysynaptic circuits. Separate regions of the cerebellum are connected to distinct cerebral areas, forming a complex topography. In this study we explored the organization of cerebrocerebellar circuits in the human using resting-state functional connectivity MRI (fcMRI). Data from 1,000 subjects were registered using nonlinear deformation of the cerebellum in combination with surface-based alignment of the cerebral cortex. The foot, hand, and tongue representations were localized in subjects performing movements. fcMRI maps derived from seed regions placed in different parts of the motor body representation yielded the expected inverted map of somatomotor topography in the anterior lobe and the upright map in the posterior lobe. Next, we mapped the complete topography of the cerebellum by estimating the principal cerebral target for each point in the cerebellum in a discovery sample of 500 subjects and replicated the topography in 500 independent subjects. The majority of the human cerebellum maps to association areas. Quantitative analysis of 17 distinct cerebral networks revealed that the extent of the cerebellum dedicated to each network is proportional to the network's extent in the cerebrum with a few exceptions, including primary visual cortex, which is not represented in the cerebellum. Like somatomotor representations, cerebellar regions linked to association cortex have separate anterior and posterior representations that are oriented as mirror images of one another. The orderly topography of the representations suggests that the cerebellum possesses at least two large, homotopic maps of the full cerebrum and possibly a smaller third map.
Article
Autism spectrum disorder (ASD) is defined on a clinical basis by impairments in social interaction, verbal and non-verbal communication, and repetitive or stereotyped behaviours. Voxel based morphometry (VBM), a technique that gives a probabilistic measure of local grey matter (GM) and white matter concentration, has been used to study ASD patients: modifications in GM volume have been found in various brain regions, such as the corpus callosum, brainstem, amygdala, hippocampus and cerebellum. However, the findings are inconsistent with respect to the specific localisation and direction of GM modifications, and no paper has attempted to statistically summarise the results available in the literature. The present study is a quantitative meta-analysis of the current VBM findings aimed at delineating the cortical regions with consistently increased or reduced GM concentrations. The activation likelihood estimation (ALE) was used, which is a quantitative voxel based meta-analysis method which can be used to estimate consistent activations across different imaging studies. Co-occurrence statistics of a PubMed query were generated, employing 'autism spectrum disorder' as the neuroanatomical lexicon. Significant ALE values related to GM increases were observed bilaterally in the cerebellum, in the middle temporal gyrus, in the right anterior cingulate cortex, caudate head, insula, fusiform gyrus, precuneus and posterior cingulate cortex, and in the left lingual gyrus. GM decreases were observed bilaterally in the cerebellar tonsil and inferior parietal lobule, in the right amygdala, insula, middle temporal gyrus, caudate tail and precuneus and in the left precentral gyrus.
Article
The neurobiology of autism spectrum disorders (ASDs) has become increasingly understood since the advent of magnetic resonance imaging (MRI). Initial observations of an above-average head circumference were supported by structural MRI studies that found evidence of increased total brain volume and early rapid brain overgrowth in affected individuals. Subsequent research revealed consistent abnormalities in cortical gray and white matter volume in ASDs. The structural integrity and orientation of white matter have been further elucidated via diffusion tensor imaging methods. The emergence of functional MRI techniques led to an enhanced understanding of the neural circuitry of ASDs, demonstrating areas of dysfunctional cortical activation and atypical cortical specialization. These studies have provided evidence of underconnectivity in distributed cortical networks integral to the core impairments associated with ASDs. Abnormalities in the default-mode network during the resting state have also been identified. Overall, structural and functional MRI research has generated important insights into the neurobiology of ASDs. Additional research is needed to further delineate the underlying brain basis of this constellation of disorders.
Article
One of the most consistent features of the autism spectrum disorders (ASDs) is the predominance among males, with approximately four males to every female. We sought to examine sex differences among children who met case definition for ASD in a large, population-based cohort with respect to age at first developmental evaluation, age of diagnosis, influence of cognitive impairment on these outcomes, and sex-specific behavioral characteristics. We conducted a secondary analysis of data collected for a population-based study of the prevalence of ASD. The sample comprised 2,568 children born in 1994 who met the case definition of ASD as established by the Autism and Developmental Disabilities Monitoring (ADDM) Network for ASD surveillance. Children who had a history of developmental disability and behavioral features consistent with the DSM-IV-TR criteria for autistic disorder, Asperger's disorder, and Pervasive Developmental Disorder-Not Otherwise Specified in existing evaluation records were classified as ASD cases via two paths: streamlined and nonstreamlined. Streamlined reviews were conducted if there was an ASD diagnosis documented in the records. Data were collected in 13 sites across the United States through the ADDM Network, funded by the Centers for Disease Control and Prevention. Males constituted 81% of the sample. There were no differences by sex in average age at first evaluation or average age of diagnosis among those with an existing documented chart diagnosis of an ASD. Girls were less likely than boys to have a documented diagnosis (odds ratio [OR] = 0.76, p = .004). This analysis was adjusted for cognitive impairment status. In the logistic model, with the interaction term for sex and cognitive impairment, girls with IQ of 70 or less were less likely than boys with IQ of 70 or less to have a documented diagnosis (OR = 0.70, 95% confidence interval [CI] = 0.50-0.97, p = .035). Boys with IQ greater than 70 were less likely than boys with IQ of 70 or less to have a documented diagnosis (OR = 0.60, 95% CI = 0.49-0.74, p < .001). This finding (less likely to have a documented diagnosis) was also true for girls with IQ greater than 70 (OR = 0.45, 95% CI = 0.32-0.66, p < .001). Girls were more likely to have notations of seizure-like behavior (p < .001). Boys were more likely to have notations of hyperactivity or a short attention span and aggressive behavior (p < .01). Girls, especially those without cognitive impairment, may be formally identified at a later age than boys. This may delay referral for early intervention. Community education efforts should alert clinicians and parents to the potential of ASDs in boys and girls.
Article
Autism spectrum disorders (ASDs) are characterized by deficits in social and communication processes. Recent data suggest that altered functional connectivity (FC), i.e. synchronous brain activity, might contribute to these deficits. Of specific interest is the FC integrity of the default mode network (DMN), a network active during passive resting states and cognitive processes related to social deficits seen in ASD, e.g. Theory of Mind. We investigated the role of altered FC of default mode sub-networks (DM-SNs) in 16 patients with high-functioning ASD compared to 16 matched healthy controls of short resting fMRI scans using independent component analysis (ICA). ICA is a multivariate data-driven approach that identifies temporally coherent networks, providing a natural measure of FC. Results show that compared to controls, patients showed decreased FC between the precuneus and medial prefrontal cortex/anterior cingulate cortex, DMN core areas, and other DM-SNs areas. FC magnitude in these regions inversely correlated with the severity of patients' social and communication deficits as measured by the Autism Diagnostic Observational Schedule and the Social Responsiveness Scale. Importantly, supplemental analyses suggest that these results were independent of treatment status. These results support the hypothesis that DM-SNs under-connectivity contributes to the core deficits seen in ASD. Moreover, these data provide further support for the use of data-driven analysis with resting-state data for illuminating neural systems that differ between groups. This approach seems especially well suited for populations where compliance with and performance of active tasks might be a challenge, as it requires minimal cooperation.
Article
The functional organization of the cerebellum is reflected in large part by the unique afferent and efferent connectivity of the individual cerebellar lobules. This functional diversity on a relatively small spatial scale makes accurate localization methods for human functional imaging and anatomical patient-based research indispensable. Here we present a probabilistic atlas of the cerebellar lobules in the anatomical space defined by the MNI152 template. We separately masked the lobules on T1-weighted MRI scans (1 mm isotropic resolution) of 20 healthy young participants (10 male, 10 female, average age 23.7 yrs). These cerebella were then aligned to the standard or non-linear version of the whole-brain MNI152 template using a number of commonly used normalization algorithms, or to a previously published cerebellum-only template (Diedrichsen, J., 2006. A spatially unbiased atlas template of the human cerebellum. NeuroImage 33, 127-138.). The resulting average overlap was higher for the cerebellum-only template than for any of the whole-brain normalization methods. The probabilistic maps allow for the valid assignment of functional activations to specific cerebellar lobules, while providing a quantitative measure of the uncertainty of such assignments. Furthermore, maximum probability maps derived from these atlases can be used to define regions of interest (ROIs) in functional neuroimaging and neuroanatomical research. The atlas, made freely available online, is compatible with a number of widely used analysis packages.
Article
The Autism Diagnostic Observation Schedule (ADOS), a standardized protocol for observation of social and communicative behavior associated with autism, is described. The instrument consists of a series of structured and semistructured presses for interaction, accompanied by coding of specific target behaviors associated with particular tasks and by general ratings of the quality of behaviors. Interrater reliability for five raters exceeded weighted kappas of .55 for each item and each pair of raters for matched samples of 15 to 40 autistic and nonautistic, mildly mentally handicapped children (M IQ = 59) between the ages of 6 and 18 years. Test-retest reliability was adequate. Further analyses compared these groups to two additional samples of autistic and nonautistic subjects with normal intelligence (M IQ = 95), matched for sex and chronological age. Analyses yielded clear diagnostic differences in general ratings of social behavior, specific aspects of communication, and restricted or stereotypic behaviors and interests. Clinical guidelines for the diagnosis of autism in the draft version of ICD-10 were operationalized in terms of abnormalities on specific ADOS items. An algorithm based on these items was shown to have high reliability and discriminant validity.
Article
As part of an autopsy research project, the brains of four autistic subjects were examined and compared with those of three comparison subjects without CNS pathology and one with phenytoin toxicity. The cerebellum was selected for initial investigation because pathognomonic symptoms and neurophysiological measures suggest that pathology may exist in the cerebellar-vestibular axis in certain patients. Total Purkinje cell counts were significantly lower in the cerebellar hemisphere and vermis of each autistic subject than in the comparison subjects.
Article
Early infantile autism is a behaviorally defined syndrome that is often associated with abnormalities on neurologic examination and seizures. We report on the brain of a 29-year-old autistic man as compared with that of an age- and sex-matched normal control, using gapless sections of whole brain. Abnormalities were found in the hippocampus, subiculum, entorhinal cortex, septal nuclei, mamillary body, selected nuclei of the amygdala, neocerebellar cortex, roof nuclei of the cerebellum, and inferior olivary nucleus.
Article
Infantile autism is a neurobehavioral disorder that is widely believed to have etiologically distinct subtypes, including subtypes with a genetic basis, but no neuroanatomic evidence firmly supports this belief. To date, only one type of cerebellar abnormality has been identified in patients with autism: hypoplasia of the vermis and hemispheres. By using a large sample of autistic patients and healthy volunteers along with precise MR imaging and quantitative procedures, we sought to replicate previous reports of cerebellar vermian hypoplasia in autism and to identify additional subtypes of cerebellar abnormality. Using MR technology, we imaged and measured posterior and anterior vermian regions in 50 autistic patients (2-40 years old) and 53 healthy control subjects (3-37 years old). The autistic patients had social, language, cognitive, behavioral, and medical history characteristics that were typical of the general autistic population. By using precise procedures for positioning and aligning MR slices, we obtained comparable MR images within and across subject groups. Statistical analyses showed two subgroups of autistic patients, one (86% of the patients) with findings consistent with vermian hypoplasia and another (12% of the patients) with evidence of vermian hyperplasia. The hypoplasia subgroup included 43 patients whose mean midsagittal area for vermian lobules VI and VII was 237 +/- 38 mm2, and the hyperplasia subgroup included six patients whose mean area was 377 +/- 12 mm2. Thus, the area of lobules VI and VII in the hypoplasia subgroup was 16% smaller than the mean area in the control subjects (282 +/- 42 mm2) (p < .0001), whereas that in the hyperplasia subgroup was 34% larger (p < .0001). Analyses showed that these two subtypes of vermian abnormalities were present across all ages of autistic patients studied. Two different subtypes of autistic patients can be identified on the basis of the presence of vermian hypoplasia or hyperplasia as seen on MR images. Possible origins for vermian hypoplasia include environmental trauma and genetic factors.
Article
Recent autopsy and/or quantitative magnetic resonance imaging studies of autistic patients have identified agenesis of the superior olive, dysgenesis of the facial nucleus, reduced numbers of Purkinje neurons, hypoplasia of the brainstem and posterior cerebellum, and increased neuron-packing density of the medial, cortical and central nuclei of the amygdala and the medial septum. As neurogenesis occurs for these different neuron types during approximately the fifth week of gestation, the possibility is raised that this may be a 'window of vulnerability' for autism; the likely etiologic heterogeneity of autism suggests that other windows of vulnerability are also possible.
Article
We have recently demonstrated using functional magnetic resonance imaging the presence of synchronous low-frequency fluctuations of signal intensities from the resting human brain that have a high degree of temporal correlation (p < 0.0001) both within and across the sensorimotor cortex. A statistically significant overlap between the resting-state functional connectivity map and the task-activation map due to bilateral finger tapping was obtained. Similar results have been obtained in the auditory and visual cortex. Because the pulse sequence used for collecting data was sensitive to blood flow and blood oxygenation, these low-frequency fluctuations of signal intensity may have arisen from variations of both. The objective of this study was simultaneously to determine the contribution of the blood oxygenation level signal and the flow signal to physiological fluctuations in the resting brain using the flow-sensitive alternating inversion recovery pulse sequence. In all subjects, the functional connectivity maps obtained from BOLD had a greater coincidence with task-activation maps than the corresponding functional connectivity maps obtained from blood-flow signals at the same level of statistical significance. Results of this study suggest that while variations in blood flow might contribute to functional connectivity maps, BOLD signals play a dominant role in the mechanism that gives rise to functional connectivity in the resting human brain.
Article
We used retrograde transneuronal transport of herpes simplex virus type 1 to map the origin of cerebellar and basal ganglia "projections" to leg, arm, and face areas of the primary motor cortex (M1). Four to five days after virus injections into M1, we observed many densely labeled neurons in localized regions of the output nuclei of the cerebellum and basal ganglia. The largest numbers of these neurons were found in portions of the dentate nucleus and the internal segment of the globus pallidus (GPi). Smaller numbers of labeled neurons were found in portions of the interpositus nucleus and the substantia nigra pars reticulata. The distribution of neuronal labeling varied with the cortical injection site. For example, within the dentate, neurons labeled from leg M1 were located rostrally, those from face M1 caudally, and those from arm M1 at intermediate levels. In each instance, labeled neurons were confined to approximately the dorsal third of the nucleus. Within GPi, neurons labeled from leg M1 were located in dorsal and medial regions, those from face M1 in ventral and lateral regions, and those from arm M1 in intermediate regions. These results demonstrate that M1 is the target of somatotopically organized outputs from both the cerebellum and basal ganglia. Surprisingly, the projections to M1 originate from only 30% of the volume of the dentate and <15% of GPi. Thus, the majority of the outputs from the cerebellum and basal ganglia are directed to cortical areas other than M1.