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Resting-State Functional Connectivity Changes Between Dentate Nucleus and Cortical Social Brain Regions in Autism Spectrum Disorders

DOI:10.1007/s12311-016-0795-8
Authors:
Giusy Olivito at Sapienza University of Rome
Giusy Olivito
Silvia Clausi at Sapienza University of Rome
Silvia Clausi
Fiorenzo Laghi at Sapienza University of Rome
Fiorenzo Laghi
Anna Maria Tedesco
Anna Maria Tedesco
Anna Maria Tedesco
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Abstract and Figures

Autism spectrum disorders (ASDs) are known to be characterized by restricted and repetitive behaviors and interests and by impairments in social communication and interactions mainly including “theory of mind” (ToM) processes. The cerebellum has emerged as one of the brain regions affected by ASDs. As the cerebellum is known to influence cerebral cortex activity via cerebello-thalamo-cortical (CTC) circuits, it has been proposed that cerebello-cortical “disconnection” could in part underlie autistic symptoms. We used resting-state (RS) functional magnetic resonance imaging (fMRI) to investigate the potential RS connectivity changes between the cerebellar dentate nucleus (DN) and the CTC circuit targets, that may contribute to ASD pathophysiology. When comparing ASD patients to controls, we found decreased connectivity between the left DN and cerebral regions known to be components of the ToM network and the default mode network, implicated in specific aspects of mentalizing, social cognition processing, and higher order emotional processes. Further, a pattern of overconnectivity was also detected between the left DN and the supramodal cerebellar lobules associated with the default mode network. The presented RS-fMRI data provide evidence that functional connectivity (FC) between the dentate nucleus and the cerebral cortex is altered in ASD patients. This suggests that the dysfunction reported within the cerebral cortical network, typically related to social features of ASDs, may be at least partially related to an impaired interaction between cerebellum and key cortical social brain regions.
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ORIGINAL PAPER
Resting-State Functional Connectivity Changes Between Dentate
Nucleus and Cortical Social Brain Regions in Autism Spectrum
Disorders
Giusy Olivito
1,2
&Silvia Clausi
1,2
&Fiorenzo Laghi
3
&Anna Maria Tedesco
1,2
&
Roberto Baiocco
3
&Chiara Mastropasqua
4
&Marco Molinari
5
&Mara Cercignani
4,6
&
Marco Bozzali
4
&Maria Leggio
1,2
Published online: 1 June 2016
#Springer Science+Business Media New York 2016
Abstract Autism spectrum disorders (ASDs) are known to be
characterized by restricted and repetitive behaviors and inter-
ests and by impairments in social communication and interac-
tions mainly including Btheory of mind^(ToM) processes.
The cerebellum has emerged as one of the brain regions af-
fected by ASDs. As the cerebellum is known to influence
cerebral cortex activity via cerebello-thalamo-cortical (CTC)
circuits, it has been proposed that cerebello-cortical
Bdisconnection^could in part underlie autistic symptoms.
We used resting-state (RS) functional magnetic resonance im-
aging (fMRI) to investigate the potential RS connectivity
changes between the cerebellar dentate nucleus (DN) and
the CTC circuit targets, that may contribute to ASD patho-
physiology. When comparing ASD patients to controls, we
found decreased connectivity between the left DN and cere-
bral regions known to be components of the ToM network and
the default mode network, implicated in specific aspects of
mentalizing, social cognition processing, and higher order
emotional processes. Further, a pattern of overconnectivity
was also detected between the left DN and the supramodal
cerebellar lobules associated with the default mode network.
The presented RS-fMRI data provide evidence that functional
connectivity (FC) between the dentate nucleus and the cere-
bral cortex is altered in ASD patients. This suggests that the
dysfunction reported within the cerebral cortical network, typ-
ically related to social features of ASDs, may be at least par-
tially related to an impaired interaction between cerebellum
and key cortical social brain regions.
Keywords Cerebellum .Cerebral cortex .Default mode
network .Social cognition .Theory of mind
Introduction
Autism spectrum disorders (ASDs) are neurodevelopmental
conditions mainly characterized by core deficits in social
communication and interaction, as well as the presence of
restricted and repetitive behaviors and interests [1]. It has
been proposed that ASDs’deficits can be explained by
individuals’difficulties with Btheory of mind^(ToM) pro-
cesses, a crucial component of social behavior referring to
the ability of attributing mental states to self and other in
order to predict and explain behaviors [2,3]. According to
the ToM hypothesis, pragmatic impairments of language
and communication typically observed in ASDs may be
explained in terms of social behavior deficits. The theory
that individuals with ASD are unable to represent mental
states shed light on the nature of social communication
impairments, assuming that a specific communication
*Maria Leggio
maria.leggio@uniroma1.it
1
Ataxia Laboratory, IRCCS Santa Lucia Foundation, Via Ardeatina
306, 00179 Rome, Italy
2
Department of Psychology, BSapienza^University of Rome, Via dei
Marsi 78, 00185 Rome, Italy
3
Department of Developmental and Social Psychology, Faculty of
Medicine and Psychology, BSapienza^University of Rome, Via dei
Marsi 78, 00185 Rome, Italy
4
Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Via
Ardeatina 306, 00179 Rome, Italy
5
Neurological and Spinal Cord Injury Rehabilitation Department A,
IRCCS Santa Lucia Foundation, Via Ardeatina 306,
00179 Rome, Italy
6
Clinical Imaging Sciences Centre, Brighton and Sussex Medical
School, University of Sussex, Falmer, BN1 9RR Brighton, UK
Cerebellum (2017) 16:283–292
DOI 10.1007/s12311-016-0795-8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Functional connectivity has been used vastly in ASD studies. These studies show changes in functional connectivity in ASD (Di Martino et al., 2008;Smith et al., 2013;von dem Hagen et al., 2013;Ray et al., 2014;Tyszka et al., 2014;Uddin et al., 2015;Olivito et al., 2016;Hull et al., 2017;Guo et al., 2019;Bathelt and Geurts, 2020). A brain region or network can be both under-connected with some areas and simultaneously over-connected with other areas in ASDs compared to healthy controls (HCs; Just et al., 2004;Cherkassky et al., 2006;Kennedy et al., 2006;Assaf et al., 2010;Jones et al., 2010;Weng et al., 2010;Di Martino et al., 2011;Delmonte et al., 2013;Keown et al., 2013;Redcay et al., 2013;Nebel et al., 2014;Cerliani et al., 2015;Chien et al., 2015;Holiga et al., 2019). ...
... DMN, one of the restingstate networks, is active when the brain is in the resting state but deactivates during cognitive tasks or goal-directed behaviors (Raichle and Synder, 2007;Washington et al., 2014). According to different studies, under-connectivity and over-connectivity of DMN have been seen in ASD (Kennedy et al., 2006;Kennedy and Courchesne, 2008;Monk et al., 2009;Assaf et al., 2010;Weng et al., 2010;Wiggins et al., 2011;Jung et al., 2014;Yerys et al., 2015;Lee et al., 2016;Olivito et al., 2016;Padmanabhan et al., 2017). DMN changes are more consistent findings in autistic individuals. ...
Cognitive theories of autism based on the interactions between brain functional networks
Article
Full-text available
Cognitive functions are directly related to interactions between the brain's functional networks. This functional organization changes in the autism spectrum disorder (ASD). However, the heterogeneous nature of autism brings inconsistency in the findings, and specific pattern of changes based on the cognitive theories of ASD still requires to be well-understood. In this study, we hypothesized that the theory of mind (ToM), and the weak central coherence theory must follow an alteration pattern in the network level of functional interactions. The main aim is to understand this pattern by evaluating interactions between all the brain functional networks. Moreover, the association between the significantly altered interactions and cognitive dysfunctions in autism is also investigated. We used resting-state fMRI data of 106 subjects (5–14 years, 46 ASD: five female, 60 HC: 18 female) to define the brain functional networks. Functional networks were calculated by applying four parcellation masks and their interactions were estimated using Pearson's correlation between pairs of them. Subsequently, for each mask, a graph was formed based on the connectome of interactions. Then, the local and global parameters of the graph were calculated. Finally, statistical analysis was performed using a two-sample t -test to highlight the significant differences between autistic and healthy control groups. Our corrected results show significant changes in the interaction of default mode, sensorimotor, visuospatial, visual, and language networks with other functional networks that can support the main cognitive theories of autism. We hope this finding sheds light on a better understanding of the neural underpinning of autism.
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... Consistent with these data, altered cerebellocerebral functional connectivity has been reported in adults with autism spectrum disorder (Olivito et al. 2017a, a neurodevelopmental disorder typically characterized by an impairment in social mentalizing (Baron-Cohen 1995;Hill and Frith 2003). In particular, altered FC was found between the cerebellar Crus II and cortical . ...
... Further support for this idea has been derived from resting-state functional connectivity studies in individuals with ASD that reported reduced functional connectivity between specific regions in the posterior cerebellum and regions in the "social brain" relevant for social interaction. Indeed, low resting-state functional connectivity between the Crus II and the TPJ adjacent to the STS (Igelström et al. 2017) and altered functional connectivity between the dentate nucleus and the cortical regions involved in social cognition were reported in adults with ASD (Olivito et al. 2017a. Accordingly, a recent study in ASD showed that more severe scores on the Autism Diagnostic Observation Schedule were associated with the degree of hypo-connectivity between Crus I/II and lobule IX and brain areas involved in language, emotional and social domains, including the bilateral STS, inferior frontal gyrus, amygdala and specific nodes in the default mode network (Arnold Anteraper et al. 2019). ...
Cerebellum and Emotion in Social Behavior
Article
Accumulating evidence suggests that the cerebellum plays a crucial role not only in the motor and cognitive domains but also in emotions and social behavior. In the present chapter, after a general introduction on the significance of the emotional components of social behavior, we describe recent efforts to understand the contributions of the cerebellum in social cognition focusing on the emotional and affective aspects. Specifically, starting from the description of the cerebello-cortical networks subtending the social-affective domains, we illustrate the most recent findings on the social cerebellum and the possible functional mechanisms by which the cerebellum modulate social-affective behavior. Finally, we discuss the possible consequences of cerebellar dysfunction in the social-affective domain, focusing on those neurological and psychopathological conditions in which emotional and social behavior difficulties have been described as being associated with cerebellar structural or functional alterations.
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... According to earlier research, the corticocerebellocortical loops provide the structural basis for the behaviorally-regulating functional networks of executive, salience, default mode, dorsal attentional, and motor [34][35][36][37]. So far, the disrupted interactions of the cerebral-cerebellum have been observed in many neurological disorders such as autism spectrum disorders, Parkinson's disease, Alzheimer's disease, and frontotemporal dementia [38][39][40]. These investigations support the existence In these comparisons, two sample t test after a generalized linear model (GLM) with age, sex, and resting state microstate parameters regressed out. ...
Dynamics of Cerebral Function in Patients with Acute Cerebellar Infarction
Article
Full-text available
Few studies were devoted to investigating cerebral functional changes after acute cerebellar infarction (CI). The purpose of this study was to examine the brain functional dynamics of CI using electroencephalographic (EEG) microstate analysis. And the possible heterogenicity in neural dynamics between CI with vertigo and CI with dizziness was explored. Thirty-four CI patients and 37 age- and gender-matched healthy controls(HC) were included in the study. Each included subject underwent a 19-channel video EEG examination. Five 10-s resting-state EEG epochs were extracted after data preprocessing. Then, microstate analysis and source localization were performed using the LORETA-KEY tool. Microstate parameters such as duration, coverage, occurrence, and transition probability are all extracted. The current study showed that the duration, coverage, and occurrence of microstate(Ms) B significantly increased in CI patients, but the duration and coverage of MsA and MsD decreased. Compared CI with vertigo to dizziness, finding a decreased trend in the coverage of MsD and the transition from MsA and MsB to MsD. Taken together, our study sheds new light on the dynamics of cerebral function after CI, mainly reflecting increased activity in functional networks involved in MsB and decreased activity in functional networks involved in MsA and MsD. Vertigo and dizziness post-CI may be suggested by cerebral functional dynamics. Further longitudinal studies are needed to validate and explore the alterations in brain dynamics to what extent depict the clinical traits and their potential applications in the recovery of CI.
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... The 3xTg-AD cerebellar nuclei show a gradient of neural loss through the mediolateral axis, with the fastigial nucleus being the most affected area, followed by the interpositus nucleus, and the Lat not being affected. [360,361] Autism spectrum disorders (ASD) [362,363] Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Cerebellum Lecture: the Cerebellar Nuclei—Core of the Cerebellum
Article
Full-text available
The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the cerebellum, are often overlooked. This neglect is because research on the cerebellum typically focuses on the cortex and tends to treat the CN as relatively simple output nuclei conveying an inverted signal from the cerebellar cortex to the rest of the brain. In this review, by adopting a nucleocentric perspective we aim to rectify this impression. First, we describe CN anatomy and modularity and comprehensively integrate CN architecture with its highly organized but complex afferent and efferent connectivity. This is followed by a novel classification of the specific neuronal classes the CN comprise and speculate on the implications of CN structure and physiology for our understanding of adult cerebellar function. Based on this thorough review of the adult literature we provide a comprehensive overview of CN embryonic development and, by comparing cerebellar structures in various chordate clades, propose an interpretation of CN evolution. Despite their critical importance in cerebellar function, from a clinical perspective intriguingly few, if any, neurological disorders appear to primarily affect the CN. To highlight this curious anomaly, and encourage future nucleocentric interpretations, we build on our review to provide a brief overview of the various syndromes in which the CN are currently implicated. Finally, we summarize the specific perspectives that a nucleocentric view of the cerebellum brings, move major outstanding issues in CN biology to the limelight, and provide a roadmap to the key questions that need to be answered in order to create a comprehensive integrated model of CN structure, function, development, and evolution.
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... described as involved in the pathogenesis of psychiatric disorders (i.e., schizophrenia) and neurodevelopmental conditions (i.e., autism spectrum disorders) characterized by social behavior difficulties 77,78 . Structural and functional cerebellar alterations have been reported in these conditions 77,[79][80][81] . In line with this, knowing more about the cerebellar tDCS-induced changes in mental state recognition ability would aid in developing new therapeutic protocols in these patient populations 82 . ...
Modulating mental state recognition by anodal tDCS over the cerebellum
Article
Full-text available
  • Dec 2022
Increasing evidence from neuroimaging and clinical studies has demonstrated cerebellar involvement in social cognition components, including the mentalizing process. The aim of this study was to apply transcranial direct current stimulation (tDCS) to modulate cerebellar excitability to investigate the role the cerebellum plays in mental state recognition. Forty-eight healthy subjects were randomly assigned to different groups in which anodal, cathodal, or sham tDCS (2 mA for 20 min) was delivered centering the electrode on the vermis to stimulate the posterior portion of the cerebellum. The ability to attribute mental states to others was tested before and after tDCS using a digital version of the 'Reading the Mind in the Eyes test', which includes visual perceptive and motor stimuli as control conditions. Correct response and reaction times (RTs) were recorded. The results revealed a significant reduction in RTs between the baseline and post-stimulation sessions after cerebellar anodal tDCS only for mental state stimuli (Wilcoxon test p = 0.00055), whereas no significant effect was found in the cathodal or sham conditions or for visual perceptive and motor stimuli. Overall, our study suggests that cerebellar anodal tDCS might selectively improve mental state recognition and constitute an effective strategy to positively modulate the mentalizing process.
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... Subjects affected by ASD had decreased white matter in the dentato-rubro-thalamic tract [470] and lower FA of the superior [471,472] and medial cerebellar peduncle [473][474][475]. Accordingly, patients with ASD had decreased functional connectivity between various parts of the cerebellar cortex and nuclei and different cortical regions [476][477][478][479][480], which may suggest an important cerebellar role in the pathophysiology of ASD. Like in schizophrenia, ASD was not only associated with reduced connectivity of particular projections, but also with increased strength of others [480][481][482][483]. ...
A Systematic Review of Direct Outputs from the Cerebellum to the Brainstem and Diencephalon in Mammals
Article
Full-text available
The cerebellum is involved in many motor, autonomic and cognitive functions, and new tasks that have a cerebellar contribution are discovered on a regular basis. Simultaneously, our insight into the functional compartmentalization of the cerebellum has markedly improved. Additionally, studies on cerebellar output pathways have seen a renaissance due to the development of viral tracing techniques. To create an overview of the current state of our understanding of cerebellar efferents, we undertook a systematic review of all studies on monosynaptic projections from the cerebellum to the brainstem and the diencephalon in mammals. This revealed that important projections from the cerebellum, to the motor nuclei, cerebral cortex, and basal ganglia, are predominantly di- or polysynaptic, rather than monosynaptic. Strikingly, most target areas receive cerebellar input from all three cerebellar nuclei, showing a convergence of cerebellar information at the output level. Overall, there appeared to be a large level of agreement between studies on different species as well as on the use of different types of neural tracers, making the emerging picture of the cerebellar output areas a solid one. Finally, we discuss how this cerebellar output network is affected by a range of diseases and syndromes, with also non-cerebellar diseases having impact on cerebellar output areas.
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... 11,13 Recent studies have suggested that the cerebello-cerebral neural network, involving lateral portions of the cerebellar hemispheres, the semilunar and posterior quadrangular lobules, is involved in higher brain functions. [18][19][20][21][22][23][24][25] In addition, autism is also associated with focal abnormalities in the cerebellum, especially in the semilunar lobule, [26][27][28][29][30][31][32] where cerebellar tubers occurred most commonly in this study. In patients with TSC, the strong correlation between cerebral tubers and ASD has been reported 13,33-36 ; however, the relationship between cerebellar tubers and autism has not been fully established. ...
Cerebellar Tubers in Tuberous Sclerosis Complex Patients: New Imaging Characteristics and the Relationship with Cerebral Tubers
Article
Full-text available
  • Oct 2022
Objective The imaging characteristics, evolution, and clinical features of cerebellar tubers in tuberous sclerosis complex (TSC) patients have not been well described. The purpose of this study is to investigate the imaging characteristics of cerebellar tubers, including their dynamic changes, and to evaluate the relationship with cerebral tubers in TSC patients. Materials and Methods Two observers retrospectively reviewed 75 consecutive TSC patients to identify cerebellar tubers and to evaluate their imaging characteristics, including location, presence of retraction change, calcification, contrast enhancement, and the presence of an associated vascular anomaly, as well as dynamic changes in these characteristics. The number of cerebral tubers was compared between TSC patients with and without cerebellar tubers. Results Twenty-five TSC patients with 28 cerebellar tubers were identified. All cerebellar tubers occurred within the lateral portions of the cerebellar hemispheres. Thirteen cerebellar tubers demonstrated calcification. Ten cerebellar tubers showed contrast enhancement, half of which demonstrated a zebra-like appearance. A vascular anomaly was associated with 12 tubers, one of which subsequently developed parenchymal hemorrhage. Fifteen cerebellar tubers demonstrated complex dynamic changes in size and contrast enhancement. Patients with cerebellar tubers had more cerebral tubers (p = 0.001). Conclusion Cerebellar tubers demonstrate a specific distribution, suggesting a possible influence on higher brain function. The presence of an associated vascular anomaly may be an important imaging characteristic. Cerebellar tubers may be associated with a more severe manifestation of TSC, given their association with increased numbers of cerebral tubers. These findings may provide insights into the pathogenesis and clinical manifestations of cerebellar tubers in TSC patients.
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... Lesions in the posterior CB, a subregion anatomically and functionally associated with non-motor function in both humans and non-human primates (Dum and Strick, 2003;Kelly and Strick, 2003;Strick et al., 2009;Bernard et al., 2012;Guell et al., 2018;Ren et al., 2019), are linked to cerebellar cognitive affective syndrome, named for its wide-varying deficits in executive function and working memory, visuospatial and verbal memory, affect, and language generation (Schmahmann and Sherman, 1998;Hoche et al., 2018). Further, differences in CB anatomy, CB functional activation, or functional connectivity are associated with many disorders including post-traumatic stress disorder (Baldaçara et al., 2012;Holmes et al., 2018;Rabellino et al., 2018), anxiety (Liu et al., 2015;Doruyter et al., 2016;Li et al., 2016), obsessivecompulsive disorder (OCD; Pujol et al., 2004;Xu et al., 2019), depression (Alalade et al., 2011;Ma et al., 2013;Lai and Wu, 2016;Zhu et al., 2020), schizophrenia and psychosis-related disorders (Meltzer and Stahl, 1976;Collin et al., 2011;Liu et al., 2011;Kim et al., 2014;Giraldo-Chica et al., 2018;Gong et al., 2019;Clark et al., 2020), autism spectrum disorders (Verly et al., 2014;Khan et al., 2015;Olivito et al., 2017;Hegarty et al., 2018), and addiction (Bora et al., 2012;Kühn et al., 2012;Moulton et al., 2014). ...
Cerebellar and basal ganglia motor network predicts trait depression and hyperactivity
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Full-text available
  • Sep 2022
In the human brain, the cerebellum (CB) and basal ganglia (BG) are implicated in cognition-, emotion-, and motor-related cortical processes and are highly interconnected, both to cortical regions via separate, trans-thalamic pathways and to each other via subcortical disynaptic pathways. We previously demonstrated a distinction between cognitive and motor CB-BG networks (CCBN, MCBN, respectively) as it relates to cortical network integration in healthy young adults, suggesting the subcortical networks separately support cortical networks. The CB and BG are also implicated in the pathophysiology of schizophrenia, Parkinson's, and compulsive behavior; thus, integration within subcortical CB-BG networks may be related to transdiagnostic symptomology. Here, we asked whether CCBN or MCBN integration predicted Achenbach Self-Report scores for anxiety, depression, intrusive thoughts, hyperactivity and inactivity, and cognitive performance in a community sample of young adults. We computed global efficiency for each CB-BG network and 7 canonical resting-state networks for all right-handed participants in the Human Connectome Project 1200 release with a complete set of preprocessed resting-state functional MRI data (N = 783). We used multivariate regression to control for substance abuse and age, and permutation testing with exchangeability blocks to control for family relationships. MCBN integration negatively predicted depression and hyperactivity, and positively predicted cortical network integration. CCBN integration predicted cortical network integration (except for the emotional network) and marginally predicted a positive relationship with hyperactivity, indicating a potential dichotomy between cognitive and motor CB-BG networks and hyperactivity. These results highlight the importance of CB-BG interactions as they relate to motivation and symptoms of depression.
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Theory of Mind and Cerebellum
Chapter
  • Mar 2023
In recent decades, the consensus has been reached about the role of the cerebellum in social cognition. In addition to its well-known role in emotional processing, the specific involvement of the cerebellum in modulating theory of mind (ToM) abilities has been documented. With a focus on this topic, we open the current chapter with a general introduction of the definition of ToM and the importance of considering the cerebellum as a crucial hub in the brain network involved in predicting mental states and related behaviors, function needed to adaptively engage in social interactions. We then report the recent advances on cerebro-cerebellar circuits related to ToM functions as studied on healthy subjects, and we emphasize the cerebellar sequential and predictive coding as responsible for cerebellar modulation on ToM-related cortical areas. Afterward, we highlight the effects of cerebellar damages on ToM impairments focusing on clinical populations, starting from patients with primary cerebellar damages and then broadening this issue to further pathological populations. Specifically, we take into account other neurological conditions, together with psychiatric and neurodevelopmental disorders, whose ToM and resulting social struggles have also been linked to cerebellar structural or functional alterations. Conclusively, we briefly outline the significance of the collected findings on cerebellar functioning related to clinical practice and to the implementation of therapeutic interventions aiming at improving ToM and social skills.KeywordsTheory of mindCerebellumFunctional connectivityMentalizing networkPrediction
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Cerebellar Developmental Disorders and Cerebellar Nuclei
Chapter
  • Feb 2023
While significant progress has been made in the last 10 years in understanding the development of cerebellar nuclei, they remain a relatively less well-studied cell group in the brain. In this chapter, we review the anatomical organisation of the cerebellar nuclei and their connections to highlight outstanding developmental questions. We then describe recent progress in dissecting the lineages of cerebellar neurons that may point to new understanding of their involvement in congenital clinical disorders.Keywords Dentate nucleus Interposed nucleusFastigial nucleusInferior olivePurkinje cellRhombic lipVentricular zonePtf1aAtoh1Pax2Nuclear transitory zone
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Cerebellar Projections to the Prefrontal Cortex of the Primate
Article
Full-text available
  • Jan 2001
The cerebellum is known to project via the thalamus to multiple motor areas of the cerebral cortex. In this study, we examined the extent and anatomical organization of cerebellar input to multiple regions of prefrontal cortex. We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12. Only areas 46d, 9m, and 9l received substantial input from thalamic regions included within the zone of termination of cerebellar efferents. This suggested that these cortical areas were the target of cerebellar output. We tested this possibility using retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 from areas of prefrontal cortex. Neurons labeled by retrograde transneuronal transport of virus were found in the dentate nucleus only after injections into areas 46d, 9m, and 9l. The precise location of labeled neurons in the dentate varied with the prefrontal area injected. In addition, the dentate neurons labeled after virus injections into prefrontal areas were located in regions spatially separate from those labeled after virus injections into motor areas of the cerebral cortex. Our observations indicate that the cerebellum influences several areas of prefrontal cortex via the thalamus. Furthermore, separate output channels exist in the dentate to influence motor and cognitive operations. These results provide an anatomical substrate for the cerebellum to be involved in cognitive functions such as planning, working memory, and rule-based learning.
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Castelli F, Frith C, Happ?? F, Frith U. Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes. Brain 125(Part 8): 1839-1849
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Full-text available
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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Cerebro-cerebellar Resting-State Functional Connectivity in Children and Adolescents with Autism Spectrum Disorder
Article
Full-text available
  • Apr 2015
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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Cerebellar areas dedicated to social cognition? A comparison of meta-analytic and connectivity results
Article
Full-text available
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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Cerebellar Grey Matter and Lobular Measures Correlate with Core Autism Symptoms
Conference Paper
Full-text available
  • May 2014
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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Sex/Gender Differences and Autism: Setting the Scene for Future Research
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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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Intermittent Theta-Burst Stimulation of the Lateral Cerebellum Increases Functional Connectivity of the Default Network
Article
Full-text available
  • Sep 2014
Cerebral cortical intrinsic connectivity networks share topographically arranged functional connectivity with the cerebellum. However, the contribution of cerebellar nodes to distributed network organization and function remains poorly understood. In humans, we applied theta-burst transcranial magnetic stimulation, guided by subject-specific connectivity, to regions of the cerebellum to evaluate the functional relevance of connections between cerebellar and cerebral cortical nodes in different networks. We demonstrate that changing activity in the human lateral cerebellar Crus I/II modulates the cerebral default mode network, whereas vermal lobule VII stimulation influences the cerebral dorsal attention system. These results provide novel insights into the distributed, but anatomically specific, modulatory impact of cerebellar effects on large-scale neural network function.
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Reduced Intrinsic Connectivity in the Default Network in Adolescents with Autism Spectrum Disorders
Conference Paper
  • May 2009
Background: ASD is associated with disturbances of neural connectivity. Connectivity is typically examined within the context of a cognitive task. However, connectivity also exists in the absence of a task. This intrinsic connectivity, known as resting-state connectivity is particularly active in a set of structures called the default network, which includes the posterior cingulate cortex (PCC), retro-splenial cortex, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus. Exploring resting-state connectivity in ASD is of interest as these networks might be active during self-referencing and introspection, domains in which deficits in empathy and social cognition hinge upon. In addition, no prior study has explored resting-state connectivity within adolescents with ASD. Objectives: We sought to examine resting-state connectivity within the default network in adolescents with ASD and to examine how various measures of symptom severity and adaptive functioning relate to patterns of connectivity. Following the results from a previous resting connectivity study in our lab that showed patterns of weaker and tighter connectivity in adults with ASD, we hypothesized that adolescents with ASD would show weaker coupling between the PCC and the superior frontal gyrus relative to controls. Second, we hypothesized that adolescents with ASD would show tighter coupling between the PCC and the superior temporal gyrus and parahippocampal gyrus relative to controls. Finally, in an exploratory analysis we sought to examine if symptom severity was associated strength of connectivity. Methods: 12 adolescents with ASD and 12 age-matched controls between the ages of 13-17 took part in a functional MRI study. Participants were instructed to “let your mind wander freely” while looking at a fixation cross displayed in the middle of the screen for 10 minutes during fMRI acquisition. A seed region was placed in the PCC and functional connectivity was examined by obtaining the correlational activity between the PCC and other areas of the default network. Results: Both ASD and control groups activated the default network of the brain at p<0.05 (whole brain corrected). Analyses of group differences revealed that individuals with ASD relative to controls showed weaker connectivity between the PCC and all regions in the default network (p<0.05 small volume corrected). Moreover, ASD relative to the control groups showed tighter connectivity between the PCC and the superior temporal gyrus. A correlation analysis revealed that poorer social functioning was associated with weaker connectivity between the PCC and left angular gyrus. Greater impairments in the restricted and repetitive behavior domain were associated with weaker connectivity between the PCC and the temporal lobe. Finally, lower overall adaptive functioning in the ASD group was associated with weaker connectivity between the PCC and the angular gyrus. Conclusions: Relative to the control group, the ASD group showed weaker functional connectivity within the default network in the absence of a task. In addition, more severe symptoms were associated with weaker connectivity within the default network. These findings suggest evidence for altered connectivity within the default network and that connectivity between these structures is associated with core impairments in ASD.
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