Giusy Olivito

Cerebellar damage impairs executive control and monitoring of movement generation

Abstract Executive control of motor responses is a psychological construct of the executive system. Several studies have demonstrated the involvement of the cerebral cortex, basal ganglia, and thalamus in the inhibition of actions and monitoring of performance. The involvement of the cerebellum in cognitive function and its functional interaction with basal ganglia have recently been reported. Based on these findings, we examined the hypothesis of cerebellar involvement in executive control by administering a countermanding task in patients with focal cerebellar damage. The countermanding task requires one to make a movement in response to a ‘go’ signal and to halt it when a ‘stop’ signal is presented. The duration of the go process (reaction time; RT), the duration of the stop process (stop signal reaction time; SSRT), and their relationship, expressed by a psychometric function, are recorded as measures of executive control. All patients had longer go process duration in general and in particular, as a proactive control, as demonstrated by the increase in RT after erroneously performed stop trials. Further, they were defective in the slope of the psychometric function indicating a difficulty on triggering the stop process, although the SSRT did not differ from controls. Notably, their performance was worse when lesions affected deep cerebellar nuclei. Our results support the hypothesis that the cerebellum regulates the executive control of voluntary actions. We speculate that its activity is attributed to specific cerebellar influence over the cortico-striatal loop.

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

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.

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

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

Bilateral effects of unilateral cerebellar lesions as detected by voxel based morphometry and diffusion imaging

Over the last decades, the importance of cerebellar processing for cortical functions has been acknowledged and consensus was reached on the strict functional and structural cortico-cerebellar interrelations. From an anatomical point of view strictly contralateral interconnections link the cerebellum to the cerebral cortex mainly through the middle and superior cerebellar peduncle. Diffusion MRI (dMRI) based tractography has already been applied to address cortico-cerebellar-cortical loops in healthy subjects and to detect diffusivity alteration patterns in patients with neurodegenerative pathologies of the cerebellum. In the present study we used dMRI-based tractography to determine the degree and pattern of pathological changes of cerebellar white matter microstructure in patients with focal cerebellar lesions. Diffusion imaging and high-resolution volumes were obtained in patients with left cerebellar lesions and in normal controls. Middle cerebellar peduncles and superior cerebellar peduncles were reconstructed by multi fiber diffusion tractography. From each tract, measures of microscopic damage were assessed, and despite the presence of unilateral lesions, bilateral diffusivity differences in white matter tracts were found comparing patients with normal controls. Consistently, bilateral alterations were also evidenced in specific brain regions linked to the cerebellum and involved in higher-level functions. This could be in line with the evidence that in the presence of unilateral cerebellar lesions, different cognitive functions can be affected and they are not strictly linked to the side of the cerebellar lesion.

Neural substrates of motor and cognitive dysfunctions in SCA2 patients: A network based statistics analysis

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome, which can be isolated or associated with extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive impairments and psychiatric symptoms. The cerebellum is known to modulate cortical activity and to contribute to distinct functional networks related to higher-level functions beyond motor control. It is therefore conceivable that one or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain the widespread deficits typically observed in patients. In the present study, the network-based statistics (NBS) approach was used to assess differences in functional connectivity between specific cerebellar and cerebral “nodes” in SCA2 patients. Altered inter-nodal connectivity was found between more posterior regions in the cerebellum and regions in the cerebral cortex clearly related to cognition and emotion. Furthermore, more anterior cerebellar lobules showed altered inter-nodal connectivity with motor and somatosensory cerebral regions. The present data suggest that in SCA2 a cerebellar dysfunction affects long-distance cerebral regions and that the clinical symptoms may be specifically related with connectivity changes between motor and non-motor cerebello-cortical nodes.

Development of a psychiatric disorder linked to cerebellar lesions

Cerebellar dysfunction plays a critical role in neurodevelopmental disorders with long-term behavioral and neuropsychiatric symptoms. A 43-year-old woman with a cerebellum arteriovenous malformation and history of behavioral dysregulation since childhood is described. After the rupture of the cerebellar malformation in adulthood, her behavior morphed into specific psychiatric symptoms and cognitive deficits occurred. The neuropsychological assessment evidenced impaired performance in attention, visuospatial, memory, and language domains. Moreover, psychiatric assessment indicated a borderline personality disorder. Brain MRI examination detected macroscopic abnormalities in the cerebellar posterior lobules VI, VIIa (Crus I), and IX, and in the posterior area of the vermis, regions usually involved in cognitive and emotional processing. The described patient suffered from cognitive and behavioral symptoms that are part of the cerebellar cognitive affective syndrome. This case supports the hypothesis of a cerebellar role in personality disorders emphasizing the importance of also examining the cerebellum in the presence of behavioral disturbances in children and adults.

Atrophic degeneration of cerebellum impairs both the reactive and the proactive control of movement in the stop signal paradigm

Abstract The cognitive control of movement suppression, including performance monitoring, is one of the core properties of the executive system. A complex cortical and subcortical network involving cerebral cortex, thalamus, subthalamus, and basal ganglia has been regarded as the neural substrate of inhibition of programmed movements. Using the countermanding task, a suitable tool to explore behavioral components of movement suppression, the contribution of the cerebellum in the proactive control and monitoring of voluntary action has been recently described in patients affected by focal lesions involving in particular the cerebellar dentate nucleus. Here, we evaluated the performance on the countermanding task in a group of patients with cerebellar degeneration, in which the cerebellar cortex was diffusely affected, and showed that they display additionally a longer latency in countermanding engaged movements. Overall, the present data confirm the role of the cerebellum in executive control of action inhibition by extending the contribution to reactive motor suppression.

Topography of the cerebellum in relation to social brain regions and emotions

In the last few decades, an increasing number of studies have focused on better characterizing the cerebellar functions beyond motor control, including emotional and social domains. Anatomic and functional evidence strongly contributes to delineating the cerebellar functional subdivisions and their integration with cerebral functional networks strictly related to emotional regulation and social functioning, thus suggesting a model of cerebellar organization that resembles that of the cerebral cortex. Overcoming the traditional segregation of cerebrocerebellar networks in sensorimotor/cognitive functional modules, during emotional/social processes, the cerebellar activity reflects a domain-specific mentalizing functionality that is strongly connected with corresponding mentalizing networks in the cerebrum. Additionally, the cerebrocerebellar organization has been shown to have a specific functional and maturational trajectory that is only in part dependent on a structural maturational process and that is protracted from an early stage of life through adolescence and adulthood, when the mature control networks involve both segregation and integration of the brain regions that comprise them. Altogether, these findings underscore the importance of regional functional differences within the cerebellum in relation to emotional and social processing and raise questions about the clinical implication of cerebellar injury on emotional/social behaviors, both in the developing and the adult brain.

The cerebellar topography of attention sub-components in Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome and multiple-domain cognitive impairments. The cerebellum is known to contribute to distinct functional networks related to higher-level functions. The aims of the present study were to investigate the different sub-components of attention and to analyse possible correlations between attention deficits and specific cerebellar regions in SCA2 patients. To this purpose, 11 SCA2 patients underwent an exhaustive attention battery that evaluated several attention sub-components. The SCA2 group performed below the normal range in tasks assessing selective attention, divided attention, and sustained attention, obtaining negative Z-scores. These results were confirmed by non-parametric Mann-Whitney U tests that showed significant differences between SCA2 and control subjects in the same sub-components of the attention battery, allowing us to speculate on cerebellar involvement when a high cognitive demand is required (i.e., multisensory integration, sequencing, prediction of events, and inhibition of inappropriate response behaviours). The voxel-based morphometry analysis showed a pattern of significantly reduced grey matter volume in specific cerebellar lobules. In particular, the SCA2 patients showed significant grey matter loss in bilateral regions of the anterior cerebellar hemisphere (IV) and in the posterior lobe (VI-IX) and posterior vermis (VI-IX). Statistical analysis found significant correlations between grey matter reductions in the VIIb/VIIIa cerebellar lobules and impairments in Sustained and Divided Attention tasks and between grey matter reduction in the vermal VI lobule and impairment in the Go/NoGo task. For the first time, the study demonstrated the involvement of specific cerebellar lobules in different sub-components of the attention domain, giving further support to the inclusion of the cerebellum within the attention network.