"Mens Sana in Corpore Sano": The Emerging Link of Motor Reserve with Motor and Cognitive Abilities and Compensatory Brain Networks in SCA2 Patients

The ability to resiliently cope with neuropathological lesions is a key scientific concern. Accordingly, this study aims to investigate whether motor reserve (MR), likely to be boosted by exercise engagement in a lifetime, affects motor symptom severity, cognitive functioning, and functional brain networks in spinocerebellar ataxia type 2 (SCA2)-a cerebellar neurodegenerative disease. The MR of 12 SCA2 patients was assessed using the Motor Reserve Index Questionnaire (MRIq), developed ad hoc for estimating lifespan MR. The International Cooperative Ataxia Rating Scale was used to assess clinical motor features, and neuropsychological tests were used to evaluate cognitive functioning. Patients underwent an MRI examination, and network-based statistics (NBS) analysis was carried out to detect patterns of functional connectivity (FC). Significant correlations were found between MRIq measures and the severity of motor symptoms, educational and intellectual levels, executive function, and processing speed. NBS analysis revealed a higher FC within subnetworks consisting of specific cerebellar and cerebral areas. FC patterns were positively correlated with MRIq measures, likely indicating the identification of an MR network. The identified network might reflect a biomarker likely to underlie MR, influenced by education and cognitive functioning, and impacting the severity of motor symptoms

The cerebellar predictions for social interactions: theory of mind abilities in patients with degenerative cerebellar atrophy

Recent studies have focused on the role of the cerebellum in the social domain, including in Theory of Mind (ToM). ToM, or the "mentalizing" process, is the ability to attribute mental states, such as emotion, intentions and beliefs, to others to explain and predict their behavior. It is a fundamental aspect of social cognition and crucial for social interactions, together with more automatic mechanisms, such as emotion contagion. Social cognition requires complex interactions between limbic, associative areas and subcortical structures, including the cerebellum. It has been hypothesized that the typical cerebellar role in adaptive control and predictive coding could also be extended to social behavior. The present study aimed to investigate the social cognition abilities of patients with degenerative cerebellar atrophy to understand whether the cerebellum acts in specific ToM components playing a role as predictive structure. To this aim, an social cognition battery was administered to 27 patients with degenerative cerebellar pathology and 27 healthy controls. In addition, 3D T1-weighted and resting-state fMRI scans were collected to characterize the structural and functional changes in cerebello-cortical loops. The results evidenced that the patients were impaired in lower-level processes of immediate perception as well as in the more complex conceptual level of mentalization. Furthermore, they presented a pattern of GM reduction in cerebellar portions that are involved in the social domain such as crus I-II, lobule IX and lobule VIIIa. These areas showed decreased functional connectivity with projection cerebral areas involved in specific aspects of social cognition. These findings boost the idea that the cerebellar modulatory function on the cortical projection areas subtends the social cognition process at different levels. Particularly, regarding the lower-level processes, the cerebellum may act by implicitly matching the external information (i.e., expression of the eyes) with the respective internal representation to guarantee an immediate judgment about the mental state of others. Otherwise, at a more complex conceptual level, the cerebellum seems to be involved in the construction of internal models of mental processes during social interactions in which the prediction of sequential events plays a role, allowing us to anticipate the other person's behavior

Aberrant cerebello-cerebral connectivity in remitted bipolar patients 1 and 2: new insight into understanding the cerebellar role in mania and hypomania

Bipolar disorder (BD) is a major mental illness characterized by periods of (hypo) mania and depression with inter-episode remission periods. Functional studies in BD have consistently implicated a set of linked cortical and subcortical limbic regions in the pathophysiology of the disorder, also including the cerebellum. However, the cerebellar role in the neurobiology of BD still needs to be clarified. Seventeen euthymic patients with BD type1 (BD1) (mean age/SD, 38.64/13.48; M/F, 9/8) and 13 euthymic patients with BD type 2 (BD2) (mean age/SD, 41.42/14.38; M/F, 6/7) were compared with 37 sex- and age-matched healthy subjects (HS) (mean age/SD, 45.65/14.15; M/F, 15/22). T1 weighted and resting-state functional connectivity (FC) scans were acquired. The left and right dentate nucleus were used as seed regions for the seed based analysis. FC between each seed and the rest of the brain was compared between patients and HS. Correlations between altered cerebello-cerebral connectivity and clinical scores were then investigated. Different patterns of altered dentate-cerebral connectivity were found in BD1 and BD2. Overall, impaired dentate-cerebral connectivity involved regions of the anterior limbic network specifically related to the (hypo)manic states of BD. Cerebello-cerebral connectivity is altered in BD1 and BD2. Interestingly, the fact that these altered FC patterns persist during euthymia, supports the hypothesis that cerebello-cerebral FC changes reflect the neural correlate of subthreshold symptoms, as trait-based pathophysiology and/or compensatory mechanism to maintain a state of euthymia

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

The cerebellum is linked to theory of mind alterations in autism. A direct clinical and MRI comparison between individuals with autism and cerebellar neurodegenerative pathologies

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 behavioural profile of individuals with cerebellar pathologies is characterized by a theory of mind (ToM) impairment, one of the main behavioural 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 (HPs) 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 grey 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

Non-linear spelling in writing after a pure cerebellar lesion

The most common deficits in processing written language result from damage to the graphemic buffer system and refer to semantic and lexical problems or difficulties in phoneme-graphene conversion. However, a writing disorder that has not yet been studied in depth is the non-linear spelling phenomenon. Indeed, although some cases have been described, no report has exhaustively explained the cognitive mechanism and the anatomical substrates underlying this process. In the present study, we analyzed the modality of non-linear writing in a patient affected by a focal cerebellar lesion, who presented with an alteration of the normal trend to write the order of the letters. Based on this evidence, we analyzed the functional connectivity between the cerebellum and the brain network that subtends handwriting and demonstrated how the cerebellar lesion of the patient affected the connections between the cerebellum and cortical areas that support the anatomical system of writing. This is the first report of non-linear spelling in a patient with a lesion outside the fronto-parietal network, specifically with a focal cerebellar lesion. We propose that non-linear writing can be interpreted in view of the role of the cerebellum in timing and sequential processing. Thus, considering the current functional connectivity data, we hypothesize that the cerebellum might be relevant in the mechanism that allows the correct activation timing of letters within a string and placement of the letters in a specific sequential writing order

The Cerebellum Gets Social: Evidence from an Exploratory Study of Cerebellar, Neurodevelopmental, and Psychiatric Disorders

Social prediction is a key feature of social cognition (SC), a function in which the modulating role of the cerebellum is recognized. Accordingly, cerebellar alterations are reported in cerebellar pathologies, neurodevelopmental disorders, and psychiatric conditions that show SC deficits. Nevertheless, to date, no study has directly compared populations representative of these three conditions with respect to SC and cerebellar alterations. Therefore, the present exploratory study aimed to compare the SC profiles of individuals with cerebellar neurodegenerative disorders (CB), autism (ASD), bipolar disorder type 2 (BD2), or healthy subjects (HS) using a battery of social tests requiring different degrees of prediction processing. The patterns of cerebellar gray matter (GM) alterations were compared among the groups using voxel-based morphometry. Compared to HS, the clinical groups showed common SC deficits in tasks involving a moderate to high level of prediction. The behavioral results of the clinical groups are consistent with the presence of overlapping GM reduction in cerebellar right Crus II, an area notably involved in complex social processing and prediction. Although exploratory and preliminary, these results deepen the cerebellar role in social prediction and highlight the transdiagnostic value of the cerebellum in social functioning and prediction in pathologies of different aetiologies, forecasting novel possibilities for shared interventions

The Cerebellum Is a Key Structure in the Neural Network for Mentalizing: An MRI Study in the Behavioral Variant of Frontotemporal Dementia

The behavioural variant of frontotemporal dementia (bvFTD) is primarily characterized by deficits in social behaviour and theory of mind (ToM). Although a consensus has been reached on the roles of the cerebellum in social cognition and ToM, its specific contribution to social impairments of bvFTD has never been specifically investigated. The aim of this study was to assess cerebellar structural and functional changes in patients with bvFTD and their potential association with ToM deficits of patients. Therefore, 15 patients with bvFTD and 34 healthy subjects underwent an MRI examination. Voxel-based morphometry was used to assess cerebellar (GM) changes, and a seed-based analysis was performed to test cerebello-cerebral functional connectivity (FC). The performance of bvFTD patients in a ToM task was then correlated with FC patterns. Compared to healthy subjects, patients with bvFTD showed significant cerebellar GM loss specifically involving cerebellar Crus I-II. Additionally, FC changes FC were observed between the cerebellum and cerebral regions related to ToM. Interestingly, patterns of changes in cerebello-cerebral FC correlated with altered ToM performances explored using the "Reading the Mind with the Eyes" test (RMET) of patients. The present findings suggest that specific changes in cerebello-cerebral FC may underlie ToM alterations in patients with bvFTD