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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.

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.

International audience; During the past decades, converging evidence from clinical, neuroimaging and neuroanatomical studies has demonstrated the key role of the cerebellum in the processing of non-motor aspects of language. Although more is known about the way in which the cerebellum participates in the mechanisms involved in written language, there is ambiguous information on its role in other aspects of language, such as in non-motor aspects of spoken language. Thus, to contribute additional insight into this important issue, in the present work, we review several original scientific papers focusing on the most frequent non-motor spoken language impairments evidenced in patients affected by cerebellar pathology, namely, verbal working memory, grammar processing and verbal fluency impairments. Starting from the collected data, we provide a common interpretation of the spoken language disorders in cerebellar patients, suggesting that sequential processing could be the main mechanism by which the cerebellum participates in these abilities. Indeed, according to the cerebellar sequential theory, spoken language impairments could be due to altered cerebellar function to supervise, synchronize and coordinate the activity of different functional modules, affecting the correct optimization of linguistic processing.

Background Several studies have shown cerebellar abnormalities during depressive and manic states, although the specific cerebellar role in mood fluctuations remains poorly defined. Therefore, the study of pathologies characterized by frequent mood swings, such as bipolar disorder, is of great interest to investigate the relationship between the cerebellum and mood alterations. Methods A systematic literature search on the occurrence of mood disorders in patients with cerebellar pathologies (1st research strategy) and on the presence of cerebellar alterations in mood disorders (2nd research strategy) was conducted using the PubMed electronic Internet database. For this systematic review all information was written based on the PRISMA-P statement. Results The results of the 1st research strategy generated 9 articles, and in one of these, a direct correlation between cerebellar damage and the onset of mood disorder was reported. The 2nd research strategy generated 14 articles that were grouped according to the patient’s mood phase (manic or depressive) or diagnosis (bipolar I or bipolar II). Conclusions The present review suggests that the cerebellum should be considered a key structure involved in the regulation of mood.

Brain imaging studies on eating disorders (EDs) often reported volumetric and functional changes involving the cerebellum. Nevertheless, few studies performed in-depth examinations and suggested a cerebellar role in the EDs' pathophysiology.A systematic literature search on volumetric changes and functional alterations involving the cerebellum in individuals with EDs was conducted using PubMed, PsychInfo and Web of Science. This review was conducted according to the Preferred Reporting Items for Systematic Reviews (PRISMA) statement and Rayyan web application for screening studies.Twenty-four papers reporting cerebellar alterations in individuals with EDs were included in the study: 9 assessing brain volumetric changes, 9 investigating task-based functional brain activation and 6 investigating brain functional connectivity at rest. Most studies focused on anorectic-type EDs (n.22), while fewer involved bulimic-type EDs (n.9) and eating disorders not otherwise specified (n.2), revealing subtypes-specific patterns of altered cerebellar volume and functionality.This review proposes critical arguments to consider the cerebellum as a key structure in the pathophysiology of EDs that requires further forthcoming exploration.

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.

The aim of this study was to compare the patterns of cerebellar alterations associated with bipolar disease with those induced by the presence of cerebellar neurodegenerative pathologies to clarify the potential cerebellar contribution to bipolar affective disturbance. Twenty-nine patients affected by bipolar disorder, 32 subjects affected by cerebellar neurodegenerative pathologies, and 37 age-matched healthy subjects underwent a 3T MRI protocol. A voxel-based morphometry analysis was used to show similarities and differences in cerebellar grey matter (GM) loss between the groups. We found a pattern of GM cerebellar alterations in both bipolar and cerebellar groups that involved the anterior and posterior cerebellar regions (p = 0.05). The direct comparison between bipolar and cerebellar patients demonstrated a significant difference in GM loss in cerebellar neurodegenerative patients in the bilateral anterior and posterior motor cerebellar regions, such as lobules I−IV, V, VI, VIIIa, VIIIb, IX, VIIb and vermis VI, while a pattern of overlapping GM loss was evident in right lobule V, right crus I and bilateral crus II. Our findings showed, for the first time, common and different alteration patterns of specific cerebellar lobules in bipolar and neurodegenerative cerebellar patients, which allowed us to hypothesize a cerebellar role in the cognitive and mood dysregulation symptoms that characterize bipolar disorder.

Clinical studies described emotional and social behaviour alterations in patients with cerebellar diseases, proposing a role of specific cerebello-cerebral circuits in social cognition. However, for a long time these difficulties were underestimated, and no studies have addressed the correlation between social cognition deficits and topography of the cerebellar damage. The present study aims to investigate the social cognition impairment and the neuroanatomical alterations in patients with spinocerebellar ataxia type 2 (SCA2) and to analyze their relationship. To this purpose a social cognition battery composed by three tests, and a MRI protocol were administered to 13 SCA2 patients and 26 healthy subjects. The pattern of gray matter (GM) atrophy was analyzed by voxel-based morphometry, and the GM volumes of each altered area were correlated with the behavioral scores to investigate anatomo-functional relationships. In addition, we investigated the relationship between social deficits and damage to the cerebellar peduncles using DTI diffusivity indices. Our patients showed impairment of the immediate perceptual component of the mental state recognition (i.e., to recognize feelings and thoughts from the eyes expression), and difficulties in anger attribution, and in the understanding of false or mistaken beliefs. They showed a pattern of GM reduction in cerebellar regions, including lobules IX and VIIIb and Crus II, all of which are involved in specific components of the mentalizing process. Interestingly, the behavioral performance, in which SCA2 patients showed impairments compared to controls, correlated with the degree of cerebellar GM reduction and with the presence of microstructural abnormalities in the cerebellar peduncles. The present study provides the first characterization of the social cognition deficits in a homogenous cohort SCA2 patients and demonstrates that alterations in specific cerebellar regions should represent the neurobiological underpinning of their social behavior difficulties. Our results offer a new point of view in considering these aspects in the clinical practice.

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.

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. Frank Van Overwalle, Elien Heleven, Qianying Ma, and Min Pu were supported by an SRP57 grant from the Vrije Universiteit Brussel, and Elien Heleven was additionally supported by an FWO G002319N/AL907 grant from the Flemish government. Zaira Cattaneo was supported by a Bando Ricerca Finalizzata (GR2016-02363640) by the Italian Ministry of Health. Marco Michelutti and Arseny A. Sokolov were supported by aMille E Una Lode fellowship from the University of Padua to MM, and fellowships from the Leenaards Foundation and the Swiss National Science Foundation, and a grant from the Helmut Horten Foundation to AAS. Catherine Stoodley and Laura C. Rice were supported by an NIH R15MH106957 grant. Van Overwalle, F (corresponding author), Vrije Univ Brussel, Dept Psychol, Pl Laan 2, B-1050 Brussels, Belgium; Vrije Univ Brussel, Ctr Neurosci, Pl Laan 2, B-1050 Brussels, Belgium. Frank.VanOverwalle@vub.ac.be; mmanto@ulb.ac.be; zaira.cattaneo@unimib.it; silvia.clausi@uniroma1.it; chiara.ferrari@unipv.it; gabrieli@mit.edu; xguellparadis@mgh.harvard.edu; Elien.Heleven@vub.be; m.lupo@hsantalucia.it; Qianying.Ma@vub.be; michelutti.marco.m@gmail.com; g.olivito@hsantalucia.it; Min.Pu@vub.be; laura.blevins@student.american.edu; jschmahmann@mgh.harvard.edu; libera.siciliano@uniroma1.it; Arseny.Sokolov@chuv.ch; stoodley@american.edu; kim.vandun@uhasselt.be; LVandervert@aol.com; maria.leggio@uniroma1.it

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.

Background Although depressive symptoms are often reported to be comorbid with degenerative cerebellar diseases, the role of the cerebellum in depressive disorder needs to be elucidated. To address this aim, we investigated self-perception of the negative mood state in patients with cerebellar pathology and depressive symptoms. Methods Thirty-eight patients with cerebellar damage (10 with depressive symptoms – CB-DP and 28 with no depressive symptoms – CB-nDP), 11 subjects with depressive disorders without cerebellar damage (DP) and 29 healthy controls (CTs) were enrolled. A device for self-monitoring of the mood state (MoMo) and validated scales such as the Profile of Mood States questionnaire (POMS), the Self-Report Symptom Inventory-Revised (SCL-90-R) and the Hamilton Depression Rating Scale (HDRS) were used to evaluate depressive symptoms. Results Both CB-DP and DP patients showed higher scores than CTs on the POMS and SCL-90-R for depressive factors and on the HDRS. DP patients showed a lower frequency of ‘good’ mood and a higher frequency of ‘bad’ mood than CTs when using the MoMo device. However, although the two depressed populations showed comparable scores on these validated scales, CB-DP patients showed impaired self-awareness of the mood experience in ‘the here and now’, as evidenced by the absence of significant differences, compared with CTs, in the subjective mood evaluation performed with the MoMo device. Limitations The number of CB patients and inhomogeneity across MRI scans were study limitations. Conclusion Cerebellar dysfunction might slow the data integration necessary for mood state awareness, resulting in difficulty of depressed CB patients in explicitly recognizing their mood “in the here and now”.

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.