The Human Cerebellum as a Hub of the Predictive Brain

Although the cerebellum has long been believed to be involved uniquely in sensorimotor processes, recent research works pointed to its participation in a wide range of cognitive predictive functions. Here, we review the available evidence supporting a generalized role of the cerebellum in predictive computation. We then discuss the anatomo-physiological properties that make the cerebellum the ideal hub of the predictive brain. We further argue that cerebellar involvement in cognition may follow a continuous gradient, with higher cerebellar activity occurring for tasks relying more on predictive processes, and outline the empirical scenarios to probe this hypothesis.

The Cerebellum in Drug-naive Children with Tourette Syndrome and Obsessive–Compulsive Disorder

Tourette syndrome (TS) and obsessive–compulsive disorder (OCD) are two neurodevelopmental disorders characterized by repetitive behaviors. Our recent study in drug-naive children with TS and OCD provided evidence of cerebellar involvement in both disorders. In addition, cerebellar functional connectivity (FC) was similar in TS patients without comorbidities (TSpure) and TS patients with OCD comorbidity (TS + OCD), but differed in pure OCD patients. To investigate in detail the cerebellar involvement in the pathophysiology of TS and OCD, we explored cerebellar structural and functional abnormalities in drug-naive children with TSpure, TS + OCD, and OCD and assessed possible correlations with severity scores. We examined 53 drug-naive children, classified as TSpure (n = 16), TS + OCD (n = 14), OCD (n = 11), or controls (n = 12). All subjects underwent a multimodal 3T magnetic resonance imaging examination. Cerebellar lobular volumes and quantitative diffusion tensor imaging parameters of cerebellar peduncles were used as measures of structural integrity. The dentate nucleus was selected as a region of interest to examine cerebello-cerebral functional connectivity alterations. Structural analysis revealed that both TSpure and TS + OCD patients had higher fractional anisotropy in cerebellar peduncles than controls. Conversely, OCD patients were characterized by lower fractional anisotropy than both controls and TSpure and TS + OCD patients. Lastly, cerebellar functional connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical circuit in TSpure, TS + OCD, and OCD patients. Early cerebellar structural and functional changes in drug-naive pediatric TSpure, TS + OCD, and OCD patients support a primary role of the cerebellum in the pathophysiology of these disorders.

Infratentorial MRI Findings in Rasmussen Encephalitis Suggest Primary Cerebellar Involvement

Background and ObjectiveRasmussen encephalitis (RE) is characterized by its unilateral cerebral involvement. However, both ipsi- and contralesional cerebellar atrophy have been anecdotally reported raising questions about the nature and extent of infratentorial findings. Using MRI, we morphometrically investigated the cerebellum and hypothesized abnormalities beyond the effects of secondary atrophy, implicating a primary involvement of the cerebellum by RE.MethodsVoxel-based morphometry of the cerebellum and brainstem was conducted in 57 patients with RE and in 57 matched controls. Furthermore, patient-specific asymmetry indices (AIs) of cerebellar morphometry and fluid-attenuated inversion recovery (FLAIR) intensity were calculated. Using diffusion tensor imaging, the integrity of the cortico-ponto-cerebellar (CPC) tract was assessed. Finally, a spatial independent component analysis (ICA) was used to compare atrophy patterns between groups.ResultsPatients with RE showed bilateral cerebellar and predominantly ipsilesional mesencephalic atrophy (p < 0.01). Morphometric AIs revealed ipsilesional < contralesional asymmetry in 27 and ipsilesional > contralesional asymmetry in 30 patients. In patients with predominant ipsilesional atrophy, morphometric AIs strongly correlated with FLAIR intensity AIs (r = 0.86, p < 0.0001). Fractional anisotropy was lower for ipsilesional-to-contralesional CPC tracts than opposite tracts (T = 2.30, p < 0.05). ICA revealed bilateral and strictly ipsi- and contralesional atrophy components in patients with RE (p < 0.05).DiscussionWe demonstrated atrophy of the ipsilesional-to-contralesional CPC pathway and, consequently, interpret the loss of contralesional gray matter as secondary crossed cerebellar atrophy. The ipsilesional cerebellar atrophy, however, defies this explanation. Based on FLAIR hyperintensities, we interpret ipsilesional atrophy to be due to inflammation in the scope of a primary involvement of the cerebellum by RE.

CACNA1A-p.Thr501Met mutation associated with familial hemiplegic migraine: a family report

Background and aims Hemiplegic migraine (HM) is a rare form of migraine characterized by the presence of a motor and other types of aura. HM can be sporadic or familial. Familial hemiplegic migraine (FHM) is an autosomal dominant disorder, classified into 3 subtypes, based on the gene involved (CACNA1A in FHM1, ATP1A2 in FHM2 and SCN1A in FHM3). The clinical presentation is highly heterogeneous and some attacks may be severe. We report the clinical characteristics and genetic analysis of 12 patients belonging to a family with CACNA1A-p.Thr501Met gene mutation. Methods We screened for mutations in CACNA1A gene 15 patients belonging to the same family. The exonic sequences of CACNA1A were analyzed using a Tru-seq® Custom Amplicon (TSCA) (Illumina Inc., San Diego, CA) targeted capture and paired end library kit. Sanger sequencing was used to confirm CACNA1A variants and segregation analysis. Results CACNA1A-p.Thr501Met mutation was found in 12 of the 15 patients screened, which was compatible with the diagnosis of FHM1. Attacks of hemiplegic migraine were reported by 10 of the 12 subjects (83.33%). Only one subject developed persistent mild cerebellar symptoms and none of the subjects developed cerebellar atrophy. Discussion The variant p.Thr501Met was described previously in association with episodic ataxia and rarely with FHM related to cerebellar symptoms. FHM1 has a broad clinical spectrum and about half of the families have cerebellar involvement. In our study, only one patient developed persistent cerebellar deficits. These data suggest that CACNA1A-p.Thr501Met mutation can occur prevalently as hemiplegic migraine.

Probing cerebellar involvement in cognition through a meta-analysis of TMS evidence

Traditionally, the cerebellum has been linked to motor coordination, but growing evidence points to its involvement in a wide range of non-motor functions. Though the number of studies using transcranial magnetic stimulation (TMS) to investigate cerebellar involvement in cognitive processes is growing exponentially, these findings have not yet been synthesized in a meta-analysis. Here, we used meta-analysis to estimate the effects of cerebellar TMS on performance in cognitive tasks for healthy participants. Outcomes included participants’ accuracy and response times (RTs) of several non-motor tasks performed either during or after the administration of TMS. We included overall 41 studies, of which 44 single experiments reported effects on accuracy and 41 on response times (RTs). The meta-analyses showed medium effect sizes (for accuracy: d = 0.61 [95% CI = 0.48, .073]; for RTs: d = 0.40 [95% CI = 0.30, 0.49]), with leave-one-out analyses indicating that cumulative effects were robust, and with moderate heterogeneity. For both accuracy and RTs, the effect of TMS was moderated by the stimulation paradigm adopted but not by the cognitive function investigated, while the timing of the stimulation moderated only the effects on RTs. Further analyses on lateralization revealed no moderation effects of the TMS site. Taken together, these findings indicate that TMS administered over the cerebellum is able to modulate cognitive performance, affecting accuracy or RTs, and suggest that the various stimulation paradigms play a key role in determining the efficacy of cerebellar TMS.

Structural Changes on MRI Demonstrate Specific Cerebellar Involvement in SLE Patients—A VBM Study

The purpose of this study is to investigate possible differences in brain structure, as measured by T1-weighted MRI, between patients with systemic lupus erythematosus (SLE) and healthy controls (HC), and whether any observed differences were in turn more severe in SLE patients with neuropsychiatric manifestations (NPSLE) than those without (non-NPSLE). Structural T1-weighted MRI was performed on 69 female SLE patients (mean age = 35.8 years, range = 18–51 years) and 24 age-matched female HC (mean age = 36.8 years, range = 23–52 years) in conjunction with neuropsychological assessment using the CNS Vital Signs test battery. T1-weighted images were preprocessed and analyzed by FSL-VBM. The results show that SLE patients had lower grey matter probability values than the control group in the VIIIa of the cerebellum bilaterally, a region that has previously been implied in sensorimotor processing in human and non-human primates. No structural differences for this region were found between NPSLE and non-NPSLE patients. VBM values from the VIIIa region showed a weak positive correlation with the psychomotor speed domain from CNS Vital Signs (p = 0.05, r = 0.21), which is in line with its presumed role as a sensorimotor processing area.