Cerebellar Contribution Research Articles

The lateralized cerebellum: insights into motor, cognitive, and affective functioning across ages: a scoping review.

Research on the cerebellum and its functional organization has significantly expanded over the last decades, expanding our comprehension of its role far beyond motor control, including critical contributions to cognition and affective processing. Notably, the cerebellar lateralization mirrors contralateral brain lateralization, a complex phenomenon that remains unexplored, especially across different stages of life. The present work aims to bridge this gap by providing a comprehensive scoping review of the lateralization of motor, cognitive, and affective functioning within the cerebellum across the lifespan. A methodical search in electronic databases (i.e., PubMed, Embase, and PsycINFO) was conducted up to October 2024, focusing on neuroimaging studies with healthy participants of all ages performing motor, cognitive, or affective tasks. Our selection process, which involved multiple independent reviewers, identified 128 studies reporting cerebellar asymmetries in individuals from early childhood to older age, with a significant portion of studies regarding young-middle adults (19-45years old). The majority of the findings confirmed established lateralization patterns in motor and language processing, such as ipsilateral motor control and right-lateralized language functions. However, less attention has been paid to other cognitive functions and affective processing where more heterogeneous and less consistent asymmetries have been observed. To the best of our knowledge, this scoping review is the first to comprehensively investigate the motor, cognitive, and affective functional lateralization of the cerebellum across lifespan, highlighting previously overlooked dimensions of cerebellar contributions.

Behavioral decline in Shank3Δex4–22 mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes

BackgroundSHANK3, a gene encoding a synaptic scaffolding protein, is implicated in autism spectrum disorder (ASD) and is disrupted in Phelan-McDermid syndrome (PMS). Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although Shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in Shank3Δex4–22 mice at two developmental stages.MethodsShank3Δex4–22 wildtype, heterozygous, and homozygous knockout mice lacking exons 4–22 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5–7 weeks old) and adult (3–5 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of Shank3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology.ResultsDeletion of Shank3 caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult Shank3Δex4–22 knockout male mice, while self-grooming was uniquely elevated in males across both age groups. Heterozygous mice showed little to no changes in behavioral phenotypes in most behavioral tests. Immunofluorescence staining indicated the presence of Shank3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identified a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs.LimitationsOther behavioral tests of muscle strength (grip strength test), memory (Barnes/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how Shank3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum and whether these changes shape the behavioral phenotype.ConclusionsOur findings reveal an age-related exacerbation of behavioral impairments in Shank3Δex4–22 mutant mice. These results suggest that Shank3 may alter the function of glutamatergic receptors at the mossy fiber-cerebellar granule cell synapse as a potential mechanism causing cerebellar disruption in ASD.

Cerebellar contribution to emotion regulation and its association with medial frontal GABA level.

Distancing involves changing perspectives to alter the psychological distance from stimuli that elicit emotional reactions as a tactic to regulate emotions. Using magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging, this study aimed to examine 1) whether the neural correlates of emotion upregulation via distancing differ across emotional valence (i.e., emotional responses toward positive and negative pictures), and 2) whether the gamma-aminobutyric acid (GABA) concentration in the medial prefrontal cortex (MPFC), one of the crucial areas of emotion regulation, is correlated with brain activity related to either negative or positive emotion upregulation. Thirty-four healthy Japanese adults participated in this study. Compared to the condition involving positive emotion upregulation, negative emotion upregulation induced increased activation in the MPFC, left temporoparietal junction, bilateral anterior insula, pre-supplementary motor area, and bilateral cerebellum. In contrast, when comparing positive emotion upregulation with negative emotion upregulation, no significant activation was found. Right cerebellar activity during negative emotion upregulation positively correlated with GABA concentration in the MPFC. These findings provide evidence of cerebellar involvement in the upregulation of negative emotion via distancing and its association with the prefrontal GABA concentration.

Cerebellar Purkinje Cells Control Posture in Larval Zebrafish (Danio rerio).

Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells - the output neurons of the cerebellar cortex - as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically-tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.

Abstract 143: Social cognition impairments in patients with isolated cerebellar stroke

Introduction/Purpose Recent studies point to an important role for the cerebellum in nonmotor functions, primarily including higher cognitive functions and affect. However, the available evidence on the cerebellar contribution to social cognitive faculties are currently sparse and the exact role of the cerebellum in social cognition is yet to be elucidated. The present study aimed to investigate the impairments in social cognition in a group of patients who suffered from isolated cerebellar stroke. We hypothesized that patients in earlier stages of their stroke and patients with posterior cerebellar lesions would be more affected in the social cognition domain than the rest of the group. Materials/Methods We tested 30 patients with isolated ischemic cerebellar stroke and 30 age, sex‐ and education‐matched healthy controls. Patients were classified according to the duration after stroke (acute, subacute and chronic) as well as the location of the cerebellar lesion. A cognitive battery primarily focusing on social cognition was performed and included Montreal Cognitive Assessment (MoCA), Reading the Mind in the Eyes Test, Penn CNB Emotion Recognition Test, Faux Pas test, Tromso Social Intelligent Scale, The Social‐Emotional Expertise Scale and Geriatric Depression Scale. A thorough neurological examination was performed and Brief Ataxia Rating Scale was administered to assess ataxia symptoms specifically. The results were analyzed according to the timeline of ischemic insult and location of the lesions (e.g. anterior cerebellum, posterior cerebellum, right and left cerebellar hemispheres). Results Our results revealed a significant difference for the Penn Emotion Recognition Test pointing to significantly reduced anger recognition in the cerebellar stroke group compared to the healthy controls (p<0.05). The Faux‐Pas test revealed a significant impairment confined to the affective theory of mind section of the test (p<0.05). Data from the Reading the mind in the Eyes test did not reveal statistical significance between the cerebellar stroke and control groups (p>0.05). However, when analyzed for subgroups, the performance score was significantly lower in patients with left posterior cerebellar stroke (p=0.015). The scales and the MOCA test did not show significant differences among the patients and the healthy controls (p>0.05). Conclusion Our findings provide critical information regarding the cerebellar contributions on the social cognition network and expands the available evidence regarding the impairment in the social cognition following cerebellar stroke. Further research comprising more patients and detailed neuroimaging data will be able to illuminate the details of social cognition after cerebellar insult.

Behavioral regression in shank3Δex4-22 mice during early adulthood corresponds to cerebellar granule cell glutamatergic synaptic changes.

Shank3, a gene encoding a synaptic scaffolding protein, is implicated in autism spectrum disorder (ASD) and is disrupted in Phelan-McDermid syndrome (PMS). Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in shank3 Δex4-22 mice at two developmental stages. Shank3 Δex4-22 wildtype, heterozygous, and homozygous knockout mice lacking exons 4-22 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5-7 weeks old) and adult (3-5 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of SHANK3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology. Deletion of shank3 ex4-22 caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult shank3 Δex4-22 knockout mice and self-grooming was uniquely elevated only in males across both age groups. Immunofluorescence staining indicates the presence of SHANK3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identify a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs. Other behavioral tests of muscle strength (grip strength test), memory (Barnes/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how SHANK3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum. Our findings reveal an age-related exacerbation of behavioral impairments in shank3 Δex4-22 mutant mice. These results suggest that SHANK3 may play a role in maintaining glutamatergic receptors and synapses in CGCs, as well as the potential involvement of the cerebellum in ASD.

The significance of cerebellar contributions in early-life through aging.

The significance of cerebellar contributions in early-life through aging.

Cerebellar Contributions to Traumatic Autobiographical Memory in People with Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a debilitating mental health condition characterized by recurrent re-experiencing of traumatic events. Despite increasing evidence suggesting that the cerebellum is involved in PTSD pathophysiology, it remains unclear whether this involvement is related to symptoms directly resulting from previous trauma exposure, such as involuntary re-experiencing of the traumatic events, or reflects a broader cerebellar engagement in negative affective states. In this study, we investigated the specific role of the cerebellum in PTSD by employing a script reactivation paradigm with personalized traumatic and sad autobiographical memories in 28 individuals diagnosed with chronic PTSD. Functional magnetic resonance imaging (fMRI) data were collected while participants listened to their own autobiographical narratives recounted by a third person. Activation in the right cerebellar lobule VI was uniquely associated with traumatic autobiographical recall and was parametrically modulated by the severity of re-experiencing symptoms. In contrast, cerebellar Crus II showed increased activation during both traumatic and sad autobiographical recall, suggesting a broader involvement in processing negative emotions. Our findings highlight the unique contribution of the right cerebellar lobule VI in the processing of traumatic autobiographical memories, potentially through its engagement in low-level representation of sensory and emotional aspects of traumatic events.

Cerebellar Roles in Motor and Social Functions and Implications for ASD.

The cerebellum, traditionally linked to voluntary motor coordination, is now recognized for its role in nonmotor functions, including cognitive and social behaviors. This expanded understanding is vital for identifying neurodevelopmental disorders such as autism spectrum disorder (ASD), where cerebellar abnormalities are common. Recent research has identified specific cerebellar circuits contributing to these diverse functions, revealing interconnected pathways that regulate both motor and social behaviors. The cerebellum communicates extensively with the cerebral cortex, thalamus, and limbic structures through converging and diverging pathways, integrating sensory and motor information to fine-tune outputs and influence higher-order functions. Mouse models have been instrumental in dissecting cerebellar functions, with studies using genetic and neuroanatomical techniques to manipulate specific circuits and observe behavioral outcomes. Disruptions in cerebellar pathways can lead to motor deficits and social impairments, mirroring human neurodevelopmental disorders. This review explores the anatomical and functional organization of cerebellar pathways in mice, their role in behavior, and the implications of cerebellar dysfunction in disorders such as ASD. Understanding these pathways enhances knowledge of cerebellar contributions to behavior and informs therapeutic strategies for cerebellar and neurodevelopmental disorders, emphasizing the integral role of the cerebellum in motor and social functions.

Unveiling altered connectivity between cognitive networks and cerebellum in schizophrenia

Cognitive functioning is a crucial aspect in schizophrenia (SZ), and when altered it has devastating effects on patients' quality of life and treatment outcomes. Several studies suggested that they could result from altered communication between the cortex and cerebellum. However, the neural correlates underlying these impairments have not been identified. In this study, we investigated resting state functional connectivity (rsFC) in SZ patients, by considering the interactions between cortical networks supporting cognition and cerebellum. In addition, we investigated the relationship between SZ patients' rsFC and their symptoms.We used fMRI data from 74 SZ patients and 74 matched healthy controls (HC) downloaded from the publicly available database SchizConnect. We implemented a seed-based connectivity approach to identify altered functional connections between specific cortical networks and cerebellum. We considered ten commonly studied resting state networks, whose functioning encompasses specific cognitive functions, and the cerebellum, whose involvement in supporting cognition has been recently identified. We then explored the relationship between altered rsFC values and Positive and Negative Syndrome Scale (PANSS) scores.The SZ group showed increased connectivity values compared with HC group for cortical networks involved in attentive processes, which were also linked to PANSS items describing attention and language-related processing. We also showed decreased connectivity between cerebellar regions, and increased connectivity between them and attentive networks, suggesting the contribution of cerebellum to attentive and affective deficits.In conclusion, our findings highlighted the link between negative symptoms in SZ and altered connectivity within the cerebellum and between the same and cortical networks supporting cognition.

Consensus Paper: Cerebellum and Reward.

Cerebellum is a key-structure for the modulation of motor, cognitive, social and affective functions, contributing to automatic behaviours through interactions with the cerebral cortex, basal ganglia and spinal cord. The predictive mechanisms used by the cerebellum cover not only sensorimotor functions but also reward-related tasks. Cerebellar circuits appear to encode temporal difference error and reward prediction error. From a chemical standpoint, cerebellar catecholamines modulate the rate of cerebellar-based cognitive learning, and mediate cerebellar contributions during complex behaviours. Reward processing and its associated emotions are tuned by the cerebellum which operates as a controller of adaptive homeostatic processes based on interoceptive and exteroceptive inputs. Lobules VI-VII/areas of the vermis are candidate regions for the cortico-subcortical signaling pathways associated with loss aversion and reward sensitivity, together with other nodes of the limbic circuitry. There is growing evidence that the cerebellum works as a hub of regional dysconnectivity across all mood states and that mental disorders involve the cerebellar circuitry, including mood and addiction disorders, and impaired eating behaviors where the cerebellum might be involved in longer time scales of prediction as compared to motor operations. Cerebellar patients exhibit aberrant social behaviour, showing aberrant impulsivity/compulsivity. The cerebellum is a master-piece of reward mechanisms, together with the striatum, ventral tegmental area (VTA) and prefrontal cortex (PFC). Critically, studies on reward processing reinforce our view that a fundamental role of the cerebellum is to construct internal models, perform predictions on the impact of future behaviour and compare what is predicted and what actually occurs.

Dissociated cerebellar contributions to feedforward gait adaptation

The cerebellum is important for motor adaptation. Lesions to the vestibulo-cerebellum selectively cause gait ataxia. Here we investigate how such damage affects locomotor adaptation when performing the ‘broken escalator’ paradigm. Following an auditory cue, participants were required to step from the fixed surface onto a moving platform (akin to an airport travellator). The experiment included three conditions: 10 stationary (BEFORE), 15 moving (MOVING) and 10 stationary (AFTER) trials. We assessed both behavioural (gait approach velocity and trunk sway after stepping onto the moving platform) and neuromuscular outcomes (lower leg muscle activity, EMG). Unlike controls, cerebellar patients showed reduced after-effects (AFTER trials) with respect to gait approach velocity and leg EMG activity. However, patients with cerebellar damage maintain the ability to learn the trunk movement required to maximise stability after stepping onto the moving platform (i.e., reactive postural behaviours). Importantly, our findings reveal that these patients could even initiate these behaviours in a feedforward manner, leading to an after-effect. These findings reveal that the cerebellum is crucial for feedforward locomotor control, but that adaptive locomotor behaviours learned via feedback (i.e., reactive) mechanisms may be preserved following cerebellum damage.

Population-wide cerebellar growth models of children and adolescents

In the past, the cerebellum has been best known for its crucial role in motor function. However, increasingly more findings highlight the importance of cerebellar contributions in cognitive functions and neurodevelopment. Using a total of 7240 neuroimaging scans from 4862 individuals, we describe and provide detailed, openly available models of cerebellar development in childhood and adolescence (age range: 6–17 years), an important time period for brain development and onset of neuropsychiatric disorders. Next to a traditionally used anatomical parcellation of the cerebellum, we generated growth models based on a recently proposed functional parcellation. In both, we find an anterior-posterior growth gradient mirroring the age-related improvements of underlying behavior and function, which is analogous to cerebral maturation patterns and offers evidence for directly related cerebello-cortical developmental trajectories. Finally, we illustrate how the current approach can be used to detect cerebellar abnormalities in clinical samples.

Frontal and cerebellar contributions to pitch and rhythm processing: a TMS study.

Music represents a salient stimulus for the brain with two key features: pitch and rhythm. Few data are available on cognitive analysis of music listening in musically naïve healthy participants. Beyond auditory cortices, neuroimaging data showed the involvement of prefrontal cortex in pitch and of cerebellum in rhythm. The present study is aimed at investigating the role of prefrontal and cerebellar cortices in both pitch and rhythm processing. The performance of fifteen participants without musical expertise was investigated in a listening discrimination task. The task required to decide whether two eight-element melodic sequences were equal or different according to pitch or rhythm characteristics. Before the task, we applied a protocol of continuous theta burst transcranial magnetic stimulation interfering with the activity of the left cerebellar hemisphere (lCb), right inferior frontal gyrus (rIFG), or vertex (Cz-control site), in a within cross-over design. Our results showed that participants were more accurate in pitch than rhythm tasks. Importantly, the reaction times were slower following rIFG or lCb stimulations in both tasks. Notably, frontal and cerebellar stimulations did not induce any motor effect in right and left hand. The present findings point to the role of the fronto-cerebellar network in music processing with a single mechanism for both pitch and rhythm patterns.

The effect of cerebellar TMS on error processing: A combined single-pulse TMS and ERP study

AbstractThe present study investigated temporal aspects of cerebellar contributions to the processing of performance errors as indexed by the error-related negativity (ERN) in the response-locked event-related potential (ERP). We co-registered EEG and applied single-pulse transcranial magnetic stimulation (spTMS) to the left posterolateral cerebellum and an extra-cerebellar control region (vertex) while healthy adult volunteers performed a Go/Nogo Flanker Task. In Go trials, TMS pulses were applied at four different time points, with temporal shifts of -100 ms, -50 ms, 0 ms, or +50 ms relative to the individual error latency (IEL, i.e., individual ERN peak latency + median error response time). These stimulation timings were aggregated into early (-100 ms, -50 ms) and late (0 ms, +50 ms) stimulation for the analysis. In Nogo trials, TMS pulses occurred 0 ms, 100 ms, or 300 ms after stimulus onset. Mixed linear model analyses revealed that cerebellar stimulation did not affect error rates overall. No effects were found for response times. As hypothesized, ERN amplitudes were decreased for cerebellar stimulation. No significant differences were found for the error positivity (Pe). Similar to TMS application to probe cerebellar-brain inhibition in the motor domain, the inhibitory tone of the cerebellar cortex may have been disrupted by the pulses. Reduced inhibitory output of the cerebellar cortex may have facilitated the processing of error information for response selection, which is reflected in a decreased ERN.

Linking inter-subject variability of cerebellar functional connectome to clinical symptoms in major depressive disorder

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with remarkable inter-subject variability in clinical manifestations. Neuroimaging changes of the cerebellum have been recently proposed as a way to characterize MDD-related brain disruptions and might further explain various clinical symptoms. However, the cerebellar contributions to MDD clinical heterogeneity remain largely unknown.The analyzed data consisted of 251 MDD patients and 235 matching healthy controls (HC). The inter-subject variability of functional connectomes (IVFC) was estimated via Pearson's correlation analysis between each pair of the cerebellar and cerebral regions based on resting-state functional magnetic resonance imaging (rs-fMRI). A partial least squares (PLS) regression analysis was performed to determine the potential dimension linking the IVFC to clinical symptom measures.The results indicated that similar spatial distribution patterns of the cerebellar IVFC were observed between MDD and HC, but the MDD group exhibited abnormal IVFC alterations in the bilateral Cerebelum_4_5, bilateral Cerebelum_6, Vermis_1_2 and Vermis_8. The PLS model revealed that the IVFC pattern in the left Cerebelum_6 was significantly associated with three HAMD-17 items including the work and activities, psychomotor retardation, and depressed mood. These findings provided new evidence for the cerebellar changes in MDD. Specifically, we found that the altered inter-subject variability measurements correlated with clinical manifestations of this illness. Elucidating this variability could prove helpful for the evaluation of MDD heterogeneity as well as for understanding its pathophysiological mechanism.

Knockdown of the Non-canonical Wnt Gene Prickle2 Leads to Cerebellar Purkinje Cell Abnormalities While Cerebellar-Mediated Behaviors Remain Intact.

Autism spectrum disorders (ASD) involve brain wide abnormalities that contribute to a constellation of symptoms including behavioral inflexibility, cognitive dysfunction, learning impairments, altered social interactions, and perceptive time difficulties. Although a single genetic variation does not cause ASD, genetic variations such as one involving a non-canonical Wnt signaling gene, Prickle2, has been found in individuals with ASD. Previous work looking into phenotypes of Prickle2 knock-out (Prickle2-/-) and heterozygous mice (Prickle2-/+) suggest patterns of behavior similar to individuals with ASD including altered social interaction and behavioral inflexibility. Growing evidence implicates the cerebellum in ASD. As Prickle2 is expressed in the cerebellum, this animal model presents a unique opportunity to investigate the cerebellar contribution to autism-like phenotypes. Here, we explore cerebellar structural and physiological abnormalities in animals with Prickle2 knockdown using immunohistochemistry, whole-cell patch clamp electrophysiology, and several cerebellar-associated motor and timing tasks, including interval timing and eyeblink conditioning. Histologically, Prickle2-/- mice have significantly more empty spaces or gaps between Purkinje cells in the posterior lobules and a decreased propensity for Purkinje cells to fire action potentials. These structural cerebellar abnormalities did not impair cerebellar-associated behaviors as eyeblink conditioning and interval timing remained intact. Therefore, although Prickle-/- mice show classic phenotypes of ASD, they do not recapitulate the involvement of the adult cerebellum and may not represent the pathophysiological heterogeneity of the disorder.

Cerebellum's Contribution to Attention, Executive Functions and Timing: Psychophysiological Evidence from Event-Related Potentials.

Since 1998, when Schmahmann first proposed the concept of the "cognitive affective syndrome" that linked cerebellar damage to cognitive and emotional impairments, a substantial body of literature has emerged. Anatomical, neurophysiological, and functional neuroimaging data suggest that the cerebellum contributes to cognitive functions through specific cerebral-cerebellar connections organized in a series of parallel loops. The aim of this paper is to review the current findings on the involvement of the cerebellum in selective cognitive functions, using a psychophysiological perspective with event-related potentials (ERPs), alone or in combination with non-invasive brain stimulation techniques. ERPs represent a very informative method of monitoring cognitive functioning online and have the potential to serve as valuable biomarkers of brain dysfunction that is undetected by other traditional clinical tools. This review will focus on the data on attention, executive functions, and time processing obtained in healthy subjects and patients with varying clinical conditions, thus confirming the role of ERPs in understanding the role of the cerebellum in cognition and exploring the potential diagnostic and therapeutic implications of ERP-based assessments in patients.

High-density transcranial direct current stimulation to improve upper limb motor function following stroke: study protocol for a double-blind randomized clinical trial targeting prefrontal and/or cerebellar cognitive contributions to voluntary motion

BackgroundFocal brain lesions following a stroke of the middle cerebral artery induce large-scale network disarray with a potential to impact multiple cognitive and behavioral domains. Over the last 20 years, non-invasive brain neuromodulation via electrical (tCS) stimulation has shown promise to modulate motor deficits and contribute to recovery. However, weak, inconsistent, or at times heterogeneous outcomes using these techniques have also highlighted the need for novel strategies and the assessment of their efficacy in ad hoc controlled clinical trials.MethodsWe here present a double-blind, sham-controlled, single-center, randomized pilot clinical trial involving participants having suffered a unilateral middle cerebral artery (MCA) stroke resulting in motor paralysis of the contralateral upper limb. Patients will undergo a 10-day regime (5 days a week for 2 consecutive weeks) of a newly designed high-definition transcranial direct current stimulation (HD-tDCS) protocol. Clinical evaluations (e.g., Fugl Meyer, NIHSS), computer-based cognitive assessments (visuo-motor adaptation and AX-CPT attention tasks), and electroencephalography (resting-state and task-evoked EEG) will be carried out at 3 time points: (I) Baseline, (II) Post-tDCS, and (III) Follow-up. The study consists of a four-arm trial comparing the impact on motor recovery of three active anodal tDCS conditions: ipsilesional DLPFC tDCS, contralesional cerebellar tDCS or combined DLPFC + contralesional cerebellar tDCS, and a sham tDCS intervention. The Fugl-Meyer Assessment for the upper extremity (FMA-UE) is selected as the primary outcome measure to quantify motor recovery. In every stimulation session, participants will receive 20 min of high-density tDCS stimulation (HD-tDCS) (up to 0.63 mA/cm2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\mathrm{cm}}^{2}$$\\end{document}) with πcm2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\mathrm{\\pi cm}}^{2}$$\\end{document} electrodes. Electrode scalp positioning relative to the cortical surface (anodes and cathodes) and intensities are based on a biophysical optimization model of current distribution ensuring a 0.25 V/m impact at each of the chosen targets.DiscussionOur trial will gauge the therapeutic potential of accumulative sessions of HD-tDCS to improve upper limb motor and cognitive dysfunctions presented by middle cerebral artery stroke patients. In parallel, we aim at characterizing changes in electroencephalographic (EEG) activity as biomarkers of clinical effects and at identifying potential interactions between tDCS impact and motor performance outcomes. Our work will enrich our mechanistic understanding on prefrontal and cerebellar contributions to motor function and its rehabilitation following brain damage.Trial registrationClinicalTrials.gov NCT05329818. April 15, 2022.

Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models

Cerebellar dysfunction has been linked to autism spectrum disorders (ASDs). Although cerebellar pathology has been observed in individuals with fragile X syndrome (FXS) and in mouse models of the disorder, a cerebellar functional contribution to ASD-relevant behaviors in FXS has yet to be fully characterized. In this study, we demonstrate a critical cerebellar role for Fmr1 (fragile X messenger ribonucleoprotein 1) in ASD-relevant behaviors. First, we identify reduced social behaviors, sensory hypersensitivity, and cerebellar dysfunction, with loss of cerebellar Fmr1. We then demonstrate that cerebellar-specific expression of Fmr1 is sufficient to impact social, sensory, cerebellar dysfunction, and cerebro-cortical hyperexcitability phenotypes observed in global Fmr1 mutants. Moreover, we demonstrate that targeting the ASD-implicated cerebellar region Crus1 ameliorates behaviors in both cerebellar-specific and global Fmr1 mutants. Together, these results demonstrate a critical role for the cerebellar contribution to FXS-related behaviors, with implications for future therapeutic strategies.