Sustained reduction of Essential Tremor with low-power non-thermal transcranial focused ultrasound stimulations in humans.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. OBJECTIVE: /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremors. METHODS: The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N=9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. RESULTS: VIM neurostimulations followed by a low-duty cycle (5%) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9% reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5%) also experienced a sustained reduction of the tremor (up to 93.4%). Four patients (N=4) did not respond. The temperature at target was 37.2 ± 1.4°C compared to 36.8 ± 1.4°C for a 3cm away control point. CONCLUSIONS: MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.

Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia.

Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders. Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition. In this study, we compared the explicit and implicit sense of agency in patients with myoclonus dystonia caused by a pathogenic variant of SGCE (DYT-SGCE) and control participants. We utilized behavioural tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modelling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioural performance, symptom severity, and neuroimaging findings. We compared 19 patients with DYT-SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey-matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area. Dynamic causal modelling analysis further identified reduced inhibitory effects of the cerebellum on the pre-supplementary motor area, decreased excitatory effects of the pre-supplementary motor area on the cerebellum, and increased self-inhibition within the pre-supplementary motor area. Importantly, both cerebellar grey-matter alterations and functional connectivity abnormalities between the cerebellum and pre-supplementary motor area were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-supplementary motor area was associated with less severe myoclonus symptoms. These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder.

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.

BACKGROUND: Focal 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. METHODS: We 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/[Formula: see text]) with [Formula: see text] 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. DISCUSSION: Our 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 REGISTRATION: ClinicalTrials.gov NCT05329818. April 15, 2022.

Non-Motor Symptoms and Quality of Life in Patients with PRRT2-Related Paroxysmal Kinesigenic Dyskinesia.

Background: Monoallelic pathogenic variants of PRRT2 often result in paroxysmal kinesigenic dyskinesia (PKD). Little is known about health-related quality of life (HrQoL), non-motor manifestations, self-esteem, and stigma in patients with PKD. Objectives: We investigated non-motor symptoms and how they related to HrQoL in a genetically homogeneous group of PRRT2-PKD patients. We paid special attention to perceived stigmatization and self-esteem. Methods: We prospectively enrolled 21 consecutive PKD patients with a pathogenic variant of PRRT2, and 21 healthy controls matched for age and sex. They were evaluated with dedicated standardized tests for non-motor symptoms, HrQoL, anxiety, depression, stigma, self-esteem, sleep, fatigue, pain, and psychological well-being. Results: Patients reported an alteration of the physical aspects of HrQoL, regardless of the presence of residual paroxysmal episodes. Non-motor manifestations were frequent, and were an important determinant of the alteration of HrQoL. In addition, patients perceived a higher level of stigmatization which positively correlated with a delay in diagnosis (ρ = 0.615, P = 0.003) and the fear of being judged (ρ = 0.452, P = 0.04), but not with the presence of paroxysmal episodes (ρ = 0.203, P = 0.379). Conclusions: Our findings have important implications for care givers concerning patient management and medical education about paroxysmal dyskinesia. PRRT2-PKD patients should be screened for non-motor disorders in routine care. A long history of misdiagnosis may play a role in the high level of perceived stigmatization. Improving knowledge about diagnostic clues suggestive of PKD is mandatory.

Can neuroscience enlighten the philosophical debate about free will?

Free will has been at the heart of philosophical and scientific discussions for many years. However, recent advances in neuroscience have been perceived as a threat to the commonsense notion of free will as they challenge two core requirements for actions to be free. The first is the notion of determinism and free will, i.e., decisions and actions must not be entirely determined by antecedent causes. The second is the notion of mental causation, i.e., our mental state must have causal effects in the physical world, in other words, actions are caused by conscious intention. We present the classical philosophical positions related to determinism and mental causation, and discuss how neuroscience could shed a new light on the philosophical debate based on recent experimental findings. Overall, we conclude that the current evidence is insufficient to undermine free will.

Fixel-Based Analysis Reveals Whole-Brain White Matter Abnormalities in Cervical Dystonia.

BACKGROUND: Cervical dystonia (CD) is a form of isolated focal dystonia typically associated to abnormal head, neck, and shoulder movements and postures. The complexity of the clinical presentation limits the investigation of its pathophysiological mechanisms, and the neural networks associated to specific motor manifestations are still the object of debate. OBJECTIVES: We investigated the morphometric properties of white matter fibers in CD and explored the networks associated with motor symptoms, while regressing out nonmotor scores. METHODS: Nineteen patients affected by CD and 21 healthy controls underwent diffusion-weighted magnetic resonance imaging. We performed fixel-based analysis, a novel method evaluating fiber orientation within specific fiber bundles, and compared fiber morphometric properties between groups. Moreover, we correlated fiber morphometry with the severity of motor symptoms in patients. RESULTS: Compared to controls, patients exhibited decreased white matter fibers in the right striatum. Motor symptom severity negatively correlated with white matter fibers passing through inferior parietal areas and the head representation area of the motor cortex. CONCLUSIONS: Abnormal white matter integrity at the basal ganglia level may affect several functional networks involved, for instance, in motor preparation and execution, visuomotor coordination, and multimodal integration. This may result in progressive maladaptive plasticity, culminating in overt symptoms of dystonia. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Brain dysfunction in gait disorders of Caribbean atypical Parkinsonism and progressive supranuclear palsy patients: A comparative study.

INTRODUCTION: Gait disorders and falls occur early in progressive supranuclear palsy (PSP-RS) and Caribbean atypical parkinsonism (Caribbean AP). However, the link between these signs and brain lesions has never been explored in these patient populations. Here, we investigate and compare the imaging factors that relate to gait and balance disorders in Caribbean AP and PSP-RS patients. METHODS: We assessed gait and balance using clinical scales and gait recordings in 16 Caribbean AP and 15 PSP-RS patients and 17 age-matched controls. We measured the grey and white matter brain volumes on 3 T brain MRI images. We performed a principal component analysis (PCA) including all the data to determine differences and similarities between groups, and explore the relationship between gait disorders and brain volumes. RESULTS: Both Caribbean AP patients and PSP-RS have marked gait and balance disorders with similar severity. In both groups, gait and balance disorders were found to be most strongly related to structural changes in the lateral cerebellum, caudate nucleus, and fronto-parietal areas. In Caribbean AP patients, gait disorders were also related to additional changes in the cortex, including frontal, insular, temporal and cuneus lobes, whereas in PSP-RS patients, additional white matter changes involved the mesencephalon and parahippocampal gyrus. CONCLUSION: Gait and balance disorders in Caribbean AP patients are mainly related to dysfunction of cortical brain areas involved in visuo-sensorimotor processing and self-awareness, whereas these signs mainly result from premotor-brainstem-cerebellar network dysfunction in PSP-RS patients, brain areas involved in initiation and maintenance of locomotor pattern and postural adaptation.

Developmental coordination disorder subtypes in children: An unsupervised clustering.

AIM: To identify subtypes of developmental coordination disorder (DCD) in children. METHOD: Children with DCD diagnosed through comprehensive evaluation at Robert-Debré Children's University Hospital (Paris, France) were consecutively enrolled from February 2017 to March 2020. We performed an unsupervised hierarchical clustering based on principal component analysis using a large set of variables encompassing cognitive, motor, and visuospatial scores (Wechsler Intelligence Scale for Children, Fifth Edition; Developmental Neuropsychological Assessment, Second Edition; Movement Assessment Battery for Children, Second Edition). RESULTS: One hundred and sixty-four children with DCD were enrolled (median age 10 years 3 months; male:female ratio 5.56:1). We identified distinct subgroups with mixed visuospatial and gestural disorders, or with pure gestural disorders that predominantly impaired either speed or precision. Associated neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder, did not influence the results of the clustering. Importantly, we identified a subgroup of children with marked visuospatial impairment with the lowest scores in almost all of the evaluated domains, and the poorest school performance. INTERPRETATION: The classification of DCD into distinct subgroups could be indicative of prognosis and provide critical information to guide patient management, taking into account the child's neuropsychological profile. Beyond this clinical interest, our findings also provide a relevant framework with homogeneous subgroups of patients for research on the pathogenesis of DCD. WHAT THIS PAPER ADDS: Unsupervised hierarchical clustering identified four subgroups of children with developmental coordination disorder. Two subgroups had combined visuospatial/gestural difficulties, and two had pure gestural disorders. Severe visuospatial impairment was associated with poor performance in most domains including school. Difficulties in the gestural-only clusters were predominantly either gestural precision or speed.

Cerebellar and basal ganglia structural connections in humans: Effect of aging and relation with memory and learning.

Introduction: The cerebellum and basal ganglia were initially considered anatomically distinct regions, each connected via thalamic relays which project to the same cerebral cortical targets, such as the motor cortex. In the last two decades, transneuronal viral transport studies in non-human primates showed bidirectional connections between the cerebellum and basal ganglia at the subcortical level, without involving the cerebral cortical motor areas. These findings have significant implications for our understanding of neurodevelopmental and neurodegenerative diseases. While these subcortical connections were established in smaller studies on humans, their evolution with natural aging is less understood. Methods: In this study, we validated and expanded the previous findings of the structural connectivity within the cerebellum-basal ganglia subcortical network, in a larger dataset of 64 subjects, across different age ranges. Tractography and fixel-based analysis were performed on the 3 T diffusion-weighted dataset using Mrtrix3 software, considering fiber density and cross-section as indicators of axonal integrity. Tractography of the well-established cerebello-thalamo-cortical tract was conducted as a control. We tested the relationship between the structural white matter integrity of these connections with aging and with the performance in different domains of Addenbrooke's Cognitive Examination. Results: Tractography analysis isolated connections from the dentate nucleus to the contralateral putamen via the thalamus, and reciprocal tracts from the subthalamic nucleus to the contralateral cerebellar cortex via the pontine nuclei. Control tracts of cerebello-thalamo-cortical tracts were also isolated, including associative cerebello-prefrontal tracts. A negative linear relationship was found between the fiber density of both the ascending and descending cerebellum-basal ganglia tracts and age. Considering the cognitive assessments, the fiber density values of cerebello-thalamo-putaminal tracts correlated with the registration/learning domain scores. In addition, the fiber density values of cerebello-frontal and subthalamo-cerebellar (Crus II) tracts correlated with the cognitive assessment scores from the memory domain. Conclusion: We validated the structural connectivity within the cerebellum-basal ganglia reciprocal network, in a larger dataset of human subjects, across wider age range. The structural features of the subcortical cerebello-basal ganglia tracts in human subjects display age-related neurodegeneration. Individual morphological variability of cerebellar tracts to the striatum and prefrontal cortex was associated with different cognitive functions, suggesting a functional contribution of cerebellar tracts to cognitive decline with aging. This study offers new perspectives to consider the functional role of these pathways in motor learning and the pathophysiology of movement disorders involving the cerebellum and striatum.

Local Alterations of Left Arcuate Fasciculus and Transcallosal White Matter Microstructure in Schizophrenia Patients with Medication-resistant Auditory Verbal Hallucinations: A Pilot Study.

Auditory verbal hallucinations (AVH) in schizophrenia (SZ) have been associated with abnormalities of the left arcuate fasciculus and transcallosal white matter projections linking homologous language areas of both hemispheres. While most studies have used a whole-tract approach, here we focused on analyzing local alterations of the above-mentioned pathways in SZ patients suffering medication-resistant AVH. Fractional anisotropy (FA) was estimated along the left arcuate fasciculus and interhemispheric projections of the rostral and caudal corpus callosum. Then, potential associations between white matter tracts and SZ symptoms were explored by correlating local site-by-site FA values and AVH severity estimated via the Auditory Hallucinations Rating Scale (AHRS). Compared to a sample of healthy controls, SZ patients displayed lower FA values in the rostral portion of the left arcuate fasciculus, near the frontal operculum, and in the left and right lateral regions of the rostral portion of the transcallosal pathways. In contrast, SZ patients showed higher FA values than healthy controls in the medial portion of the latter transcallosal pathway and in the midsagittal section of the interhemispheric auditory pathway. Finally, significant correlations were found between local FA values in the left arcuate fasciculus and the severity of the AVH's attentional salience. Contributing to the study of associations between local white matter alterations of language networks and SZ symptoms, our findings highlight local alterations of white matter integrity in these pathways linking language areas in SZ patients with AVH. We also hypothesize a link between the left arcuate fasciculus and the attentional capture of AVH.

Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study.

BACKGROUND: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine. OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia. METHODS: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire. RESULTS: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening. CONCLUSION: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.

Cerebellum Dysfunction in Patients With PRRT2-Related Paroxysmal Dyskinesia.

BACKGROUND AND OBJECTIVES: The main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicates that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans. METHODS: We enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2 and their matched controls. Participants underwent a multimodal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state fMRI, during which we tested the aftereffects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified the structural integrity of gray matter using voxel-based morphometry, the structural integrity of white matter using fixel-based analysis, and the strength and direction of functional cerebellar connections using spectral dynamic causal modeling. RESULTS: Patients with PRRT2 had decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex, microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas, and dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks and tended to restore this communication to the level observed in healthy controls. DISCUSSION: Patients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output toward the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT03481491.

Somatotopy of cervical dystonia in motor-cerebellar networks: Evidence from resting state fMRI.

INTRODUCTION: Cervical dystonia is the most frequent form of isolated focal dystonia. It is often associated with a dysfunction in brain networks, mostly affecting the basal ganglia, the cerebellum, and the somatosensory cortex. However, it is unclear if such a dysfunction is somato-specific to the brain areas containing the representation of the affected body part, and may thereby account for the focal expression of cervical dystonia. In this study, we investigated resting state functional connectivity in the areas within the motor cortex and the cerebellum containing affected and non-affected body representations in cervical dystonia patients. METHODS: Eighteen patients affected by cervical dystonia and 21 healthy controls had resting state fMRI. The functional connectivity between the motor cortex and the cerebellum, as well as their corresponding measures of gray matter volume and cortical thickness, were compared between groups. We performed seed-based analyses, selecting the different body representation areas in the precentral gyrus as seed regions, and all cerebellar areas as target regions. RESULTS: Compared to controls, patients exhibited increased functional connectivity between the bilateral trunk representation area of the motor cortex and the cerebellar vermis 6 and 7b, respectively. These functional abnormalities did not correlate with structural changes or symptom severity. CONCLUSIONS: Our findings indicate that the abnormal function of the motor network is somato-specific to the areas encompassing the neck representation. Functional abnormalities in discrete relevant areas of the motor network could thus contribute to the focal expression of CD.

Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor.

Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning. In 27 patients with dystonic tremor syndrome (dystonic tremor: n = 23; tremor associated with dystonia: n = 4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n = 27) and matched controls (n = 27). We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral posterior and anterior ventral lateral nuclei of the thalamus (VLp and VLa), contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power. These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome.

Identification of a Brain Network Underlying the Execution of Freely Chosen Movements.

Action selection refers to the decision regarding which action to perform in order to reach a desired goal, that is, the "what" component of intention. Whether the action is freely chosen or externally instructed involves different brain networks during the selection phase, but it is assumed that the way an action is selected should not influence the subsequent execution phase of the same movement. Here, we aim to test this hypothesis by investigating whether the modality of movement selection influences the brain networks involved during the execution phase of the movement. Twenty healthy volunteers performed a delayed response task in an event-related functional magnetic resonance imaging design to compare freely chosen and instructed unimanual or bimanual movements during the execution phase. Using activation analyses, we found that the pre-supplementary motor area (preSMA) and the parietal and cerebellar areas were more activated during the execution phase of freely chosen as compared to instructed movements. Connectivity analysis showed an increase of information flow between the right posterior parietal cortex and the cerebellum for freely chosen compared to instructed movements. We suggest that the parieto-cerebellar network is particularly engaged during freely chosen movement to monitor the congruence between the intentional content of our actions and their outcome.

The Forward Model: A Unifying Theory for the Role of the Cerebellum in Motor Control and Sense of Agency.

For more than two decades, there has been converging evidence for an essential role of the cerebellum in non-motor functions. The cerebellum is not only important in learning and sensorimotor processes, some growing evidences show its implication in conditional learning and reward, which allows building our expectations about behavioral outcomes. More recent work has demonstrated that the cerebellum is also required for the sense of agency, a cognitive process that allows recognizing an action as our own, suggesting that the cerebellum might serve as an interface between sensorimotor function and cognition. A unifying model that would explain the role of the cerebellum across these processes has not been fully established. Nonetheless, an important heritage was given by the field of motor control: the forward model theory. This theory stipulates that movements are controlled based on the constant interactions between our organism and its environment through feedforward and feedback loops. Feedforward loops predict what is going to happen, while feedback loops confront the prediction with what happened so that we can react accordingly. From an anatomical point of view, the cerebellum is at an ideal location at the interface between the motor and sensory systems, as it is connected to cerebral, striatal, and spinal entities via parallel loops, so that it can link sensory and motor systems with cognitive processes. Recent findings showing that the cerebellum participates in building the sense of agency as a predictive and comparator system will be reviewed together with past work on motor control within the context of the forward model theory.

Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements.

In humans, execution of unimanual movements requires lateralized activation of the primary motor cortex, which then transmits the motor command to the contralateral hand through the crossed corticospinal tract (CST). Mutations in NTN1 alter motor control lateralization, leading to congenital mirror movements. To address the role of midline Netrin-1 on CST development and subsequent motor control, we analyze the morphological and functional consequences of floor plate Netrin-1 depletion in conditional knockout mice. We show that depletion of floor plate Netrin-1 in the brainstem critically disrupts CST midline crossing, whereas the other commissural systems are preserved. The only associated defect is an abnormal entry of CST axons within the inferior olive. Alteration of CST midline crossing results in functional ipsilateral projections and is associated with abnormal symmetric movements. Our study reveals the role of Netrin-1 in CST development and describes a mouse model recapitulating the characteristics of human congenital mirror movements.

Impulsive prepotent actions and tics in Tourette disorder underpinned by a common neural network.

Tourette disorder (TD), which is characterized by motor and vocal tics, is not in general considered as a product of impulsivity, despite a frequent association with attention deficit hyperactivity disorder and impulse control disorders. It is unclear which type of impulsivity, if any, is intrinsically related to TD and specifically to the severity of tics. The waiting type of motor impulsivity, defined as the difficulty to withhold a specific action, shares some common features with tics. In a large group of adult TD patients compared to healthy controls, we assessed waiting motor impulsivity using a behavioral task, as well as structural and functional underpinnings of waiting impulsivity and tics using multi-modal neuroimaging protocol. We found that unmedicated TD patients showed increased waiting impulsivity compared to controls, which was independent of comorbid conditions, but correlated with the severity of tics. Tic severity did not account directly for waiting impulsivity, but this effect was mediated by connectivity between the right orbito-frontal cortex with caudate nucleus bilaterally. Waiting impulsivity in unmedicated patients with TD also correlated with a higher gray matter signal in deep limbic structures, as well as connectivity with cortical and with cerebellar regions on a functional level. Neither behavioral performance nor structural or functional correlates were related to a psychometric measure of impulsivity or impulsive behaviors in general. Overall, the results suggest that waiting impulsivity in TD was related to tic severity, to functional connectivity of orbito-frontal cortex with caudate nucleus and to structural changes within limbic areas.

Parkinson Disease Propagation Using MRI Biomarkers and Partial Least Squares Path Modeling.

OBJECTIVES: The classic Braak neuropathologic staging model in Parkinson disease (PD) suggests that brain lesions progress from the medulla oblongata to the cortex. An alternative model in which neurodegeneration first occurs in the cortex has also been proposed. These 2 models may correspond to different patient phenotypes. To test these 2 models and to investigate whether they were influenced by the presence of REM sleep behavior disorder (RBD), we used multimodal MRI and partial least squares path modeling (PLS-PM) assuming that patients with RBD followed distinct neurodegeneration pattern. METHODS: Fifty-four patients with PD (34 with RBD) and 25 healthy volunteers were scanned with T1-weighted, diffusion tensor, and neuromelanin-sensitive imaging. Volume, signal, and mean, axial, and radial diffusivities were calculated in brainstem, basal forebrain, and cortical regions. PLS-PM, estimating a network of causal relationships between blocks of variables, was used to build and test an analytical model based on Braak staging. The overall quality of the model was assessed with goodness of fit coefficient (Gof). RESULTS: PLS-PM was run on patients with PD with RBD and without RBD separately. In PD with RBD, a brainstem-to-cortex model had significant Gof (0.71, p = 0.01), whereas a cortex-to-brainstem model did not. In contrast, in patients with PD without RBD, the brainstem-to-cortex model was not significant (Gof = 0.64, p = 0.27), and the cortex-to-brainstem model was highly significant (Gof = 0.72, p = 0.008). CONCLUSIONS: With the PLS-PM imaging-based model, the neurodegeneration pattern of patients with PD with RBD was consistent with the Braak brainstem-to-cortex model, whereas that of patients without RBD followed the cortex-to-brainstem model.

Antisaccade, a predictive marker for freezing of gait in Parkinson's disease and gait/gaze network connectivity.

Freezing of gait is a challenging sign of Parkinson's disease associated with disease severity and progression and involving the mesencephalic locomotor region. No predictive factor of freezing has been reported so far. The primary objective of this study was to identify predictors of freezing occurrence at 5 years. In addition, we tested whether functional connectivity of the mesencephalic locomotor region could explain the oculomotor factors at baseline that were predictive of freezing onset. We performed a prospective study investigating markers (parkinsonian signs, cognitive status and oculomotor recordings, with a particular focus on the antisaccade latencies) of disease progression at baseline and at 5 years. We identified two groups of patients defined by the onset of freezing at 5 years of follow-up; the 'Freezer' group was defined by the onset of freezing in the ON medication condition during follow-up (n = 17), while the 'non-Freezer' group did not (n = 8). Whole brain resting-state functional MRI was recorded at baseline to determine how antisaccade latencies were associated with connectivity of the mesencephalic locomotor region networks in patients compared to 25 age-matched healthy volunteers. Results showed that, at baseline and compared to the non-Freezer group, the Freezer group had equivalent motor or cognitive signs, but increased antisaccade latencies (P = 0.008). The 5-year course of freezing of gait was correlated with worsening antisaccade latencies (P = 0.0007). Baseline antisaccade latencies was also predictive of the freezing onset (χ2 = 0.008). Resting state connectivity of mesencephalic locomotor region networks correlated with (i) antisaccade latency differently in patients and healthy volunteers at baseline; and (ii) the further increase of antisaccade latency at 5 years. We concluded that antisaccade latency is a predictive marker of the 5-year onset of freezing of gait. Our study suggests that functional networks associated with gait and gaze control are concurrently altered during the course of the disease.