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.

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.

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.

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.

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.

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.

Multimodal Magnetic Resonance Imaging Quantification of Brain Changes in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative clinically heterogeneous disorder, formal diagnosis being based on postmortem histological brain examination. OBJECTIVE: We aimed to perform a precise in vivo staging of neurodegeneration in PSP using quantitative multimodal MRI. The ability of MRI biomarkers to differentiate PSP from PD was also evaluated. METHODS: Eleven PSP patients were compared to 26 age-matched healthy controls and 51 PD patients. Images were acquired at 3 Tesla (three-dimensional T1 -weighted, diffusion tensor, and neuromelanin-sensitive images) and 7 Tesla (three-dimensional-T2 * images). Regions of interest included the cortical areas, hippocampus, amygdala, basal ganglia, basal forebrain, brainstem nuclei, dentate nucleus, and cerebellum. Volumes, mean diffusivity, and fractional anisotropy were measured. In each region, a threshold value for group categorization was calculated, and four grades of change (0-3) were determined. RESULTS: PSP patients showed extensive volume decreases and diffusion changes in the midbrain, SN, STN, globus pallidus, basal forebrain, locus coeruleus, pedunculopontine nucleus, and dentate nucleus, in close agreement with the degrees of impairment in histological analyses. The predictive factors for the separation of PSP and healthy controls were, in descending order, the neuromelanin-based SN volume; midbrain fractional anisotropy; volumes of the midbrain, globus pallidus, and putamen; and fractional anisotropy in the locus coeruleus. The best predictors for separating PSP from PD were the neuromelanin-based volume in the SN, fractional anisotropy in the pons, volumes of the midbrain and globus pallidus, and fractional anisotropy in the basal forebrain. CONCLUSIONS: These results suggest that it is possible to evaluate brain neurodegeneration in PSP noninvasively, even in small brainstem nuclei, in close agreement with previously published histological data. © 2019 International Parkinson and Movement Disorder Society.

The supplementary motor area modulates interhemispheric interactions during movement preparation.

The execution of coordinated hand movements requires complex interactions between premotor and primary motor areas in the two hemispheres. The supplementary motor area (SMA) is involved in movement preparation and bimanual coordination. How the SMA controls bimanual coordination remains unclear, although there is evidence suggesting that the SMA could modulate interhemispheric interactions. With a delayed-response task, we investigated interhemispheric interactions underlying normal movement preparation and the role of the SMA in these interactions during the delay period of unimanual or bimanual hand movements. We used functional MRI and transcranial magnetic stimulation in 22 healthy volunteers (HVs), and then in two models of SMA dysfunction: (a) in the same group of HVs after transient disruption of the right SMA proper by continuous transcranial magnetic theta-burst stimulation; (b) in a group of 22 patients with congenital mirror movements (CMM), whose inability to produce asymmetric hand movements is associated with SMA dysfunction. In HVs, interhemispheric connectivity during the delay period was modulated according to whether or not hand coordination was required for the forthcoming movement. In HVs following SMA disruption and in CMM patients, interhemispheric connectivity was modified during the delay period and the interhemispheric inhibition was decreased. Using two models of SMA dysfunction, we showed that the SMA modulates interhemispheric interactions during movement preparation. This unveils a new role for the SMA and highlights its importance in coordinated movement preparation.

Multimodal magnetic resonance imaging investigation of basal forebrain damage and cognitive deficits in Parkinson's disease.

BACKGROUND: Cognitive deficits in Parkinson's disease (PD) may result from damage in the cortex as well as in the dopaminergic, noradrenergic, and cholinergic inputs to the cortex. Cholinergic inputs to the cortex mainly originate from the basal forebrain and are clustered in several regions, called Ch1 to Ch4, that project to the hippocampus (Ch1-2), the olfactory bulb (Ch3), and the cortex and amygdala (Ch4). OBJECTIVE: We investigated changes in basal forebrain and their role in cognitive deficits in PD. METHODS: We studied 52 nondemented patients with PD (Hoehn & Yahr 1-2) and 25 age-matched healthy controls using diffusion and resting state functional MRI. RESULTS: PD patients had a loss of structural integrity within the Ch1-2 and Ch3-4 nuclei of the basal forebrain as well as in the fornix. Tractography showed that the probability of anatomical connection was decreased in PD between Ch3-4 and the associative prefrontal cortex, occipital cortex, and peri-insular regions. There was a reduction in functional connectivity between Ch1-2 and the bilateral hippocampi and parahippocampal gyri, the left middle and superior temporal gyri, and the left fusiform gyrus and between Ch3-4 and the right inferior frontal gyrus and the right and left thalamus. In Ch1-2, loss of structural integrity and connectivity correlated with scores at the memory tests, whereas changes in Ch3-4 correlated with scores of global cognition and executive functions. CONCLUSION: This study highlights the association between deficits of different cholinergic nuclei of the basal forebrain and the extent of cognitive impairments in nondemented PD patients. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Neural Scaffolding as the Foundation for Stable Performance of Aging Cerebellum.

Although recently conceptualized as a neural node essential for a vast spectrum of associative and cognitive processes, the cerebellum has largely eluded attention in the research of aging, where it is marginalized mainly to structural analyses. In the current cross-sectional study of 67 healthy subjects of various ages (20 to 76 years), we sought to provide a comprehensive, multimodal account of age-related changes in the cerebellum during predictive motor timing, which was previously shown to engage this structure. We combined behavioral assessments of performance with functional MRI and voxel-based morphometry using an advanced method to avoid cerebellar deformation and registration imprecisions inherent to the standard processing at the whole-brain level. Higher age was surprisingly associated with stable behavioral performance during predictive motor timing, despite the massive decrease of infratentorial gray matter volume of a far higher extent than in the supratentorial region, affecting mainly the posterior cerebellar lobe. Nonetheless, this very area showed extensive hyperactivation directly correlated with age. The same region had decreased connectivity with the left caudate and increased connectivity with the left fusiform gyrus, the right pallidum, the hippocampus, and the lingual gyrus. Hence, we propose to extend the scaffolding theory of aging, previously limited mainly to the frontal cortices, to include also the cerebellum, which is likewise suffering from atrophy to a far greater extent than the rest of the brain and is similarly counteracting it by bilateral hyperactivation.

The patchy tremor landscape: recent advances in pathophysiology.

PURPOSE OF REVIEW: We focus on new insights in the pathophysiology of Parkinson's disease tremor, essential tremor, tremor in dystonia, and orthostatic tremor. RECENT FINDINGS: Neuroimaging findings suggest that Parkinson's disease resting tremor is associated with dopaminergic dysfunction, serotonergic dysfunction, or both. Not all tremors in Parkinson's disease have the same pathophysiology: postural tremor in Parkinson's disease can be subdivided into pure postural tremor, which involves nondopaminergic mechanisms, and re-emergent tremor, which has a dopaminergic basis. Unlike Parkinson's disease tremor, essential tremor has an electrophysiological signature suggestive of a single (or several tightly coupled) oscillators. Visual feedback increases essential tremor and enhances cerebral activity in the cerebello-thalamo-cortical circuit, supplementary motor area, and parietal cortex. Little is known about dystonic tremor but the available evidence suggests that both the basal ganglia and the cerebellum play a role. Finally, recent work in orthostatic tremor points towards the role of the pontine tegmentum and dysfunctional cerebellar-SMA circuitry. SUMMARY: Many pathological tremors involve the cerebello-thalamo-cortical circuitry, and the clinical and pathophysiological boundaries between tremor disorders are not always clear. Differences between tremor disorders - or even individual patients - may be explained by the specific balance of neurotransmitter degeneration, by distinct circuit dynamics, or by the role of regions interconnected to the cerebello-thalamo-cortical circuit.

Disruption in cerebellar and basal ganglia networks during a visuospatial task in cervical dystonia.

BACKGROUND: Although dystonia is traditionally conceptualized as a basal ganglia disorder, increasing interest has been directed at a different neural network node, the cerebellum, which may play a significant role in the pathophysiology of dystonia. Abnormal sensorimotor processing and disturbed motor schemes, possibly attributable to cerebellar changes, remain unclear. METHODS: We sought to characterize the extent of cerebellar dysfunction within the motor network using functional MRI activation analysis, connectivity analysis, and voxel-based morphometry in cervical dystonia patients (n = 25, 15 women, mean age 45.8 years) and healthy volunteers (n = 25, 15 women, mean age 44.7 years) in a visuospatial task requiring predictive motor timing. RESULTS: Cervical dystonia patients showed decreased activation in the posterior cerebellar lobules as well as in the premotor areas, the associative parietal cortex, and visual regions. Patients also had decreased cerebellar connectivity with bilateral basal ganglia structures and the dorsolateral prefrontal cortex. CONCLUSIONS: This promotes the view that dystonia results from miscommunication between the basal ganglia and cerebellar loops, thus providing new insights into the brain regions essential for the development of cervical dystonia. © 2017 International Parkinson and Movement Disorder Society.

Pedunculopontine network dysfunction in Parkinson's disease with postural control and sleep disorders.

BACKGROUND: The objective of this study was to investigate pedunculopontine nucleus network dysfunctions that mediate impaired postural control and sleep disorder in Parkinson's disease. METHODS: We examined (1) Parkinson's disease patients with impaired postural control and rapid eye movement sleep behavior disorder (further abbreviated as sleep disorder), (2) Parkinson's disease patients with sleep disorder only, (3) Parkinson's disease patients with neither impaired postural control nor sleep disorder, and (4) healthy volunteers. We assessed postural control with clinical scores and biomechanical recordings during gait initiation. Participants had video polysomnography, daytime sleepiness self-evaluation, and resting-state functional MRIs. RESULTS: Patients with impaired postural control and sleep disorder had longer duration of anticipatory postural adjustments during gait initiation and decreased functional connectivity between the pedunculopontine nucleus and the supplementary motor area in the locomotor network that correlated negatively with the duration of anticipatory postural adjustments. Both groups of patients with sleep disorder had decreased functional connectivity between the pedunculopontine nucleus and the anterior cingulate cortex in the arousal network that correlated with daytime sleepiness. The degree of dysfunction in the arousal network was related to the degree of connectivity in the locomotor network in all patients with sleep disorder, but not in patients without sleep disorder or healthy volunteers. CONCLUSIONS: These results shed light on the functional neuroanatomy of pedunculopontine nucleus networks supporting the clinical manifestation and the interdependence between sleep and postural control impairments in Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.

Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia.

A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.

Orthostatic tremor: a cerebellar pathology?

SEE MUTHURAMAN ET AL DOI101093/AWW164 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Primary orthostatic tremor is characterized by high frequency tremor affecting the legs and trunk during the standing position. Cerebellar defects were suggested in orthostatic tremor without direct evidence. We aimed to characterize the anatomo-functional defects of the cerebellar motor pathways in orthostatic tremor. We used multimodal neuroimaging to compare 17 patients with orthostatic tremor and 17 age- and gender-matched healthy volunteers. Nine of the patients with orthostatic tremor underwent repetitive transcranial stimulation applied over the cerebellum during five consecutive days. We quantified the duration of standing position and tremor severity through electromyographic recordings. Compared to healthy volunteers, grey matter volume in patients with orthostatic tremor was (i) increased in the cerebellar vermis and correlated positively with the duration of the standing position; and (ii) increased in the supplementary motor area and decreased in the lateral cerebellum, which both correlated with the disease duration. Functional connectivity between the lateral cerebellum and the supplementary motor area was abnormally increased in patients with orthostatic tremor, and correlated positively with tremor severity. After repetitive transcranial stimulation, tremor severity and functional connectivity between the lateral cerebellum and the supplementary motor area were reduced. We provide an explanation for orthostatic tremor pathophysiology, and demonstrate the functional relevance of cerebello-thalamo-cortical connections in tremor related to cerebellar defects.

Impairment of a parieto-premotor network specialized for handwriting in writer's cramp.

Handwriting with the dominant hand is a highly skilled task singularly acquired in humans. This skill is the isolated deficit in patients with writer's cramp (WC), a form of dystonia with maladaptive plasticity, acquired through intensive and repetitive motor practice. When a skill is highly trained, a motor program is created in the brain to execute the same movement kinematics regardless of the effector used for the task. The task- and effector-specific symptoms in WC suggest that a problem particularly occurs in the brain when the writing motor program is carried out by the dominant hand. In this MRI study involving 12 WC patients (with symptoms only affecting the right dominant hand during writing) and 15 age matched unaffected controls we showed that: (1) the writing program recruited the same network regardless of the effector used to write in both groups; (2) dominant handwriting recruited a segregated parieto-premotor network only in the control group; (3) local structural alteration of the premotor area, the motor component of this network, predicted functional connectivity deficits during dominant handwriting and symptom duration in the patient group. Dysfunctions and structural abnormalities of a segregated parieto-premotor network in WC patients suggest that network specialization in focal brain areas is crucial for well-learned motor skill. Hum Brain Mapp 37:4363-4375, 2016. © 2016 Wiley Periodicals, Inc.

Intrinsic signature of essential tremor in the cerebello-frontal network.

Essential tremor is a movement disorder characterized by tremor during voluntary movements, mainly affecting the upper limbs. The cerebellum and its connections to the cortex are known to be involved in essential tremor, but no task-free intrinsic signatures of tremor related to structural cerebellar defects have so far been found in the cortical motor network. Here we used voxel-based morphometry, tractography and resting-state functional MRI at 3 T to compare structural and functional features in 19 patients with essential tremor and homogeneous symptoms in the upper limbs, and 19 age- and gender-matched healthy volunteers. Both structural and functional abnormalities were found in the patients' cerebellum and supplementary motor area. Relative to the healthy controls, the essential tremor patients' cerebellum exhibited less grey matter in lobule VIII and less effective connectivity between each cerebellar cortex and the ipsilateral dentate nucleus. The patient's supplementary motor area exhibited (i) more grey matter; (ii) a lower amplitude of low-frequency fluctuation of the blood oxygenation level-dependent signal; (iii) less effective connectivity between each supplementary motor area and the ipsilateral primary motor hand area, and (iv) a higher probability of connection between supplementary motor area fibres and the spinal cord. Structural and functional changes in the supplementary motor area, but not in the cerebellum, correlated with clinical severity. In addition, changes in the cerebellum and supplementary motor area were interrelated, as shown by a correlation between the lower amplitude of low-frequency fluctuation in the supplementary motor area and grey matter loss in the cerebellum. The structural and functional changes observed in the supplementary motor area might thus be a direct consequence of cerebellar defects: the supplementary motor area would attempt to reduce tremor in the motor output by reducing its communication with M1 hand areas and by directly modulating motor output via its corticospinal projections.See Raethjen and Muthuraman (doi:10.1093/brain/awv238) for a scientific commentary on this article.

The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson's disease.

In Parkinson's disease, rapid eye movement sleep behaviour disorder is an early non-dopaminergic syndrome with nocturnal violence and increased muscle tone during rapid eye movement sleep that can precede Parkinsonism by several years. The neuronal origin of rapid eye movement sleep behaviour disorder in Parkinson's disease is not precisely known; however, the locus subcoeruleus in the brainstem has been implicated as this structure blocks muscle tone during normal rapid eye movement sleep in animal models and can be damaged in Parkinson's disease. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex in patients with Parkinson's disease using combined neuromelanin-sensitive, structural and diffusion magnetic resonance imaging approaches. We compared 24 patients with Parkinson's disease and rapid eye movement sleep behaviour disorder, 12 patients without rapid eye movement sleep behaviour disorder and 19 age- and gender-matched healthy volunteers. All subjects underwent clinical examination and characterization of rapid eye movement sleep using video-polysomnography and multimodal imaging at 3 T. Using neuromelanin-sensitive imaging, reduced signal intensity was evident in the locus coeruleus/subcoeruleus area in patients with Parkinson's disease that was more marked in patients with than those without rapid eye movement sleep behaviour disorder. Reduced signal intensity correlated with the percentage of abnormally increased muscle tone during rapid eye movement sleep. The results confirmed that this complex is affected in Parkinson's disease and showed a gradual relationship between damage to this structure, presumably the locus subcoeruleus, and abnormal muscle tone during rapid eye movement sleep, which is the cardinal marker of rapid eye movement sleep behaviour disorder. In longitudinal studies, the technique may also provide early markers of non-dopaminergic Parkinson's disease pathology to predict the occurrence of Parkinson's disease.

RAD51 deficiency disrupts the corticospinal lateralization of motor control.

Mirror movements are involuntary symmetrical movements of one side of the body that mirror voluntary movements of the other side. Congenital mirror movement disorder is a rare condition characterized by mirror movements that persist throughout adulthood in subjects with no other clinical abnormalities. The affected individuals have mirror movements predominating in the muscles that control the fingers and are unable to perform purely unimanual movements. Congenital mirror movement disorder thus provides a unique paradigm for studying the lateralization of motor control. We conducted a multimodal, controlled study of patients with congenital mirror movements associated with RAD51 haploinsufficiency (n = 7, mean age 33.3 ± 16.8 years) by comparison with age- and gender-matched healthy volunteers (n = 14, mean age 33.9 ± 16.1 years). We showed that patients with congenital mirror movements induced by RAD51 deficiency had: (i) an abnormal decussation of the corticospinal tract; (ii) abnormal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements; and (iii) an abnormal involvement of the supplementary motor area during both unimanual and bimanual movements. The lateralization of motor control thus requires a fine interplay between interhemispheric communication and corticospinal wiring. This fine interplay determines: (i) the delivery of appropriate motor plans from the supplementary motor area to the primary motor cortex; (ii) the lateralized activation of the primary motor cortex; and (iii) the unilateral transmission of the motor command to the limb involved in the intended movement. Our results also unveil an unexpected function of RAD51 in corticospinal development of the motor system.

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 tremor. 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 3 cm 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.