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Musician's dystonia presents with a persistent deterioration of motor control during musical performance. A predominant hypothesis has been that this is underpinned by maladaptive neural changes to the somatotopic organization of finger representations within primary somatosensory cortex. Here, we tested this hypothesis by investigating the finger-specific activity patterns in the primary somatosensory and motor cortex using functional MRI and multivariate pattern analysis in nine musicians with dystonia and nine healthy musicians. A purpose-built keyboard device allowed characterization of activity patterns elicited during passive extension and active finger presses of individual fingers. We analysed the data using both traditional spatial analysis and state-of-the art multivariate analyses. Our analysis reveals that digit representations in musicians were poorly captured by spatial analyses. An optimized spatial metric found clear somatotopy but no difference in the spatial geometry between fingers with dystonia. Representational similarity analysis was confirmed as a more reliable technique than all spatial metrics evaluated. Significantly, the dissimilarity architecture was equivalent for musicians with and without dystonia. No expansion or spatial shift of digit representation maps were found in the symptomatic group. Our results therefore indicate that the neural representation of generic finger maps in primary sensorimotor cortex is intact in musician's dystonia. These results speak against the idea that task-specific dystonia is associated with a distorted hand somatotopy and lend weight to an alternative hypothesis that task-specific dystonia is due to a higher-order disruption of skill encoding. Such a formulation can better explain the task-specific deficit and offers alternative inroads for therapeutic interventions.
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Distonía , Trastornos Distónicos , Música , Corteza Sensoriomotora , Humanos , Dedos , Corteza Somatosensorial/diagnóstico por imagenRESUMEN
BACKGROUND: Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered. OBJECTIVE: To systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex. METHODS: Original neurophysiological data from all published studies (until 2019) were shared and compared to an age- and sex-matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model. RESULTS: Isolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT-TOR1A, DYT-THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies. CONCLUSIONS: The similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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Trastornos Distónicos , Tortícolis , Proteínas Reguladoras de la Apoptosis , Parpadeo , Cerebelo , Condicionamiento Clásico , Proteínas de Unión al ADN , Humanos , Chaperonas MolecularesRESUMEN
The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson's disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders.
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Enfermedad de Parkinson , Estimulación Transcraneal de Corriente Directa , Animales , Estimulación Transcraneal de Corriente Directa/métodos , Consenso , Cerebelo/fisiología , Estimulación Magnética Transcraneal/métodosRESUMEN
Functional neurological disorder is a common and phenomenologically diverse condition. Resultant disability is caused by both the dominant clinical presentation, e.g. paralysis or tremor and additional symptomatology such as cognitive symptoms. Recently the similarity of neuropsychiatric profiles across a range of functional syndromes has been highlighted. This is suggestive of a common underlying mechanism with a theoretical deficit of information processing proposed. Identification of an experimental biomarker for such deficits could offer novel assessment and therapeutic strategies. In this study, we took the temporal discrimination threshold as a paradigm that can be used to model sensory processing in functional movement disorders. Our hypothesis was that we would be able to delineate markers of slowed information processing in this paradigm removed from the phenomenological presentation with a movement disorder. We recorded both response accuracy and reaction time in a two-choice temporal resolution/discrimination task in 36 patients with functional movement disorders and 36 control subjects. A psychometric function was fitted to accuracy data for each individual revealing both abnormally high threshold values (P = 0.0053) and shallow psychometric slopes in patients (P = 0.0015). Patients with functional movement disorders also had significantly slower response times (P = 0.0065). We then used a well-established model for decision-making (the drift diffusion model) that uses both response accuracy and reaction time data to estimate mechanistic physiological dimensions of decision-making and sensory processing. This revealed pathologically reduced drift rate in the patient group, a parameter that quantifies the quality and rate of information accumulation within this sensory task (P = 0.002). We discuss how the deficits we observed in patients with functional movement disorders are likely to stem from abnormal allocation of attention that impairs the quality of sensory information available. Within a predictive coding framework sensory information could be down-weighted in favour of predictions encoded by the prior. Our results therefore offer a parsimonious account for a range of experimental and clinical findings. Reduced drift rate is a potential experimental marker for a generalized deficit in information processing across functional disorders that allows diverse symptomatology to be quantified under a common disease framework.
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Biomarcadores/análisis , Cognición/fisiología , Trastornos Mentales/fisiopatología , Trastornos del Movimiento/fisiopatología , Adulto , Atención/fisiología , Toma de Decisiones/fisiología , Femenino , Humanos , Masculino , Tiempo de Reacción/fisiologíaRESUMEN
Studying plasticity mechanisms with Professor John Rothwell was a shared highlight of our careers. In this article, we discuss non-invasive brain stimulation techniques which aim to induce and quantify plasticity, the mechanisms and nature of their inherent variability and use such observations to review the idea that excessive and abnormal plasticity is a pathophysiological substrate of dystonia. We have tried to define the tone of our review by a couple of Professor John Rothwell's many inspiring characteristics; his endless curiosity to refine knowledge and disease models by scientific exploration and his wise yet humble readiness to revise scientific doctrines when the evidence is supportive. We conclude that high variability of response to non-invasive brain stimulation plasticity protocols significantly clouds the interpretation of historical findings in dystonia research. There is an opportunity to wipe the slate clean of assumptions and armed with an informative literature in health, re-evaluate whether excessive plasticity has a causal role in the pathophysiology of dystonia.
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Distonía , Trastornos Distónicos , Distonía/terapia , Trastornos Distónicos/terapia , Humanos , Plasticidad NeuronalRESUMEN
BACKGROUND: Recent research has highlighted the role of the cerebellum in the pathophysiology of myoclonus-dystonia syndrome as a result of mutations in the É-sarcoglycan gene (DYT11). Specifically, a cerebellar-dependent saccadic adaptation task is dramatically impaired in this patient group. OBJECTIVES: The objective of this study was to investigate whether saccadic deficits coexist with impairments of limb adaptation to provide a potential mechanism linking cerebellar dysfunction to the movement disorder within symptomatic body regions. METHODS: Limb adaptation to visuomotor (visual feedback rotated by 30°) and forcefield (force applied by robot to deviate arm) perturbations were examined in 5 patients with DYT11 and 10 aged-matched controls. RESULTS: Patients with DYT11 successfully adapted to both types of perturbation. Modelled and averaged summary metrics that captured adaptation behaviors were equivalent to the control group across conditions. CONCLUSIONS: DYT11 is not characterized by a uniform deficit in adaptation. The previously observed large deficit in saccadic adaption is not reflected in an equivalent deficit in limb adaptation in symptomatic body regions. We suggest potential mechanisms at the root of this discordance and identify key research questions that need future study. © 2018 International Parkinson and Movement Disorder Society.
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Enfermedades Cerebelosas/fisiopatología , Cerebelo/fisiopatología , Trastornos Distónicos/fisiopatología , Sarcoglicanos/farmacología , Adaptación Fisiológica/fisiología , Anciano , Retroalimentación Sensorial/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sarcoglicanos/genéticaRESUMEN
Task-specific dystonia is a form of isolated focal dystonia with the peculiarity of being displayed only during performance of a specific skilled motor task. This distinctive feature makes task-specific dystonia a particularly mysterious and fascinating neurological condition. In this review, we cover phenomenology and its increasingly broad-spectrum risk factors for the disease, critically review pathophysiological theories and evaluate current therapeutic options. We conclude by highlighting the unique features of task-specific dystonia within the wider concept of dystonia. We emphasise the central contribution of environmental risk factors, and propose a model by which these triggers may impact on the motor control of skilled movement. By viewing task-specific dystonia through this new lens which considers the disorder a modifiable disorder of motor control, we are optimistic that research will yield novel therapeutic avenues for this highly motivated group of patients.
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Distonía/fisiopatología , Trastornos Distónicos/fisiopatología , Mano/fisiopatología , Movimiento/fisiología , Diagnóstico Diferencial , Ambiente , Humanos , Enfermedades Profesionales/fisiopatología , Factores de RiesgoRESUMEN
Surround inhibition (SI) is a neural process that has been extensively investigated in the sensory system and has been recently probed in the motor system. Muscle-specific modulation of corticospinal excitability at the onset of an isolated finger movement has been assumed to reflect the presence of SI in the motor system. This study attempted to characterise this phenomenon in a large cohort of normal volunteers and investigate its relationship with muscle activity in the hand. Corticospinal excitability of the pathways projecting to three hand muscles [first dorsal interosseus (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM)] and electromyographic (EMG) activity of the same muscles were assessed in 31 healthy volunteers during an isolated index finger movement. In the agonist FDI muscle both corticospinal excitability and EMG activity were found to be increased at the onset of the movement (P < 0.001 and P < 0.001, respectively). On the contrary, in the surround ADM, there was dissociation between the corticospinal excitability (decreased: P < 0.001) and EMG activity (increased: P < 0.001). Cross-correlation analysis of the EMG activity showed that neuronal signals driving the agonist and surround muscles are not synchronised when SI is present. The results suggest a distinctive origin of the neuronal signals driving the agonist and surround muscles. In addition, they indicate that cortical output might be simultaneously modulated by voluntary and non-voluntary activity, generated in cortical and subcortical structures, respectively.
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Dedos/fisiología , Actividad Motora/fisiología , Corteza Motora/fisiología , Músculo Esquelético/fisiología , Inhibición Neural , Tractos Piramidales/fisiología , Adulto , Electromiografía , Femenino , Dedos/inervación , Humanos , Masculino , Músculo Esquelético/inervación , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
BACKGROUND: Primary dystonia is characterized neurophysiologically by reduced inhibitory mechanisms and abnormal regulation of plasticity responses. The potential of anodal cerebellar transcranial direct current stimulation as a therapeutic tool in writing dystonia was examined, after the observation that cerebellar stimulation reduces responses to an associative plasticity protocol in healthy subjects. METHODS: Ten patients with writing dystonia completed a two-part study (sham and anodal) in which cerebellar stimulation was given simultaneously with paired associative stimulation. Electrophysiological and clinical parameters were measured before and after stimulation. RESULTS: Clinical symptoms were unchanged by cerebellar stimulation. Patients exhibited much variability in the size and direction of their plasticity responses. Excessive or topographically abnormal plasticity responses were not observed. In the subgroup of patients with facilitatory responses to paired associative stimulation in the sham condition, anodal cerebellar stimulation retained its ability to reduce the magnitude of plasticity response. CONCLUSIONS: Our limited understanding of intersubject variability of plasticity responses in writing dystonia currently undermines cerebellar stimulation as a novel treatment in this subset of dystonia. Cerebellar stimulation may be beneficial in other neurological disorders with consistently exaggerated plasticity.
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Cerebelo/fisiología , Trastornos Distónicos/terapia , Corteza Motora/fisiopatología , Estimulación Magnética Transcraneal/métodos , Escritura , Electroencefalografía , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervaciónRESUMEN
Much attention has focused on the hypothesis that there is enhanced plasticity of sensorimotor circuits in patients with dystonia. A common experimental method to assess plasticity in dystonia research is paired associative stimulation (PAS). Excessive, nonfocal effects of PAS were observed in early studies of dystonia; however, these large effects have not been uniformly replicated. In this viewpoint, data from 15 patients with writing dystonia are presented. We suggest that, as in healthy individuals, the effects of PAS are highly variable. A review of previous studies examining PAS in writing dystonia highlights the range of results that have been observed. We conclude that current experimental evidence cannot be fully explained by the notion that PAS responses in writing dystonia are consistently excessive or nonspecific. The variability of PAS responses is such that enhanced plasticity should not be considered a dystonic fingerprint, because the direction of response can vary, and there is overlap between patient and healthy data. We also discuss evidence questioning the assumption that PAS responses are a clear correlate to levels of synaptic plasticity; we need to define more specifically what PAS responses signify in the dystonic brain. Our conclusions are limited to PAS in writing dystonia; however, much variation exists with other plasticity protocols. Large multicenter studies of both focal and generalized forms of dystonia, probing variability of individual neurophysiological profiles, are encouraged. This will reveal the true role of plasticity in the pathophysiology of dystonia and may expose subject-specific therapeutic interventions that are currently concealed.
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Distonía/fisiopatología , Corteza Motora/fisiopatología , Plasticidad Neuronal/fisiología , Aprendizaje por Asociación de Pares/fisiología , Escritura , Humanos , Desempeño PsicomotorRESUMEN
The potential role of the cerebellum in the pathophysiology of dystonia has become a focus of recent research. However, direct evidence for a cerebellar contribution in humans with dystonia is difficult to obtain. We examined motor adaptation, a test of cerebellar function, in 20 subjects with primary cervical dystonia and an equal number of aged matched controls. Adaptation to both visuomotor (distorting visual feedback by 30°) and forcefield (applying a velocity-dependent force) conditions were tested. Our hypothesis was that cerebellar abnormalities observed in dystonia research would translate into deficits of cerebellar adaptation. We also examined the relationship between adaptation and dystonic head tremor as many primary tremor models implicate the cerebellothalamocortical network which is specifically tested by this motor paradigm. Rates of adaptation (learning) in cervical dystonia were identical to healthy controls in both visuomotor and forcefield tasks. Furthermore, the ability to adapt was not clearly related to clinical features of dystonic head tremor. We have shown that a key motor control function of the cerebellum is intact in the most common form of primary dystonia. These results have important implications for current anatomical models of the pathophysiology of dystonia. It is important to attempt to progress from general statements that implicate the cerebellum to a more specific evidence-based model. The role of the cerebellum in this enigmatic disease perhaps remains to be proven.
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Adaptación Fisiológica/fisiología , Adaptación Psicológica/fisiología , Cerebelo/fisiopatología , Desempeño Psicomotor/fisiología , Tortícolis/congénito , Adulto , Anciano , Brazo/fisiopatología , Fenómenos Biomecánicos , Distonía/congénito , Cabeza/fisiopatología , Humanos , Aprendizaje/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estimulación Física , Robótica , Índice de Severidad de la Enfermedad , Tortícolis/fisiopatología , Tortícolis/psicología , Temblor/fisiopatología , Percepción Visual/fisiologíaRESUMEN
During a clinical lecturer role, parallel clinical and academic training is undertaken. The anticipation is that a lectureship represents an exciting and expansive time. However, a national crisis has been declared at the clinical lecturer level with a leaky pipeline of clinical academics resulting in dwindling numbers. Clinical lecturers are infrequently represented as a group partly due to their distributed nature and diverse job plans. We conducted a survey of clinical lecturers in the UK. Responses (n = 107) revealed a motivated but divided workforce. A content analysis revealed core elements that sculpt an individual's success or failure, but these were variably present. COVID-19 had a negative effect on many with various strategies reported to try and reset academic trajectories. Feelings of isolation and anxiety about a viable future in academia were significant findings. This echoes calls for a greater number of secure longer-term grants to ensure that clinical academics and their skills are retained within the research workforce. A continued effort to analytically appraise whether supportive elements are in place for all lecturers will help focus initiatives to foster excellence in clinical academic training for everyone.
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Task-specific dystonia leads to loss of sensorimotor control for a particular motor skill. Although focal in nature, it is hugely disabling and can terminate professional careers in musicians. Biomarkers for underlying mechanism and severity are much needed. In this study, we designed a keyboard device that measured the forces generated at all fingertips during individual finger presses. By reliably quantifying overflow to other fingers in the instructed (enslaving) and contralateral hand (mirroring) we explored whether this task could differentiate between musicians with and without dystonia. 20 right-handed professional musicians (11 with dystonia) generated isometric flexion forces with the instructed finger to match 25%, 50% or 75% of maximal voluntary contraction for that finger. Enslaving was estimated as a linear slope of the forces applied across all instructed/uninstructed finger combinations. Musicians with dystonia had a small but robust loss of finger dexterity. There was increased enslaving and mirroring, primarily during use of the symptomatic hand (enslaving p = 0.003; mirroring p = 0.016), and to a lesser extent with the asymptomatic hand (enslaving p = 0.052; mirroring p = 0.062). Increased enslaving and mirroring were seen across all combinations of finger pairs. In addition, enslaving was exaggerated across symptomatic fingers when more than one finger was clinically affected. Task-specific dystonia therefore appears to express along a gradient, most severe in the affected skill with subtle and general motor control dysfunction in the background. Recognition of this provides a more nuanced understanding of the sensorimotor control deficits at play and can inform therapeutic options for this highly disabling disorder.
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Trastornos Distónicos , Dedos , Destreza Motora , Música , Humanos , Dedos/fisiopatología , Dedos/fisiología , Masculino , Adulto , Femenino , Trastornos Distónicos/fisiopatología , Destreza Motora/fisiología , Persona de Mediana Edad , Adulto JovenRESUMEN
Functional neurological symptoms are one of the most common conditions observed in neurological practice, but understanding of their underlying neurobiology is poor. Historic psychological models, based on the concept of conversion of emotional trauma into physical symptoms, have not been implemented neurobiologically, and are not generally supported by epidemiological studies. In contrast, there are robust clinical procedures that positively distinguish between organic and functional motor signs that rely primarily on distracting attention away from movement or accessing it covertly. We aimed to investigate the neurobiological principles underpinning these techniques and implications for understanding functional symptoms. We assessed 11 patients with functional motor symptoms and 11 healthy controls in three experimental set-ups, where voluntary movements were made either with full explicit control or could additionally be influenced automatically by factors of which participants were much less aware (one-back reaching, visuomotor transformation, and precued reaction time with variable predictive value of the precue). Patients specifically failed in those tasks where preplanning of movement could occur and under conditions of increasing certainty regarding the movement to be performed. However, they implicitly learned to adapt to a visuomotor transformation as well as healthy controls. We propose that when the movement to be performed can be preplanned or is highly predicted, patients with functional motor symptoms shift to an explicit attentive mode of processing that impairs kinematics of movement control, but movement becomes normal when such processes cannot be employed (e.g., during unexpected movement or implicit motor adaptation).
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Actividad Motora/fisiología , Enfermedad de la Neurona Motora/fisiopatología , Movimiento/fisiología , Adaptación Fisiológica/fisiología , Adolescente , Adulto , Atención/fisiología , Femenino , Humanos , Aprendizaje/fisiología , Masculino , Persona de Mediana Edad , Tiempo de Reacción , Adulto JovenRESUMEN
It has been reported that patients who have Parkinson's disease have a high prevalence of somatisation (functional neurological symptoms) compared with patients who have other neurodegenerative conditions. Numerous explanations have been advanced for this phenomenon. Here, with illustrative cases, we discuss this topic, including its clinical importance, and suggest a link between the pathophysiology of Parkinson's disease and the proposed propensity to develop functional symptoms.
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Enfermedad de Parkinson/complicaciones , Trastornos Somatomorfos/diagnóstico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Trastornos Somatomorfos/complicaciones , Trastornos Somatomorfos/fisiopatología , Evaluación de SíntomasRESUMEN
BACKGROUND: We investigated whether clinical improvement observed after deep brain stimulation (DBS) of the globus pallidus internus (GPi) in cervical dystonia (CD) is paralleled by the normalisation of temporal discrimination thresholds (TDTs), a marker of abnormal sensory processing in CD. METHODS: TDT was tested in 11 patients with CD after they received DBS and was compared with TDT scores from 24 patients with CD and a group of 61 controls. RESULTS: A clear clinical response to GPi-DBS was demonstrated (total Toronto Western Spasmodic Torticollis Rating Scale scores fell from 50 to 18; P < 0.001). In contrast, TDT remained abnormal in the CD-DBS group (P < 0.001) and was not significantly different from the abnormal TDT range observed in CD. CONCLUSIONS: Underlying sensory abnormalities in temporal discrimination observed in dystonia do not seem to be corrected by successful GPi-DBS. This adds further data to the ongoing debate regarding which pathophysiological abnormalities observed in dystonia are likely to be causal in the genesis of the disease rather than epiphenomena observed secondary to abnormal motor activity.
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Estimulación Encefálica Profunda/métodos , Globo Pálido/fisiología , Trastornos de la Percepción/etiología , Trastornos de la Percepción/terapia , Tortícolis/complicaciones , Tortícolis/terapia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
We report a patient with young onset Parkinson's disease (PD) and a heterozygous point mutation in parkin (c.1000C>T; p.Arg334Cys). After 8 years he developed pyramidal signs and reinvestigation demonstrated MRI and laboratory findings supportive of a diagnosis of multiple sclerosis (MS) with a primary progressive (PP) clinical course. This is a previously un-described association of young onset PD with PPMS. Imaging clearly dates the occurrence of each disease as chronologically separate phenomena. There is not currently evidence for shared causation or pathogenesis between the two neurological disorders but we will follow with interest the emerging genetic characterization of parkin in both PD and MS.
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Esclerosis Múltiple Crónica Progresiva/complicaciones , Enfermedad de Parkinson/complicaciones , Adulto , Edad de Inicio , Humanos , Masculino , Esclerosis Múltiple Crónica Progresiva/patología , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Motor surround inhibition (mSI) is one mechanism by which the central nervous system individuates finger movements, and yet the neuroanatomical substrate of this phenomenon is currently unknown. In this study, we examined the role of the cerebellum in the generation of mSI, using transcranial direct current stimulation of the cerebellum (cDC). We also examined intrasubject and intersubject variability of mSI. Twelve subjects completed a three session cross over study in which mSI was measured before and after (0 and 20 minutes) sham, anodal and cathodal cDC. mSI of the surround muscle (adductor digiti minimi) at the onset of flexion of the index finger was consistently observed. Anodal and cathodal cDC did not modulate the magnitude of mSI. For individual subjects (across the three sessions), the intrasubject coefficient of variation was 27%. Between subjects, the intersubject coefficient of variation was 47%. mSI was a stable effect in individual subjects across multiple sessions. This is an important observation and contrasts with other neurophysiological paradigms such as paired associative stimulation response, which exhibit great variability. In addition, we have quantified intrasubject variability of mSI, which will allow future therapeutic studies that attempt to modulate mSI to be adequately powered. We have not found evidence that the cerebellum contributes to the neuroanatomical network needed for the generation of mSI. Understanding the mechanisms of mSI remains a challenge but is important for disorders in which it is deficient such as Parkinson's disease and focal hand dystonia.