Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

Neurofilament light chain levels reflect outcome in a patient with glutamic acid decarboxylase 65 antibody-positive autoimmune encephalitis under immune checkpoint inhibitor therapy.

Neurological immune-mediated side effects are rare but often severe complications of immune checkpoint inhibitor (ICI) treatment. This report describes a severe case of nivolumab/ipilimumab-associated glutamic acid decarboxylase 65-positive autoimmune encephalitis. It proposes neurofilament light chain levels, a biomarker indicating axonal damage, in the cerebrospinal fluid and serum as a putative novel biomarker for this diagnostically and therapeutically challenging entity with an often unfavorable outcome. Additionally, we provide an overview of previous reports of patients developing autoimmune encephalitis under ICI treatment.

[Genetic testing for Parkinson's disease: indication and practical implementation]. / Genetische Untersuchungen beim Parkinson-Syndrom: Indikation und praktische Durchführung.

More than 20 years have passed since the first description of a monogenic cause of Parkinson's disease. Despite the tremendous advances of genetic testing these techniques are rarely used in Parkinson's disease. However, genetic tests in patients with Parkinson's syndrome will play an important role in the future. This is not only to ensure the diagnosis of Parkinson's patients with a young onset and / or a positive family history, but also in the context of personalised medicine with new therapeutic options. In the following we would like to give an overview of the basics of genetic testing, the legal requirements, the procedure for genetic testing and an outlook into the future for hereditary Parkinson's diseases.

α-Synuclein in Parkinson's disease: causal or bystander?

Parkinson's disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aß) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration.

[Nutritional aspects in Parkinson's disease: disease risk, dietary therapy and treatment of digestive tract dysfunction]. / Ernährungsaspekte bei Morbus Parkinson: Erkrankungsrisiko, Diät und Therapie von Funktionsstörungen des Verdauungstraktes.

Epidemiological studies suggest an association of certain foods with the risk of Parkinson's disease. Also, a number of studies revaeled positive effects on disease progression by caffeine, higher uric acid and total cholesterol levels - especially in men. However, it is not yet clear whether a specific dietary concept or the effects of the intestinal microbiota on the human metabolism could play a role in the course of the disease. Given the lack of prospective nutrition studies, only general recommendations can be given: a "balanced" seasonal regional diet with emphasis on vegetables, fruits, nuts, fish, low amount of red meat, and non-processed foods with a low level of simple carbohydrates may be helpful. Especially for the elderly, a low-protein diet should be avoided. Rather, in order to prevent the development of sarcopenia and malnutrition, particular attention must be paid to adequate protein intake. The supply of vitamins B12 and D3 must be ensured - at the same time, the non-critical use of dietary supplements, especially micronutrients with presumed anti-oxidative properties, should be discouraged.

Changes in resting-state connectivity in musicians with embouchure dystonia.

OBJECTIVE: Embouchure dystonia is a highly disabling task-specific dystonia in professional brass musicians leading to spasms of perioral muscles while playing the instrument. As they are asymptomatic at rest, resting-state functional magnetic resonance imaging in these patients can reveal changes in functional connectivity within and between brain networks independent from dystonic symptoms. METHODS: We therefore compared embouchure dystonia patients to healthy musicians with resting-state functional magnetic resonance imaging in combination with independent component analyses. RESULTS: Patients showed increased functional connectivity of the bilateral sensorimotor mouth area and right secondary somatosensory cortex, but reduced functional connectivity of the bilateral sensorimotor hand representation, left inferior parietal cortex, and mesial premotor cortex within the lateral motor function network. Within the auditory function network, the functional connectivity of bilateral secondary auditory cortices, right posterior parietal cortex and left sensorimotor hand area was increased, the functional connectivity of right primary auditory cortex, right secondary somatosensory cortex, right sensorimotor mouth representation, bilateral thalamus, and anterior cingulate cortex was reduced. Negative functional connectivity between the cerebellar and lateral motor function network and positive functional connectivity between the cerebellar and primary visual network were reduced. CONCLUSIONS: Abnormal resting-state functional connectivity of sensorimotor representations of affected and unaffected body parts suggests a pathophysiological predisposition for abnormal sensorimotor and audiomotor integration in embouchure dystonia. Altered connectivity to the cerebellar network highlights the important role of the cerebellum in this 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.

Activity and topographic changes in the somatosensory system in embouchure dystonia.

BACKGROUND: Embouchure dystonia is a highly disabling focal task-specific dystonia affecting professional brass players. OBJECTIVE: This study was designed to analyze activity changes along with topographic representations in primary and nonprimary centers for somatosensory processing in patients with embouchure dystonia. METHODS: We used event-related functional magnetic resonance imaging with automized tactile stimulation of dystonic (upper lip) and nondystonic (forehead and dorsal hand) body regions in 15 professional brass players with and without embouchure dystonia. Statistical analyses included whole-brain between-group comparisons of stimulation-induced activation and region-of-interest-based single patient analyses of topographic activation characteristics. RESULTS: Affected musicians revealed increased stimulation-induced activity in contralateral primary and bilateral secondary somatosensory representations of dystonic and nondystonic body regions as well as in the cerebellum ipsilateral to the left dystonic upper lip. Changes of somatotopic organization with altered intracortical distances and between-group differences of the centers of representations were found in the right primary and the bilateral secondary somatosensory cortex and in the left cerebellum. Positional variability of dystonic and nondystonic body regions was reduced with an emphasis on face representations. CONCLUSIONS: The present findings are supportive of the concept of an abnormal processing of somatosensory information in embouchure dystonia affecting multiple domains. The underlying neurophysiological mechanisms (eg, changes in inhibition, maladaptive plasticity, changes in baseline activity) remain unclear. The involvement of nondystonic body areas can be viewed in the context of possible compensation or an endophenotypic predisposition. © 2016 International Parkinson and Movement Disorder Society.

Multiple changes of functional connectivity between sensorimotor areas in focal hand dystonia.

BACKGROUND: Task-specific focal hand dystonia impairs the control of arm muscles during fine motor skills such as writing (writer's cramp (WC)). Functional imaging found abnormal task-related activation of sensorimotor areas in this disorder, but little is known on their functional connectivity (FC). METHODS: Resting-state fMRI and regions of interest (ROI)-voxel cross-correlation analyses were used for systematically analysing the FC between multiple ROIs within the cerebello-basal ganglia-thalamocortical network in 15 patients with right-sided WC and 15 healthy volunteers. RESULTS: Patients with WC showed a lower positive FC of several seed ROIs (left lateral premotor cortex, left thalamus, left/right pallidum) to the symptomatic left primary sensorimotor cortex compared with controls. The FC of the left primary motor cortex to prefrontal areas, pre- supplementary motor area and right somatosensory cortex was reduced and correlated with disease severity. Several cerebellar seed ROIs (right dentate nucleus, right crus I and bilateral crus II) revealed a stronger negative FC to primary and secondary sensorimotor areas. CONCLUSIONS: An increase of negative cerebello-cortical FC at rest is in line with the hypothesis of a pathogenetic role of the cerebellum in dystonia. The deficit of positive subcortico-cortical FC indicates more generalised changes within the basal ganglia-thalamocortical motor loops beyond primary sensorimotor areas in WC. As patients with WC are asymptomatic during rest, these functional network changes could reflect an underlying abnormality or compensatory neuroplastic changes of network architecture in this disorder.

Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls.

BACKGROUND: Rare autosomal-dominant mutations in ANO3 and GNAL have been recently shown to represent novel genetic factors underlying primary torsion dystonia (PTD) with predominantly craniocervical involvement. METHODS: We used high-resolution melting to screen all exons of ANO3 and GNAL for rare sequence variants in a population of 342 German individuals with mainly sporadic PTD and 376 general population controls. RESULTS: We identified 2 novel missense variants in ANO3 (p.Ile833Val and p.Gly973Arg) and 1 novel missense variant in GNAL (p.Val146Met) in three different nonfamilial cases. Variant carriers presented with adult-onset dystonia involving the neck and/or face. In controls, 3 rare ANO3 missense variants (p.Tyr235Cys, p.Asn256Ser, and p.Pro893Leu) but no rare nonsynonymous GNAL variants were present. CONCLUSIONS: GNAL variants seem to be a rare cause of PTD in our mainly sporadic German sample. Low frequency missense variants in ANO3 occur in both cases and controls, warranting further assessment of this gene in PTD pathogenesis.

Anti-NMDA-receptor encephalitis and concurrent neuroborreliosis misdiagnosed for post-COVID-19-syndrome: a case report.

We present a case of a 42-year-old woman with paraneoplastic anti-N-Methyl-D-Aspartat (NMDA)-receptor encephalitis and concurrent neuroborreliosis that was initially misdiagnosed as post-COVID-19 syndrome. Clinically, the patient presented with a range of chronic and subacute neuropsychiatric symptoms and recalled a tick bite weeks prior to admission. The patient had undergone psychiatric and complementary medical treatments for 1 year before admission and was initially diagnosed with post-COVID-19 syndrome. Admission was performed because of acute worsening with fever, confusion, and unsteady gait. Cerebrospinal fluid (CSF) analysis revealed pleocytosis with elevated borrelia Immunoglobulin M (IgM) and Immunoglobulin M (IgG) CSF/blood antibody indices, indicating acute neuroborreliosis. Anti-NMDA receptor antibodies were identified in the CSF via a cell-based assay and were confirmed by an external laboratory. Other paraneoplastic antibodies were ruled out during in-house examination. Cranial Magnetic resonance imaging (MRI) revealed basal meningitis, rhomb- and limbic encephalitis. A subsequent pelvic Computer tomography (CT) scan identified an ovarian teratoma. The patient's clinical condition improved dramatically with antibiotic treatment and plasmapheresis, the teratoma was surgically removed and she was started on rituximab. Our case highlights that amidst the prevailing focus on COVID-19-related health concerns, other well-established, but rare neurological conditions should not be neglected. Furthermore, our case illustrates that patients may suffer from multiple, concurrent, yet pathophysiologically unrelated neuroinflammatory conditions.

Basal ganglia-premotor dysfunction during movement imagination in writer's cramp.

The pathophysiology of idiopathic focal hand dystonia (writer's cramp) is characterized by deficient inhibitory basal ganglia function and altered cortical sensorimotor processing. To explore if this is already a primary finding in dystonia for internal movement simulation independent of dystonic motor output or abnormal sensory input, we investigated the neural correlates of movement imagination and observation in patients with writer's cramp. Event-related fMRI was applied during kinesthetic motor imagery of drawing simple geometric figures (imagination task) and passively observing videos of hands drawing identical figures (observation task). Compared with healthy controls, patients with writer's cramp showed deficient activation of the left primary sensorimotor cortex, mesial and left dorsal premotor cortex, bilateral putamen, and bilateral thalamus during motor imagery. No significant signal differences between both groups were found during the observation task. We conclude that internal movement simulation and planning as tested during imagination of hand movements appear to be dysfunctional in patients with writer's cramp, whereas visual signal processing and observation-induced activation are unaffected. Deficient basal ganglia-premotor activation could be a correlate of impaired basal ganglia inhibition and focusing during the selection of motor programs in dystonia. This finding seems to be an intrinsic deficit, as it is found during motor imagery in the absence of dystonic symptoms.

Deciphering the Network Effects of Deep Brain Stimulation in Parkinson's Disease.

INTRODUCTION: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy for Parkinson's disease (PD). However, a more detailed characterization of the targeted network and its grey matter (GM) terminals that drive the clinical outcome is needed. In this direction, the use of MRI after DBS surgery is now possible due to recent advances in hardware, opening a window for the clarification of the association between the affected tissue, including white matter fiber pathways and modulated GM regions, and the DBS-related clinical outcome. Therefore, we present a computational framework for reconstruction of targeted networks on postoperative MRI. METHODS: We used a combination of preoperative whole-brain T1-weighted (T1w) and diffusion-weighted MRI data for morphometric integrity assessment and postoperative T1w MRI for electrode reconstruction and network reconstruction in 15 idiopathic PD patients. Within this framework, we made use of DBS lead artifact intensity profiles on postoperative MRI to determine DBS locations used as seeds for probabilistic tractography to cortical and subcortical targets within the motor circuitry. Lastly, we evaluated the relationship between brain microstructural characteristics of DBS-targeted brain network terminals and postoperative clinical outcomes. RESULTS: The proposed framework showed robust performance for identifying the DBS electrode positions. Connectivity profiles between the primary motor cortex (M1), supplementary motor area (SMA), and DBS locations were strongly associated with the stimulation intensity needed for the optimal clinical outcome. Local diffusion properties of the modulated pathways were related to DBS outcomes. STN-DBS motor symptom improvement was highly associated with cortical thickness in the middle frontal and superior frontal cortices, but not with subcortical volumetry. CONCLUSION: These data suggest that STN-DBS outcomes largely rely on the modulatory interference from cortical areas, particularly M1 and SMA, to DBS locations.

Deficient Interhemispheric Connectivity Underlies Movement Irregularities in Parkinson's Disease.

BACKGROUND: Movement execution is impaired in patients with Parkinson's disease. Evolving neurodegeneration leads to altered connectivity between distinct regions of the brain and altered activity at interconnected areas. How connectivity alterations influence complex movements like drawing spirals in Parkinson's disease patients remains largely unexplored. OBJECTIVE: We investigated whether deteriorations in interregional connectivity relate to impaired execution of drawing. METHODS: Twenty-nine patients and 31 age-matched healthy control participants drew spirals with both hands on a digital graphics tablet, and the regularity of drawing execution was evaluated by sample entropy. We recorded resting-state fMRI and task-related EEG, and calculated the time-resolved partial directed coherence to estimate effective connectivity for both imaging modalities to determine the extent and directionality of interregional interactions. RESULTS: Movement performance in Parkinson's disease patients was characterized by increased sample entropy, corresponding to enhanced irregularities in task execution. Effective connectivity between the motor cortices of both hemispheres, derived from resting-state fMRI, was significantly reduced in Parkinson's disease patients in comparison to controls. The connectivity strength in the nondominant to dominant hemisphere direction in both modalities was inversely correlated with irregularities during drawing, but not with the clinical state. CONCLUSION: Our findings suggest that interhemispheric connections are affected both at rest and during drawing movements by Parkinson's disease. This provides novel evidence that disruptions of interhemispheric information exchange play a pivotal role for impairments of complex movement execution in Parkinson's disease patients.

Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies.

BACKGROUND AND OBJECTIVES: Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). METHODS: We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections. RESULTS: The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected. DISCUSSION: We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.

Botulinum toxin modulates basal ganglia but not deficient somatosensory activation in orofacial dystonia.

UNLABELLED: The etiology of idiopathic orofacial dystonia is incompletely understood. Neurophysiological studies indicated that a sensory dysfunction could play a key role in the pathophysiology of focal dystonia. To explore if central sensory processing is abnormal in patients with blepharospasm and Meige's syndrome and to study the effects of botulinum toxin (BTX) treatment, we systematically mapped the somatotopic representations of punctate tactile stimuli in these patients before and after therapy. METHODS: Standardized tactile stimuli were pseudorandomly applied to the forehead, upper lip, and hand by a MR-compatible stimulation device during event-related fMRI. RESULTS: Patients showed a deficient activation in primary and secondary somatosensory representations of affected and unaffected (right hand) body regions compared to healthy controls. Although clinically effective BTX treatment did not modulate this impaired cortical activation, it reduced the activation of the thalamus and contralateral putamen during forehead stimulation. CONCLUSIONS: This study reveals a more generalized dysfunction of the somatosensory cortex including asymptomatic body representations in orofacial dystonia. Deficient cortical sensory activation may be due to a dedifferentiation of somatosensory representations and could represent a critical functional change within the basal ganglia-thalamocortical loops facilitating dystonic movements. Modulation of basal ganglia activation might reflect an indirect remote effect of BTX treatment on these sensorimotor circuits.

The link between facial feedback and neural activity within central circuitries of emotion--new insights from botulinum toxin-induced denervation of frown muscles.

Afferent feedback from muscles and skin has been suggested to influence our emotions during the control of facial expressions. Recent imaging studies have shown that imitation of facial expressions is associated with activation in limbic regions such as the amygdala. Yet, the physiological interaction between this limbic activation and facial feedback remains unclear. To study if facial feedback effects on limbic brain responses during intentional imitation of facial expressions, we applied botulinum toxin (BTX)-induced denervation of frown muscles in combination with functional magnetic resonance imaging as a reversible lesion model to minimize the occurrence of afferent muscular and cutaneous input. We show that, during imitation of angry facial expressions, reduced feedback due to BTX treatment attenuates activation of the left amygdala and its functional coupling with brain stem regions implicated in autonomic manifestations of emotional states. These findings demonstrate that facial feedback modulates neural activity within central circuitries of emotion during intentional imitation of facial expressions. Given that people tend to mimic the emotional expressions of others, this could provide a potential physiological basis for the social transfer of emotion.

Altered sensory system activity and connectivity patterns in adductor spasmodic dysphonia.

Adductor-type spasmodic dysphonia (ADSD) manifests in effortful speech temporarily relievable by botulinum neurotoxin type A (BoNT-A). Previously, abnormal structure, phonation-related and resting-state sensorimotor abnormalities as well as peripheral tactile thresholds in ADSD were described. This study aimed at assessing abnormal central tactile processing patterns, their spatial relation with dysfunctional resting-state connectivity, and their BoNT-A responsiveness. Functional MRI in 14/12 ADSD patients before/under BoNT-A effect and 15 controls was performed (i) during automatized tactile stimulus application to face/hand, and (ii) at rest. Between-group differential stimulation-induced activation and resting-state connectivity (regional homogeneity, connectivity strength within selected sensory(motor) networks), as well as within-patient BoNT-A effects on these differences were investigated. Contralateral-to-stimulation overactivity in ADSD before BoNT-A involved primary and secondary somatosensory representations, along with abnormalities in higher-order parietal, insular, temporal or premotor cortices. Dysphonic impairment in ADSD positively associated with left-hemispheric temporal activity. Connectivity was increased within right premotor (sensorimotor network), left primary auditory cortex (auditory network), and regionally reduced at the temporoparietal junction. Activation/connectivity before/after BoNT-A within-patients did not significantly differ. Abnormal ADSD central somatosensory processing supports its significance as common pathophysiologic focal dystonia trait. Abnormal temporal cortex tactile processing and resting-state connectivity might hint at abnormal cross-modal sensory interactions.

Structural brain network fingerprints of focal dystonia.

BACKGROUND: Focal dystonias are severe and disabling movement disorders of a still unclear origin. The structural brain networks associated with focal dystonia have not been well characterized. Here, we investigated structural brain network fingerprints in patients with blepharospasm (BSP) compared with those with hemifacial spasm (HFS), and healthy controls (HC). The patients were also examined following treatment with botulinum neurotoxin (BoNT). METHODS: This study included matched groups of 13 BSP patients, 13 HFS patients, and 13 HC. We measured patients using structural-magnetic resonance imaging (MRI) at baseline and after one month BoNT treatment, at time points of maximal and minimal clinical symptom representation, and HC at baseline. Group regional cross-correlation matrices calculated based on grey matter volume were included in graph-based network analysis. We used these to quantify global network measures of segregation and integration, and also looked at local connectivity properties of different brain regions. RESULTS: The networks in patients with BSP were more segregated than in patients with HFS and HC (p < 0.001). BSP patients had increased connectivity in frontal and temporal cortices, including sensorimotor cortex, and reduced connectivity in the cerebellum, relative to both HFS patients and HC (p < 0.05). Compared with HC, HFS patients showed increased connectivity in temporal and parietal cortices and a decreased connectivity in the frontal cortex (p < 0.05). In BSP patients, the connectivity of the frontal cortex diminished after BoNT treatment (p < 0.05). In contrast, HFS patients showed increased connectivity in the temporal cortex and reduced connectivity in cerebellum after BoNT treatment (p < 0.05). CONCLUSIONS: Our results show that BSP patients display alterations in both segregation and integration in the brain at the network level. The regional differences identified in the sensorimotor cortex and cerebellum of these patients may play a role in the pathophysiology of focal dystonia. Moreover, symptomatic reduction of hyperkinesia by BoNT treatment was associated with different brain network fingerprints in both BSP and HFS patients.

Abnormalities in grey matter structure in embouchure dystonia.

INTRODUCTION: Embouchure dystonia (ED) is a debilitating movement disorder in professional brass players leading to involuntary muscle contractions/spasms during play. To date, activity changes in sensorimotor cortices during motor tasks and tactile processing, as well as connectivity changes at rest in sensorimotor and auditory brain networks have been described in the disease. OBJECTIVE: To characterize differences in grey matter volume and asymmetry between brass musicians suffering from ED, healthy brass musicians and healthy nonmusicians. METHODS: High-resolution structural magnetic resonance imaging was obtained from 24 brass musicians with ED, 23 healthy brass musicians and 24 healthy nonmusicians. Whole-brain voxel-wise morphometry and asymmetry analyses, as well as region-of-interest-based volumetry analysis were performed on the subjects' images and compared between groups. Further, correlations with clinical parameters were investigated. RESULTS: ED patients showed increased grey matter volume in the primary sensorimotor cortex in relation to both healthy brass players and nonmusicians. Both healthy and diseased musicians showed increased thalamic symmetry in relation to nonmusicians; diseased brass musicians additionally showed increased basal ganglia symmetry compared to nonmusicians. There was an inverse correlation of disease duration with both mean putaminal volume and the extent of basal ganglia asymmetry. CONCLUSION: This work provides first evidence for structural abnormalities in task-specific orofacial (musician's) dystonia. Somatotopy-related structural primary sensorimotor cortex changes underlying previously observed functional abnormalities underscore the role of maladaptive plasticity in the disease. The study further shows subcortical brain (a)symmetry changes in healthy brass players and hints at a possible role of such changes in focal dystonia.