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Aberrant information processing in the basal ganglia and connected cortical areas are key to many neurological movement disorders such as Parkinson's disease. Investigating the electrophysiology of this system is difficult in humans because non-invasive methods, such as electroencephalography or magnetoencephalography, have limited sensitivity to deep brain areas. Recordings from electrodes implanted for therapeutic deep brain stimulation, in contrast, provide clear deep brain signals but are not suited for studying cortical activity. Therefore, we combine magnetoencephalography and local field potential recordings from deep brain stimulation electrodes in individuals with Parkinson's disease. Here, we make these data available, inviting a broader scientific community to explore the dynamics of neural activity in the subthalamic nucleus and its functional connectivity to cortex. The dataset encompasses resting-state recordings, plus two motor tasks: static forearm extension and self-paced repetitive fist clenching. Most patients were recorded both in the medicated and the unmedicated state. Along with the raw data, we provide metadata on channels, events and scripts for pre-processing to help interested researchers get started., (© 2024. The Author(s).)

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Previous research suggested that quadripulse (QPS)-induced synaptic plasticity is associated with both cognitive and motor function in patients with multiple sclerosis (MS) and does not appear to be reduced compared to healthy controls (HCs)., Objective: This study aimed to explore the relationship between the degree of QPS-induced plasticity and clinically significant decline in motor and cognitive functions over time. We hypothesized that MS patients experiencing functional decline would exhibit lower levels of baseline plasticity compared to those without decline., Methods: QPS-induced plasticity was evaluated in 80 MS patients (56 with relapsing-remitting MS and 24 with progressive MS), and 69 age-, sex-, and education-matched HCs. Cognitive and motor functions, as well as overall disability status were evaluated annually over a median follow-up period of 2 years. Clinically meaningful change thresholds were predefined for each outcome measure. Linear mixed-effects models, Cox proportional hazard models, logistic regression, and receiver-operating characteristic analysis were applied to analyse the relationship between baseline plasticity and clinical progression in the symbol digit modalities test, brief visuospatial memory test revised (BVMT-R), nine-hole peg test (NHPT), timed 25-foot walk test, and expanded disability status scale., Results: Overall, the patient cohort showed no clinically relevant change in any functional outcome over time. Variability in performance was observed across time points in both patients and HCs. MS patients who experienced clinically relevant decline in manual dexterity and/or visuospatial learning and memory had significantly lower levels of synaptic plasticity at baseline compared to those without such decline (NHPT: β  = -0.25, p  = 0.02; BVMT-R: β  = -0.50, p  = 0.005). Receiver-operating characteristic analysis underscored the predictive utility of baseline synaptic plasticity in discerning between patients experiencing functional decline and those maintaining stability only for visuospatial learning and memory (area under the curve = 0.85)., Conclusion: Our study suggests that QPS-induced plasticity could be linked to clinically relevant functional decline in patients with MS. However, to solidify these findings, longer follow-up periods are warranted, especially in cohorts with higher prevalences of functional decline. Additionally, the variability in cognitive performance in both patients with MS and HCs underscores the importance of conducting further research on reliable change based on neuropsychological tests., Competing Interests: CB has received speaker honoraria and travel expenses from Roche and speaker honoraria from Synaptikon GmbH. LJ has received an individual funding granted by the Research Committee of the Medical Faculty of the Heinrich Heine University Düsseldorf for her doctoral thesis (October 2021–March 2022). CH has been serving as consultant for Univar and has received honoraria for lecturing and travel expenses/speaking honoraria from Abbott and Alexion, and research support from Abbott. SM has received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, SanofiAventis, Chugai Pharma, QuintilesIMS and Teva, and research funding from the German Ministry for Education and Research (BMBF), the Deutsche Forschungsgemeinschaft, the Else Kröner Fresenius Foundation, the German Academic Exchange Service, the Hertie Foundation, the Interdisciplinary Center for Clinical Studies (IZKF) Muenster, the German Foundation for Neurology, Almirall, Amicus Therapeutics, Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche and Teva. AS has received lecture fees from Abbott, Novartis, Kyowa Kirin, and has been serving as a consultant for Abbott, Zambon, Medtronic Inc. He received royalties from Georg Thieme Verlag. He is a government employee and receives through his institution funding for his research from the German Research Council, Abbott, and the Brunhilde Moll Foundation. I-KP received honoraria for speaking at scientific meetings, serving at scientific advisory boards, and consulting activities from Almirall, Biogen, BMS, Celgene, Sanofi-Genzyme, Janssen, Merck, Novartis, Roche, and Teva. She received research support from the German MS Society, Celgene, Novartis, Roche, and Teva. PA received compensation for serving on Scientific Advisory Boards for Allergan, Abbvie, Biogen, Bristol Myers Squibb, Celgene, Janssen Cilag, Ipsen, Merck, Merz Pharmaceuticals, Novartis, Biogen; he received speaker honoraria and travel support from Novartis, Teva, Biogen, Bristol Myers Squibb, Celgene, Merz Pharmaceuticals, Ipsen, Allergan, Bayer Healthcare, Esai, UCB, Lilly, Roche, Sanofi; he received research support from German Research Association (DFG), Bristol Myers Squibb, Novartis, Allergan, Abbvie, Biogen, Celgene, Teva, Merz Pharmaceuticals, Ipsen, and Roche. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Balloff, Janßen, Hartmann, Meuth, Schnitzler, Penner and Albrecht.)

Background: Cortical plasticity induced by quadripulse stimulation (QPS) has been shown to correlate with cognitive functions in patients with relapsing-remitting multiple sclerosis (RRMS) and to not be reduced compared to healthy controls (HCs)., Objective: This study aimed to compare the degree of QPS-induced plasticity between different subtypes of multiple sclerosis (MS) and HCs and to investigate the association of the degree of plasticity with motor and cognitive functions. We expected lower levels of plasticity in patients with progressive MS (PMS) but not RRMS compared to HCs. Furthermore, we expected to find positive correlations with cognitive and motor performance in patients with MS., Methods: QPS-induced plasticity was compared between 34 patients with PMS, 30 patients with RRMS, and 30 HCs using linear mixed-effects models. The degree of QPS-induced cortical plasticity was correlated with various motor and cognitive outcomes., Results: There were no differences regarding the degree of QPS-induced cortical plasticity between HCs and patients with RRMS ( p = 0.86) and PMS ( p = 0.18). However, we only found correlations between the level of induced plasticity and both motor and cognitive functions in patients with intact corticospinal tract integrity. Exploratory analysis revealed significantly reduced QPS-induced plasticity in patients with damage compared to intact corticospinal tract integrity ( p < 0.001)., Conclusion: Our study supports the notion of pyramidal tract integrity being of more relevance for QPS-induced cortical plasticity in MS and related functional significance than the type of disease., Competing Interests: PA received compensation for serving on Scientific Advisory Boards for Allergan, Celgene, Janssen Cilag, Ipsen, Merck, Merz Pharmaceuticals, Novartis, and Biogen; he received speaker honoraria and travel support from Novartis, Teva, Biogen, Celgene, Merz Pharmaceuticals, Ipsen, Allergan, Bayer Healthcare, Esai, UCB; Roche; he received research support from Novartis, Allergan, Biogen, Celgene, Teva, Merz Pharmaceuticals, Ipsen, and Roche. CH has been serving as a consultant for Univar and has received honoraria for lecturing and travel expenses/speaking honoraria from Abbott and Alexion, and research support from Abbott. SM has received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, SanofiAventis, Chugai Pharma, QuintilesIMS, and Teva, and research funding from the German Ministry for Education and Research (BMBF), the Deutsche Forschungsgemeinschaft, the Else Kröner Fresenius Foundation, the German Academic Exchange Service, the Hertie Foundation, the Interdisciplinary Center for Clinical Studies (IZKF) Muenster, the German Foundation for Neurology, Almirall, Amicus Therapeutics, Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. AS has received lecture fees from Abbott, Novartis, and Kyowa Kirin, and has been serving as a consultant for Abbott, Zambon, and Medtronic Inc. He received royalties from Georg Thieme Verlag. He is a government employee and receives through his institution funding for his research from the German Research Council, Abbott, and the Brunhilde Moll Foundation. I-KP received honoraria for speaking at scientific meetings, serving at scientific advisory boards, and consulting activities from Almirall, Bayer Pharma, Biogen, BMS, Celgene, Sanofi-Genzyme, Janssen, Merck, Novartis, Roche, and Teva. She received research support from the German MS Society, Celgene, Novartis, Roche, and Teva. SG received honoraria and/or travel expenses from Abbott Medical, Abbvie, Boston Scientific, Medtronic, Rogue Research, and UCB, consulting fees from Zambon, and research support from Abbott and Hilde-Ulrichs Stiftung. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Balloff, Albrecht, Stucke, Scala, Novello, Hartmann, Meuth, Schnitzler, Penner and Groiss.)

Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (n = 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 [1.01-65.13], p = 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration., (© 2023. The Author(s).)

Objective: To investigate the degree of synaptic plasticity in Multiple Sclerosis (MS) patients during acute relapses compared to stable MS patients and healthy controls (HCs) and to analyze its functional relevance., Methods: Facilitatory quadripulse stimulation (QPS) was applied to the primary motor cortex in 18 acute relapsing and 18 stable MS patients, as well as 18 HCs. The degree of synaptic plasticity was measured by the change in motor evoked potential amplitude following QPS. Symptom recovery was assessed three months after relapse., Results: Synaptic plasticity was induced in all groups. The degree of induced plasticity did not differ between acute relapsing patients, HCs, and stable MS patients. Plasticity was significantly higher in relapsing patients with motor disability compared to relapsing patients without motor disability. In most patients (n = 9, 50%) symptoms had at least partially recovered three months after the relapse, impeding meaningful analysis of the functional relevance of baseline synaptic plasticity., Conclusions: QPS-induced synaptic plasticity is retained during acute MS relapses. Subgroup analyses suggest that stabilizing metaplastic mechanisms may be more important to prevent motor disability but its functional relevance needs to be verified in larger, longitudinal studies., Significance: New insights into synaptic plasticity during MS relapses are provided., Competing Interests: Conflict of Interest Statement C. Balloff reports no disclosures relevant to the manuscript. S. Novello reports no disclosures relevant to the manuscript. A-S. Stucke reports no disclosures relevant to the manuscript. L.K. Janssen has received an individual funding granted by the Research Committee of the Medical Faculty of the Heinrich Heine University Düsseldorf for her doctoral thesis (October 2021 - March 2022). E. Heinen reports no disclosures relevant to the manuscript. C.J. Hartmann reports no disclosures relevant to the manuscript. S.G. Meuth has received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, SanofiAventis, Chugai Pharma, QuintilesIMS and Teva, and research funding from the German Ministry for Education and Research (BMBF), the Deutsche Forschungsgemeinschaft, the Else Kröner Fresenius Foundation, the German Academic Exchange Service, the Hertie Foundation, the Interdisciplinary Center for Clinical Studies (IZKF) Muenster, the German Foundation for Neurology, Almirall, Amicus Therapeutics, Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche and Teva. A. Schnitzler has received lecture fees from Abbott, Novartis, Kyowa Kirin, and has been serving as a consultant for Abbott, Zambon, Medtronic Inc. He received royalties from the Georg Thieme Verlag. He is a government employee and receives through his institution funding for his research from the German Research Council, Abbott, and the Brunhilde Moll Foundation. I.-K. Penner received honoraria for speaking at scientific meetings, serving at scientific advisory boards and consulting activities from Adamas Pharma, Almirall, Bayer Pharma, Biogen, BMS, Celgene, Sanofi-Genzyme, Janssen, Merck, Novartis, Roche, and Teva. She received research support from the German MS Society, Celgene, Novartis, Roche, and Teva. S.J. Groiss received honoraria and/or travel expenses from Abbott Medical, Abbvie, Bial, Boston Scientific, Inomed, Medtronic, Rogue Research, UCB, consulting fees from Bial, Zambon and research support from Abbott and Hilde-Ulrichs Stiftung. P. Albrecht received compensation for serving on Scientific Advisory Boards for Allergan, Celgene, Janssen Cilag, Ipsen, Merck, Merz Pharmaceuticals, Novartis, Biogen; he received speaker honoraria and travel support from Novartis, Teva, Biogen, Celgene, Merz Pharmaceuticals, Ipsen, Allergan, Bayer Healthcare, Esai, UCB; Roche; he received research support from Novartis, Allergan, Biogen, Celgene, Teva, Merz Pharmaceuticals, Ipsen, and Roche., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to demonstrate that both neurological and hepatic symptoms respond to copper chelation therapy in Wilson disease (WD). However, the time course of their recovery is different., Methods: Eighteen patients with neurological WD from a single specialized center who had been listed for liver transplantation during the last ten years and two newly diagnosed homozygous twins were recruited for this retrospective study. The mean duration of conventional treatment was 7.3 years (range: 0.25 to 36.2 years). A custom Wilson disease score with seven motor items, three non-motor items, and 33 biochemical parameters of the blood and urine, as well as the MELD score, was determined at various checkup visits during treatment. These data were extracted from the charts of the patients., Results: Treatment was initiated with severity-dependent doses (≥900 mg) of D-penicillamine (DPA) or triethylene-tetramin-dihydrochloride (TRIEN). The motor score improved in 10 and remained constant in 8 patients. Worsening of neurological symptoms was observed only in two patients who developed comorbidities (myasthenia gravis or hemispheric stroke). The neurological symptoms continuously improved over the years until the majority of patients became only mildly affected. In contrast to this slow recovery of the neurological symptoms, the MELD score and liver enzymes had already started to improve after 1 month and rapidly improved over the next 6 months in 19 patients. The cholinesterase levels continued to increase significantly ( p < 0.0074) even further. One patient whose MELD score indicated further progression of liver disease received an orthotopic liver transplantation 3 months after the diagnosis of WD and the onset of DPA treatment., Conclusions: Neurological and hepatic symptoms both respond to copper chelation therapy. For patients with acute liver failure, the first 4 months are critical. This is the time span in which patients have to wait either for a donor organ or until significant improvement has occurred under conventional therapy. For patients with severe neurological symptoms, it is important that they are treated with fairly high doses over several years.

Background: Diagnosis of atypical parkinsonian syndromes (APS) mostly relies on clinical presentation as well as structural and molecular brain imaging. Whether parkinsonian syndromes are distinguishable based on neuronal oscillations has not been investigated so far., Objective: The aim was to identify spectral properties specific to atypical parkinsonism., Methods: We measured resting-state magnetoencephalography in 14 patients with corticobasal syndrome (CBS), 16 patients with progressive supranuclear palsy (PSP), 33 patients with idiopathic Parkinson's disease, and 24 healthy controls. We compared spectral power as well as amplitude and frequency of power peaks between groups., Results: Atypical parkinsonism was associated with spectral slowing, distinguishing both CBS and PSP from Parkinson's disease (PD) and age-matched healthy controls. Patients with atypical parkinsonism showed a shift in β peaks (13-30 Hz) toward lower frequencies in frontal areas bilaterally. A concomitant increase in θ/α power relative to controls was observed in both APS and PD., Conclusion: Spectral slowing occurs in atypical parkinsonism, affecting frontal β oscillations in particular. Spectral slowing with a different topography has previously been observed in other neurodegenerative disorders, such as Alzheimer's disease, suggesting that spectral slowing might be an electrophysiological marker of neurodegeneration. As such, it might support differential diagnosis of parkinsonian syndromes in the future. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone., Objective: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments., Methods: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months., Results: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III., Conclusion: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The aim of this study was to demonstrate that pseudocholinesterase (CHE) serum level is a useful diagnostic biomarker for untreated Wilson's disease (WD). Between 2013 and 2019, about 75 patients were referred to the outpatient department of the University of Düsseldorf with suspected Wilson's disease. In 31 patients with suspected Wilson's disease (WD-SUS-group), WD was excluded by means of investigations other than analysis of blood and urine. A total of 27 parameters of blood and urine in these 31 patients were compared to those of 20 de novo patients with manifest WD (WD-DEF-group), which parameter showed the highest significance level of difference between the WD-DEF-group and the WD-SUS-group. Thereafter, receiver operating characteristics (ROC-curves) were analyzed to evaluate which parameter showed the largest area under the curve (AUC) to detect WD. Finally, a logistic regression analysis was performed to analyze which combination of parameters allowed the best classification of the 51 patients either into the WD-DEF-group or into the WD-SUS-group. CHE showed the highest significance level for a difference between the WD-DEF- and WD-SUS-group, had the highest AUC, and, in combination with ceruloplasmin, allowed 100% correct classification. Without CHE, no other combination of parameters reached this level of correct classification. After the initiation of treatment, which regularly results in an improvement in CHE, the high diagnostic accuracy of this biomarker was lost. Cholinesterase turns out to be an excellent biomarker for differentiation between untreated de novo patients with manifest WD and heterozygotic gene carriers.

Objectives: One of the main challenges posed by the surgical deep brain stimulation (DBS) procedure is the successful targeting of the structures of interest and avoidance of side effects, especially in asleep surgery. Here, intraoperative motor evoked potentials (MEPs) might serve as tool to identify the pyramidal tract. We hypothesized that intraoperative MEPs are useful to define the distance to the pyramidal tract and reduce the occurrence of postoperative capsular side effects., Materials and Methods: Motor potentials were evoked through both microelectrode and DBS-electrode stimulation during stereotactic DBS surgery on 25 subthalamic nuclei and 3 ventral intermediate thalamic nuclei. Internal capsule proximity was calculated for contacts on microelectrode trajectories, as well as for DBS-electrodes, and correlated with the corresponding MEP thresholds. Moreover, the predictivity of intraoperative MEP thresholds on the probability of postoperative capsular side effects was calculated., Results: Intraoperative MEPs thresholds correlated significantly with internal capsule proximity, regardless of the stimulation source. Furthermore, MEPs thresholds were highly accurate to exclude the occurrence of postoperative capsular side effects., Conclusions: Intraoperative MEPs provide additional targeting guidance, especially in asleep DBS surgery, where clinical value of microelectrode recordings and test stimulation may be limited. As this technique can exclude future capsular side effects, it can directly be translated into clinical practice., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease., Materials and Methods: Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life., Results: The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period., Conclusion: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians., (Copyright © 2022. Published by Elsevier Inc.)

Background and Purpose: Patients with a corticobasal syndrome (CBS) present a rare form of atypical parkinsonism characterized by asymmetric clinical symptoms and progressive motor and nonmotor impairment, such as apraxia, alien limb phenomenon, aphasia, myoclonus, dystonia, and cognitive impairment. At early stages, clinical differentiation between CBS and idiopathic Parkinson's disease (IPD) can be challenging., Methods: Using high-resolution T1-weighted images and voxel-based morphometry (VBM), we sought to identify disease-specific patterns of brain atrophy in a small sample of CBS and IPD patients at early stages of disease. We acquired MR images of 17 patients diagnosed with CBS and compared them with MR images of 17 subjects affected by IPD. Images were preprocessed and analyzed using VBM., Results: When compared to each other, the CBS and IPD patients of our cohort showed differences in regional gray and white matter volume depending on the diagnosis, specifically in the superior longitudinal fascicle., Conclusions: In our small patients' group, VBM was able to detect changes in regional gray and white matter volume between patients affected by CBS and patients with IPD as early as 1.5-2 years after the onset of the first motor symptoms., (© 2022 American Society of Neuroimaging.)

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder with a broad spectrum of motor and non-motor symptoms. The neuropathological characteristics of idiopathic PD are the degeneration of dopaminergic neurons in the striatum, and the propagation of aggregates of misfolded α-synuclein in the brain following a specific pattern (Braak et al., 2006). The relationship of this pattern with motor and cognitive symptoms is still equivocal. Therefore, we investigated longitudinally the spatio-temporal patterns of atrophy propagation in PD, their inter-individual variability and associations with clinical symptoms. Magnetic resonance (MR) images of 37 PD patients and 27 controls were acquired at up to 15 time-points per subject, and over observation periods of up to 8.8 years (mean: 3.7 years). MR images were analyzed by Deformation-based Morphometry to measure region volumes and their longitudinal changes. Differences of these regional volume data between patients and controls and their associations with clinical symptoms were calculated. At baseline, group differences in the regional volumes were found mainly in areas of the sensory, motor and orbitofrontal cortices, areas in the frontal operculum, inferior frontal sulcus, hippocampus and entorhinal cortex, and in the substantia nigra, among others. The longitudinal analysis yielded more widespread and more pronounced group differences, with significantly accelerated volume decreases in PD patients in the occipital and temporal lobes, the inferior parietal lobule, as well as in the insula, putamen and nucleus basalis Meynert. The white matter was less affected than the gray matter. Worse clinical scores (MMSE, PDQ-39, UPDRS-III) were in particular associated with volume decreases of cortical areas, amygdala and basal forebrain nuclei, but not of the basal ganglia. The observed longitudinal patterns of accelerated volume decrease in PD patients largely coincide with the pattern of α-synuclein pathology in PD stages 3-5 as proposed by Braak and colleagues. Thus, longitudinal DBM appears to depict already in-vivo the progression of neuropathological changes., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for Parkinson's disease (PD) patients suffering from motor response fluctuations despite optimal medical treatment, or severe dopaminergic side effects. Despite careful clinical selection and surgical procedures, some patients do not benefit from STN DBS. Preoperative prediction models are suggested to better predict individual motor response after STN DBS. We validate a preregistered model, DBS-PREDICT, in an external multicenter validation cohort., Methods: DBS-PREDICT considered eleven, solely preoperative, clinical characteristics and applied a logistic regression to differentiate between weak and strong motor responders. Weak motor response was defined as no clinically relevant improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) II, III, or IV, 1 year after surgery, defined as, respectively, 3, 5, and 3 points or more. Lower UPDRS III and IV scores and higher age at disease onset contributed most to weak response predictions. Individual predictions were compared with actual clinical outcomes., Results: 322 PD patients treated with STN DBS from 6 different centers were included. DBS-PREDICT differentiated between weak and strong motor responders with an area under the receiver operator curve of 0.76 and an accuracy up to 77%., Conclusion: Proving generalizability and feasibility of preoperative STN DBS outcome prediction in an external multicenter cohort is an important step in creating clinical impact in DBS with data-driven tools. Future prospective studies are required to overcome several inherent practical and statistical limitations of including clinical decision support systems in DBS care., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Purpose: Parkinson's disease (PD) is primarily defined by motor symptoms and is associated with alterations of sensorimotor areas. Evidence for network changes of the sensorimotor network (SMN) in PD is inconsistent and a systematic evaluation of SMN in PD yet missing. We investigate functional connectivity changes of the SMN in PD, both, within the network, and to other large-scale connectivity networks., Methods: Resting-state fMRI was assessed in 38 PD patients under long-term dopaminergic treatment and 43 matched healthy controls (HC). Independent component analysis (ICA) into 20 components was conducted and the SMN was identified within the resulting networks. Functional connectivity within the SMN was analyzed using a dual regression approach. Connectivity between the SMN and the other networks from group ICA was investigated with FSLNets. We investigated for functional connectivity changes between patients and controls as well as between medication states (OFF vs. ON) in PD and for correlations with clinical parameters., Results: There was decreased functional connectivity within the SMN in left inferior parietal and primary somatosensory cortex in PD OFF. Across networks, connectivity between SMN and two motor networks as well as two visual networks was diminished in PD OFF. All connectivity decreases partially normalized in PD ON., Conclusion: PD is accompanied by functional connectivity losses of the SMN, both, within the network and in interaction to other networks. The connectivity changes in short- and long-range connections are probably related to impaired sensory integration for motor function in PD. SMN decoupling can be partially compensated by dopaminergic therapy., (© 2021. The Author(s).)

Background: A reliable measure of PSP-specific midbrain atrophy, the midbrain-to-pons ratio (MTPR) has been reported to support the differential diagnosis of progressive supranuclear palsy (PSP) from idiopathic Parkinson's disease (IPD). Since longitudinal analyses are lacking so far, the present study aimed to evaluate the diagnostic value of the relative change of MTPR (relΔt&#95;MTPR) over a 1-year period in patients with PSP, IPD, and healthy controls (HC)., Methods: Midsagittal individual MRIs of patients with PSP (n = 15), IPD (n = 15), and healthy controls (HC; n = 15) were assessed and the MTPR at baseline and after 1 year were defined. The diagnostic accuracy of the MTPR and its relative change were evaluated using ROC curve analyses., Results: PSP-patients had a significantly lower MTPR at baseline (M = 0.45 ± 0.06), compared to both non-PSP groups (F (2, 41) = 62.82, p < 0.001), with an overall predictive accuracy of 95.6% for an MTPR ≤ 0.54. PSP-patients also presented a significantly stronger 1-year decline in MTPR compared to IPD (p < 0.001). Though predictive accuracy of relΔ t &#95;MTPR for PSP (M = - 4.74% ± 4.48) from IPD (M =  + 1.29 ± 3.77) was good (76.6%), ROC analysis did not reveal a significant improvement of diagnostic accuracy by combining the MTPR and relΔ t &#95;MTPR (p = 0.670). Still, specificity for PSP increased, though not significantly (p = 0.500)., Conclusion: The present results indicate that the relΔ t &#95;MTPR is a potentially useful tool to support the differential diagnosis of PSP from IPD. For its relative 1-year change, still, more evaluation is needed.

This study investigated the clinical long-term effect of incobotulinumtoxinA (incoBoNT/A) in 33 cervical dystonia (CD) patients who had developed partial secondary therapy failure (PSTF) under previous long-term botulinum toxin (BoNT) treatment. Patients were treated four times every 12 weeks with incoBoNT/A injections. Physicians assessed treatment efficacy using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at the baseline visit, week 12 and 48. Patients rated quality of life of CD with the Craniocervical Dystonia Questionnaire (CDQ-24). Titres of neutralizing antibodies(NAB) were determined at start of the study and after 48 weeks. All patients had experienced significant and progressive worsening of symptoms in the last 6 months of previous BoNT treatment. Repeated incoBoNT/A injections resulted in a significant reduction in mean TWSTRS at week 12 and 48. Patients' rating of quality of life was highly correlated with TWSTRS but did not change significantly over 48 weeks. During the 48 weeks -period of incoBoNT/A treatment NAB titres decreased in 32.2%, did not change in 45.2%, and only increased in 22.6% of the patients. Thus, repeated treatment with the low dose of 200 MU incoBoNT/A over 48 weeks provided a beneficial clinical long-term effect in PSTF and did not booster titres of NAB., Competing Interests: The research work of HH has been supported by the private Inge-Diesbach-Stiftung. This allowed to pay for the antibody testing. Otherwise this support did not have any influence on the present study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hefter, Hartmann, Kahlen, Samadzadeh, Rosenthal and Moll.)

Objective: The effect of anesthesia type in terms of asleep vs. awake deep brain stimulation (DBS) surgery on therapeutic window (TW) has not been investigated so far. The objective of the study was to investigate whether asleep DBS surgery of the subthalamic nucleus (STN) improves TW for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population., Materials and Methods: A total of 104 consecutive patients with Parkinson's disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, therapeutic threshold, side effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction., Results: Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups., Conclusions: Our study provides first evidence for improvement of therapeutic window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trials., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC. on behalf of International Neuromodulation Society.)

Objectives: Deep brain stimulation (DBS) of the posterior subthalamic area (PSA) and the ventral intermediate thalamic nucleus (VIM) is a well-established therapy for essential tremor (ET), but it is frequently associated with side effects like dysarthria or gait ataxia. Directional DBS (dDBS) may be a way to activate fiber tracts more selectively. Is dDBS for ET superior to omnidirectional DBS (oDBS) regarding therapeutic window and clinically as effective as oDBS?, Materials and Methods: Ten patients with ET treated with PSA/VIM-DBS were recruited. Therapeutic window served as primary outcome parameter; clinical efficacy, volume of neuronal activation, and total electrical energy delivered (TEED) served as secondary outcome parameters. Therapeutic window was calculated for all three dDBS directions and for oDBS by determining therapeutic thresholds and side effect thresholds. Clinical efficacy was assessed by comparing the effect of best dDBS and oDBS on tremor and ataxia rating scales, and accelerometry. Volume of neural activation and TEED were also calculated for both paradigms., Results: For best dDBS, therapeutic window was wider and therapeutic threshold was lower compared to oDBS. While side effect threshold did not differ, volume of neural activation was larger for dDBS. In terms of clinical efficacy, dDBS was as effective as oDBS., Conclusions: dDBS for ET widens therapeutic window due to reduction of therapeutic threshold. Larger volume of neural activation for dDBS at side effect threshold supports the notion of persistent directionality even at higher intensities. dDBS may compensate for slightly misplaced leads and should be considered first line for PSA/VIM-DBS., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC. on behalf of International Neuromodulation Society.)

An increasing number of neuroimaging studies addressing patients with corticobasal syndrome use macroscopic definitions of brain regions. As a closer link to functionally relevant units, we aimed at identifying magnetic resonance-based atrophy patterns in regions defined by probability maps of cortical microstructure. For this purpose, three analyses were conducted: (1) Whole-brain cortical thickness was compared between 36 patients with corticobasal syndrome and 24 controls. A pattern of pericentral atrophy was found, covering primary motor area 4, premotor area 6, and primary somatosensory areas 1, 2, and 3a. Within the central region, only area 3b was without atrophy. (2) In 18 patients, longitudinal measures with follow-ups of up to 59 months (mean 21.3 ± 15.4) were analyzed. Areas 1, 2, and 6 showed significantly faster atrophy rates than primary somatosensory area 3b. (3) In an individual autopsy case, longitudinal in vivo morphometry and postmortem pathohistology were conducted. The rate of magnetic resonance-based atrophy was significantly correlated with tufted-astrocyte load in those cytoarchitectonically defined regions also seen in the group study, with area 3b being selectively unaffected., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Aseptic meningitis epidemics may pose various health care challenges., Methods: We describe the German enterovirus meningitis epidemics in the university hospital centers of Düsseldorf, Cologne and Berlin between January 1st and December 31st, 2013 in order to scrutinize clinical differences from other aseptic meningitis cases., Results: A total of 72 enterovirus (EV-positive) meningitis cases were detected in our multicenter cohort, corresponding to 5.8% of all EV-positive cases which were voluntarily reported within the National Enterovirus surveillance (EVSurv, based on investigation of patients with suspected aseptic meningitis/encephalitis and/or acute flaccid paralysis) by physicians within this period of time. Among these 72 patients, 38 (52.8%) were enterovirus positive and typed as echovirus (18 pediatric and 20 adult cases, median age 18.5 years; echovirus 18 (1), echovirus 2 (1), echovirus 30 (31), echovirus 33 (1), echovirus 9 (4)). At the same time, 45 aseptic meningitis cases in our cohort were excluded to be due to enteroviral infection (EV-negative). Three EV-negative patients were tested positive for varicella zoster virus (VZV) and 1 EV-negative patient for herpes simplex virus 2. Hospitalization was significantly longer in EV-negative cases. Cerebrospinal fluid analysis did not reveal significant differences between the two groups. After discharge, EV-meningitis resulted in significant burden of sick leave in our pediatric cohort as parents had to care for the children at home., Conclusions: Voluntary syndromic surveillance, such as provided by the EVSurv in our study may be a valuable tool for epidemiological research. Our analyses suggest that EV-positive meningitis predominantly affects younger patients and may be associated with a rather benign clinical course, compared to EV-negative cases.

DYT-THAP1 dystonia is known to present a variety of clinical symptoms. To the best of our knowledge, this is the first case with DYT-THAP 1 dystonia and clinical signs of cerebellar involvement studied with transcranial magnetic stimulation in vivo. We report a case of a 51-year-old male DYT-THAP1 mutation carrier with dystonia, who additionally developed ataxia 1.5 years ago. To study cerebellar involvement in our patient, we used a TMS protocol called cerebellar inhibition (CBI). The lack of CBI in our patient strongly suggests cerebellar involvement. According to our findings, cerebellar syndrome may be part of the phenotypical spectrum of DYT-THAP1 mutations.

The emergence of rapidly evolving multidrug-resistant pathogens and a deficit of new compounds entering the clinical pipeline necessitate the exploration of alternative sources of antimicrobial therapeutics. Cyclotides revealed in Viola spp . are a class of highly stable, cyclic, and disulfide-bound peptides with diverse intrinsic bioactivities. Herein we have identified a novel complement of 42 putative cyclotide masses in the plant species Viola inconspicua . Cyclotide-containing fractions of a V. inconspicua peptide library revealed potent bioactivities against the Gram-negative bacteria Escherichia coli ATCC 25922 and the highly virulent and multidrug-resistant Klebsiella pneumoniae VK148. As such, six previously uncharacterized cyclotides, cycloviolacins I1-6 (cyI1-cyI6), were prioritized for molecular characterization. Cyclotides cyI3-cyI6 contain a novel "TLNGNPGA" motif in the highly variable loop six region, expanding the already substantial sequence diversity of this peptide class. Library fractions comprised of cyclotides cyI3-cyI6 exhibited MIC values of 18 and 35 μM against E. coli and K. pneumoniae , respectively, whereas isolated cyI3 killed ∼50% of E. coli at 60 μM and isolated cyI4 demonstrated no killing at concentrations >60 μM against both pathogens. This work expands the repertoire of bioactive cyclotides found in Viola spp . and highlights the potential of these antibacterial cyclic peptides.

Objective: Evaluation of a data-driven, model-based classification approach to discriminate idiopathic Parkinson's disease (PD) patients from healthy controls (HC) based on between-network connectivity in whole-brain resting-state functional MRI (rs-fMRI)., Methods: Whole-brain rs-fMRI (EPI, TR = 2.2 s, TE = 30 ms, flip angle = 90°. resolution = 3.1 × 3.1 × 3.1 mm, acquisition time ≈ 11 min) was assessed in 42 PD patients (medical OFF) and 47 HC matched for age and gender. Between-network connectivity based on full and L2-regularized partial correlation measures were computed for each subject based on canonical functional network architectures of two cohorts at different levels of granularity (Human Connectome Project: 15/25/50/100/200 networks; 1000BRAINS: 15/25/50/70 networks). A Boosted Logistic Regression model was trained on the correlation matrices using a nested cross-validation (CV) with 10 outer and 10 inner folds for an unbiased performance estimate, treating the canonical functional network architecture and the type of correlation as hyperparameters. The number of boosting iterations was fixed at 100. The model with the highest mean accuracy over the inner folds was trained using an non-nested 10-fold 20-repeats CV over the whole dataset to determine feature importance., Results: Over the outer folds the mean accuracy was found to be 76.2% (median 77.8%, SD 18.2, IQR 69.4 - 87.1%). Mean sensitivity was 81% (median 80%, SD 21.1, IQR 75 - 100%) and mean specificity was 72.7% (median 75%, SD 20.4, IQR 66.7 - 80%). The 1000BRAINS 50-network-parcellation, using full correlations, performed best over the inner folds. The top features predominantly included sensorimotor as well as sensory networks., Conclusion: A rs-fMRI whole-brain-connectivity, data-driven, model-based approach to discriminate PD patients from healthy controls shows a very good accuracy and a high sensitivity. Given the high sensitivity of the approach, it may be of use in a screening setting., Advances in Knowledge: Resting-state functional MRI could prove to be a valuable, non-invasive neuroimaging biomarker for neurodegenerative diseases. The current model-based, data-driven approach on whole-brain between-network connectivity to discriminate Parkinson's disease patients from healthy controls shows promising results with a very good accuracy and a very high sensitivity.

Purpose: Both iron deficiency (ID) and female sexual dysfunction (FSD) affect more than 25% of the world population. The aim of this study was to identify a connection between these two conditions based on the existing literature and to investigate this interrelation in a small pilot cross-sectional study., Methods: A database search for publications referring to ID and FSD was conducted. The resulting common denominators were used to formulate hypotheses regarding the interaction of these diseases. Simultaneously, 45 healthy middle-aged women completed questionnaires about their sexual function and provided a blood sample for the purpose of determining ferritin and haemoglobin levels. The main outcome measures included an analysis of responses to questions on sexuality and partnership and of blood ferritin and haemoglobin levels. The secondary outcomes included an assessment of further influences on libido, such as sex hormones, menopausal status, health, and life satisfaction., Results: Altered monoaminergic cerebral metabolism, hyperprolactinaemia and hypothyroidism, impaired socioemotional interaction, increased anxiety, and depression in both, ID and FSD, account for the most comprehensive explanations for the postulated association between the two conditions. Despite a feasible assumption, our empirical findings failed to demonstrate any correlation between ID and FSD. We identified a certain impact of menopausal hormonal status on sexual function., Conclusion: ID has no influence on FSD in the given population, although the literature suggests that FSD may at least be partly due to ID. Further research seems justified given the potential advantages for sexual health, considering that ID is an easily treatable disease.

During the last 30 years, deep brain stimulation (DBS) has evolved into the clinical standard of care as a highly effective treatment for advanced Parkinson's disease. Careful patient selection, an individualized anatomical target localization and meticulous evaluation of stimulation parameters for chronic DBS are crucial requirements to achieve optimal results. Current hardware-related advances allow for a more focused, individualized stimulation and hence may help to achieve optimal clinical results. However, current advances also increase the degrees of freedom for DBS programming and therefore challenge the skills of healthcare providers. This review gives an overview of the clinical effects of DBS, the criteria for patient, target, and device selection, and finally, offers strategies for a structured programming approach., Competing Interests: Conflict of interest statement: CJH received a travel grant from Abbott; SF declares no conflicts of interest; SJG received honoraria and travel expenses from Medtronic, Abbott, and Boston Scientific; LW received honoraria from Medtronic and Abbott/St. Jude Medical; AS received honoraria from Abbott, Boston Scientific, Medtronic and Abbvie.

Functional magnetic resonance imaging studies suggest that different subcortico-cortical circuits control different aspects of Parkinsonian rest tremor. The basal ganglia were proposed to drive tremor onset, and the cerebellum was suggested to be responsible for tremor maintenance ("dimmer-switch" hypothesis). Although several electrophysiological correlates of tremor have been described, it is currently unclear whether any of these is specific to tremor onset or maintenance. In this study, we present data from a single patient measured repeatedly within 2 years after implantation of a deep brain stimulation (DBS) system capable of recording brain activity from the target. Local field potentials (LFPs) from the subthalamic nucleus and the scalp electroencephalogram were recorded 1 week, 3 months, 6 months, 1 year, and 2 years after surgery. Importantly, the patient suffered from severe rest tremor of the lower limbs, which could be interrupted voluntarily by repositioning the feet. This provided the unique opportunity to record many tremor onsets in succession. We found that tremor onset and tremor maintenance were characterized by distinct modulations of subthalamic oscillations. Alpha/low-beta power increased transiently immediately after tremor onset. In contrast, beta power was continuously suppressed during tremor maintenance. Tremor maintenance was additionally associated with subthalamic and cortical power increases around individual tremor frequency. To our knowledge, this is the first evidence of distinct subthalamic LFP modulations in tremor onset and tremor maintenance. Our observations suggest the existence of an acceleration signal for Parkinsonian rest tremor in the basal ganglia, in line with the "dimmer-switch" hypothesis.

Beta oscillations within motor-cortical areas have been linked to sensorimotor function. In line with this, pathologically altered beta activity in cortico-basal ganglia pathways has been suggested to contribute to the pathophysiology of Parkinson's disease (PD), a neurodegenerative disorder primarily characterized by motor impairment. Although its precise function is still discussed, beta activity might subserve an anticipatory role in preparation of future actions. By reanalyzing previously published data, we aimed at investigating the role of pre-stimulus motor-cortical beta power modulation in motor sequence learning and its alteration in PD. 20 PD patients and 20 healthy controls (HC) performed a serial reaction time task (SRTT) in which reaction time gain presumably reflects the ability to anticipate subsequent sequence items. Randomly varying patterns served as control trials. Neuromagnetic activity was recorded using magnetoencephalography (MEG) and data was reanalyzed with respect to task stimuli onset. Assuming that pre-stimulus beta power modulation is functionally related to motor sequence learning, reaction time gain due to training on the SRTT should vary depending on the amount of beta power suppression prior to stimulus onset. We hypothesized to find less pre-stimulus beta power suppression in PD patients as compared to HC associated with reduced motor sequence learning in patients. Behavioral analyses revealed that PD patients exhibited smaller reaction time gain in sequence relative to random control trials than HC indicating reduced learning in PD. This finding was indeed paralleled by reduced pre-stimulus beta power suppression in PD patients. Further strengthening its functional relevance, the amount of pre-stimulus beta power suppression during sequence training significantly predicted subsequent reaction time advantage in sequence relative to random trials in patients. In conclusion, the present data provide first evidence for the contribution of pre-stimulus motor-cortical beta power suppression to motor sequence learning and support the hypothesis that beta oscillations may subserve an anticipatory, predictive function, possibly compromised in PD., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Shorter pulse widths than conventional pulse width settings may lead to reduction of side effects and therefore be a valuable therapeutic option for deep brain stimulation (DBS) in patients with essential tremor (ET)., Objective: To compare the DBS effect of shorter pulse width at 40 μs (DBS-40 μs) to conventional pulse width at 60 μs (DBS-60 μs) on the therapeutic window in ET patients., Methods: For this prospective, randomized, double-blind, crossover study 9 ET patients with chronic DBS of the ventral intermediate nucleus (VIM)/posterior subthalamic area (PSA) were recruited. Therapeutic window was calculated by determining efficacy and side effect thresholds for DBS-40 μs and DBS-60 μs. Tremor Rating Scales and Kinesia tremor analyses were used to compare clinical efficacy between the considered settings and deactivated DBS (DBS-OFF). Volume of neural activation (VNA) was calculated for both efficacy and side effect thresholds at each pulse width., Results: DBS-40 μs showed a significantly larger therapeutic window than DBS-60 μs mainly due to higher side-effect thresholds. Both conditions significantly improved tremor compared to DBS-OFF, while efficacy was comparable between DBS-40 μs and DBS-60 μs. Moreover, VNA at efficacy threshold was smaller and less energy was required for tremor suppression with DBS-40 μs compared to DBS-60 μs., Conclusions: VIM/PSA-DBS with short pulse width represents a promising programming option for DBS in ET as it reduces side effects while maintaining efficient tremor suppression. Furthermore, our data support the notion of pulse width dependent selective modulation of distinct fiber tracts leading to widening of the therapeutic window., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Motor sequence learning plays a pivotal role in various everyday activities. Motor-cortical beta oscillations have been suggested to be involved in this type of learning. In Parkinson's disease (PD), oscillatory activity within cortico-basal-ganglia circuits is altered. Pathologically increased beta oscillations have received particular attention as they may be associated with motor symptoms such as akinesia. In the present magnetoencephalography (MEG) study, we investigated PD patients and healthy controls (HC) during implicit motor sequence learning with the aim to shed light on the relation between changes of cortical brain oscillations and motor learning in PD with a particular focus on beta power. To this end, 20 PD patients (ON medication) and 20 age- and sex-matched HC were trained on a serial reaction time task while neuromagnetic activity was recorded using a 306-channel whole-head MEG system. PD patients showed reduced motor sequence acquisition and were more susceptible to interference by random trials after training on the task as compared to HC. Behavioral differences were paralleled by changes at the neurophysiological level. Diminished sequence acquisition was paralleled by less training-related beta power suppression in motor-cortical areas in PD patients as compared to HC. In addition, PD patients exhibited reduced training-related theta activity in motor-cortical areas paralleling susceptibility to interference. The results support the hypothesis that the acquisition of a new motor sequence relies on suppression of motor-cortical beta oscillations, while motor-cortical theta activity might be related to stabilization of the learned sequence as indicated by reduced susceptibility to interference. Both processes appear to be impaired in PD.

Background: Recently, therapeutic attempts to control motor choreatic hyperkinesia of Huntington's disease (HD) by means of pallidal deep brain stimulation (Gp-DBS) were successful. With respect to the clinical effects of Gp-DBS in juvenile hypokinetic-rigid HD (jHD; Westphal variant), only one single-case has been reported up to date. Oscillatory patterns of the Gp in jHD are not known., Objectives and Methods: This work aimed to analyse pallidal local field potential oscillations (LFP) in two patients with jHD treated with Gp-DBS. Safety data and clinical scores up to 12 months after DBS-electrode implantation were collected in the framework of a prospective trial (ClinicalTrials.gov; NCT00902889)., Results: Intraoperative LFP revealed local alpha and beta oscillations similar to those found in other movement disorders with akinetic rigid and dystonic presentation. Significant motor improvement was not found. There were no treatment-related complications or unresolved long-term adverse events., Conclusions: In spite of similar intraoperative LFP patterns of jHD with those of movement disorders benefitting from DBS, clinical results were not convincing in our patients, so that Gp-DBS in jHD cannot be generally recommended.

Objective: To assess whether high frequency oscillations (HFOs, >150 Hz), known to occur in basal ganglia nuclei, can be observed in the thalamus., Methods: We recorded intraoperative local field potentials from the ventral intermediate nucleus (VIM) of the thalamus in patients with Essential Tremor (N = 16), Parkinsonian Tremor (3), Holmes Tremor (2) and Dystonic Tremor (1) during implantation of electrodes for deep brain stimulation. Recordings were performed with up to five micro/macro-electrodes that were simultaneously advanced to the stereotactic target., Results: Thalamic HFOs occurred in all investigated tremor syndromes. A detailed analysis of the Essential Tremor subgroup revealed that medial channels recorded HFOs more frequently than other channels. The highest peaks were observed 4 mm above target. Macro- but not microelectrode recordings were dominated by peaks in the slow HFO band (150-300 Hz), which were stable across several depths and channels., Conclusion: HFOs occur in the thalamus and are not specific to any of the tremors investigated. Their spatial distribution is not homogeneous, and their appearance depends on the type of electrode used for recording., Significance: The occurrence of HFOs in the thalamus of tremor patients indicates that HFOs are not part of basal ganglia pathophysiology., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the spatial and temporal pattern of cortical responses evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) and ventral intermediate nucleus of the thalamus (VIM)., Methods: We investigated 7 patients suffering from Essential tremor (ET) and 7 patients with Parkinson's Disease (PD) following the implantation of DBS electrodes (VIM for ET patients, STN for PD patients). Magnetoencephalography (MEG) was used to record cortical responses evoked by electric stimuli that were applied via the DBS electrode in trains of 5 Hz. Dipole fitting was applied to reconstruct the origin of evoked responses., Results: Both VIM and STN DBS led to short latency cortical responses at about 1 ms. The pattern of medium and long latency cortical responses following VIM DBS consisted of peaks at 13, 40, 77, and 116 ms. The associated equivalent dipoles were localized within the central sulcus, 3 patients showed an additional response in the cerebellum at 56 ms. STN DBS evoked cortical responses peaking at 4 ms, 11 ms, and 27 ms, respectively. While most dipoles were localized in the pre- or postcentral gyrus, the distribution was less homogenous compared to VIM stimulation and partially included prefrontal brain areas., Conclusion: MEG enables localization of cortical responses evoked by DBS of the VIM and the STN, especially in the sensorimotor cortex. Short latency responses of 1 ms suggest cortical modulation which bypasses synaptic transmission, i.e. antidromic activation of corticofugal fiber pathways., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients suffering from Parkinson's disease (PD) often show impairments in executive function (EF) like decision-making and action control. The right dorsolateral prefrontal cortex (dlPFC) has been strongly implicated in EF in healthy subjects and has repeatedly been reported to show alterations related to EF impairment in PD. Recently, two key regions for cognitive action control have been identified within the right dlPFC by co-activation based parcellation. While the posterior region is engaged in rather basal EF like stimulus integration and working memory, the anterior region has a more abstract, supervisory function. To investigate whether these functionally distinct subdivisions of right dlPFC are differentially affected in PD, we analyzed resting-state functional connectivity (FC) in 39 PD patients and 44 age- and gender-matched healthy controls. Patients were examined both after at least 12 h withdrawal of dopaminergic drugs (OFF) and under their regular dopaminergic medication (ON). We found that only the posterior right dlPFC subdivision shows FC alterations in PD, while the anterior part remains unaffected. PD-related decreased FC with posterior right dlPFC was found in the bilateral medial posterior parietal cortex (mPPC) and left dorsal premotor region (PMd) in the OFF state. In the medical ON, FC with left PMd normalized, while decoupling with bilateral mPPC remained. Furthermore, we observed increased FC between posterior right dlPFC and the bilateral dorsomedial prefrontal cortex (dmPFC) in PD in the ON state. Our findings point to differential disturbances of right dlPFC connectivity in PD, which relate to its hierarchical organization of EF processing by stronger affecting the functionally basal posterior aspect than the hierarchically higher anterior part.

Interacting with other individuals in a social world requires fast and accurate perception of other individuals' identity, actions, or intentions. Humans are very efficient in these social tasks, as they can extract social information even if the actor is represented only by a handful of point-lights on an otherwise invisible body. Theories have argued that efficient visual perception of actions is based on intact motor system functioning. The motor system provides visuo-motor action representations shaped by the observer's own movements or motor repertoire. If the observer's motor repertoire is impaired, this should lead to impaired visuo-motor representations and ultimately to impaired visual perception of movements. Here we tested this hypothesis in a behavioral study with patients suffering from Parkinson's disease (PD). PD patients are typically impaired in movement execution. We tested these patients and a matched control group in a visual discrimination task on human movement perception. The results showed that PD patients were significantly impaired in the perception of human movements. This impairment was most prominent for transitive (object-related) movements. The results indicate that impaired movement execution critically influences movement perception. The results support the hypothesis that the motor system plays a causal role for the visual perception of human movements., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: High frequency oscillations (>200 Hz) have been observed in the basal ganglia of PD patients and were shown to be modulated by the administration of levodopa and voluntary movement., Objective: The objective of this study was to test whether the power of high-frequency oscillations in the STN is associated with spontaneous manifestation of parkinsonian rest tremor., Methods: The electromyogram of both forearms and local field potentials from the STN were recorded in 11 PD patients (10 men, age 58 [9.4] years, disease duration 9.2 [6.3] years). Patients were recorded at rest and while performing repetitive hand movements before and after levodopa intake. High-frequency oscillation power was compared across epochs containing rest tremor, tremor-free rest, or voluntary movement and related to the tremor cycle., Results: We observed prominent slow (200-300 Hz) and fast (300-400 Hz) high-frequency oscillations. The ratio between slow and fast high-frequency oscillation power increased when tremor became manifest. This increase was consistent across nuclei (94%) and occurred in medication ON and OFF. The ratio outperformed other potential markers of tremor, such as power at individual tremor frequency, beta power, or low gamma power. For voluntary movement, we did not observe a significant difference when compared with rest or rest tremor. Finally, rhythmic modulations of high-frequency oscillation power occurred within the tremor cycle., Conclusions: Subthalamic high-frequency oscillation power is closely linked to the occurrence of parkinsonian rest tremor. The balance between slow and fast high-frequency oscillation power combines information on motor and medication state. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Huntington's disease (HD) is one of the most disabling degenerative movement disorders, as it not only affects the motor system but also leads to cognitive disabilities and psychiatric symptoms. Deep brain stimulation (DBS) of the pallidum is a promising symptomatic treatment targeting the core motor symptom: chorea. This article gives an overview of preliminary evidence on pathophysiology, safety and efficacy of DBS in HD., Competing Interests: Related to Huntington’s Disease and/or deep brain stimulation: L.W. received consultant honoraria and travel grants from Medtronic, St. Jude Medical, Inomed and Desitin. S.J.G. received coverage of travel expenses and honoraria from Medtronic and Boston Scientific. C.J.H., S.E. and S.O. declare no conflicts of interest. A.S. and J.V. received consultant honoraria and travel grants from Medtronic. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Trial NCT02535884 is supported by Medtronic. Medtronic had no role in the design of the review, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. Medtronic provided Figure 1 for this manuscript on request of the authors.

Background: Reports about neural oscillatory activity in the globus pallidus internus (GPi) have targeted general (GD) and cervical dystonia (CD), however to our knowledge they are nonexistent for tardive dystonia (TD)., Methods: Local field potentials (LFPs) from seven CD and five TD patients were recorded intraoperatively. We compared LFP power in thetadelta, alpha and beta band during rest and sensory palmar stimulation (SPS) in patients with general anesthesia and local/analgo sedation., Results: We found prominent LFP power activity in thetadelta for both CD and TD. Unlike TD, a significant difference between rest and SPS was revealed for CD., Conclusions: Our data support the presence of LFP oscillatory activity in CD and TD. Thetadelta power modulation in the GPi is suggested as a signature for sensory processing in CD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Huntington's disease (HD) is a hereditary neurodegenerative disorder which is associated with severe disturbances of motor function, especially choreatic movements, cognitive decline and psychiatric symptoms. Various brain stimulation methods have been used to study brain function in patients with HD. Moreover, brain stimulation has evolved as an alternative or additive treatment option, besides current symptomatic medical treatment. This article summarizes the results of brain stimulation to better understand the characteristics of cortical excitability and plasticity in HD and gives a perspective on the therapeutic role for noninvasive and invasive neuromodulatory brain stimulation methods.

Background: Medication resistant obsessive-compulsive disorder (OCD) patients can be successfully treated with Deep Brain Stimulation (DBS) which targets the anterior limb of the internal capsule (ALIC) and the nucleus accumbens (NA). Growing evidence suggests that in patients who respond to DBS, axonal fiber bundles surrounding the electrode are activated, but it is currently unknown which discrete pathways are critical for optimal benefit. Our aim was to identify axonal pathways mediating clinical effects of ALIC-NA DBS., Methods: We created computational models of ALIC-NA DBS to simulate the activation of fiber tracts and to identify connected cerebral regions. The pattern of activated axons and their cortical targets was investigated in six OCD patients who underwent ALIC-NA DBS., Results: Modulation of the right anterior middle frontal gyrus (dorsolateral prefrontal cortex) was associated with an excellent response. In contrast, non-responders showed high activation in the orbital part of the right inferior frontal gyrus (lateral orbitofrontal cortex/anterior ventrolateral prefrontal cortex). Factor analysis followed by step-wise linear regression indicated that YBOCS improvement was inversely associated with factors that were predominantly determined by gray matter activation results., Discussion: Our findings support the hypothesis that optimal therapeutic results are associated with the activation of distinct fiber pathways. This suggests that in DBS for OCD, focused stimulation of specific fiber pathways, which would allow for stimulation with lower amplitudes, may be superior to activation of a wide array of pathways, typically associated with higher stimulation amplitudes.

Background: This study was conducted to better understand the development of clinical efficacy and impedance levels in the long-term course of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD)., Methods: In this retrospective study of twenty PD patients, the motor part of the Unified Parkinson's Disease Rating Scale was periodically assessed i) after withdrawal of medication and inactivated stimulation, ii) after withdrawal of medication with activated stimulation and iii) after challenge with l-Dopa during activated stimulation up to 13 years after surgery., Results: STN-DBS with or without medication significantly improved motor function up to 13 years after surgery. The contribution of axial symptoms increased over time. While the stimulation parameters were kept constant, the therapeutic impedances progressively declined., Conclusion: STN-DBS in PD remains effective in the long-term course of the disease. Constant current stimulation might be preferable over voltage-controlled stimulation, as it would alleviate the impact of impedance changes on the volume of tissue activated., (Copyright © 2015 Elsevier Ltd. All rights reserved.)