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The mechanism and time course of emotional side effects of subthalamic deep brain stimulation in Parkinson's disease are a matter for discussion. We report a 53-month follow-up of a patient with affective lability. Postoperative lesion plus bilateral stimulation strongly influenced mood in the first week in terms of laughing behavior, while voltage changes had only minor long-term impact up to 37 months on negative emotion, possibly caused by the right electrode stimulating the subthalamic nucleus and adjacent fiber tracts involving the internal capsule. Thus we conclude that affective lability can occur with different temporal dynamics of microlesion, and early and chronic stimulation. [ABSTRACT FROM AUTHOR]

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).)

Background: Cognitive decline is a major factor for the deterioration of the quality of life in patients suffering from Parkinson's disease (PD). Recently, it was reported that cognitive training (CT) in PD patients with mild cognitive impairment (PD-MCI) led to an increase of physical activity (PA) accompanied by improved executive function (EF). Moreover, PA has been shown to alter positively brain function and cognitive abilities in PD. Both observations suggest an interaction between CT and PA., Objectives: A previous multicenter (MC) study was slightly significant when considering independent effects of interventions (CT and PA) on EF. Here, we use MC constituent single center data that showed no effect of interventions on EF. Thus, this exploratory study considers pooling data from both interventions to gain insight into a recently reported interaction between CT and PA and provide a proof of principle for the usefulness of resting state EEG as a neurophysiological biomarker of joint intervention's effect on EF and attention in PD-MCI., Methods: Pre- and post-intervention resting state EEG and neuropsychological scores (EF and attention) were obtained from 19 PD-MCI patients (10 (CT) and 9 (PA)). We focused our EEG analysis on frontal cortical areas due to their relevance on cognitive function., Results: We found a significant joint effect of interventions on EF and a trend on attention, as well as trends for the negative correlation between attention and theta power (pre), the positive correlation between EF and alpha power (post) and a significant negative relationship between attention and theta power over time (post-pre)., Conclusions: Our results support the role of theta and alpha power at frontal areas as a biomarker for the therapeutic joint effect of interventions., (© 2023. Deutsche Gesellschaft für Neurologie e.V.)

Introduction: Cognitive impairment in Parkinson's disease (PD), especially in patients with mild cognitive impairment (PD-MCI), coincides with less physical activity. Cognitive trainings (CT) have been found to promote laboratory environment-based movement. Knowledge about their effect in natural home-based environment, reflecting everyday function, is sparse. This explorative study investigated short-term effects of CT on physical activity assessed by home-based accelerometry, and its relation to change of cognitive function over time and non-cognitive outcomes in patients with PD-MCI. Cognitive and non-cognitive correlates of movement parameters at pretest were evaluated as well., Methods: Eighteen patients with PD-MCI of the TrainParC study were analyzed. Those patients received either a 6-week multidomain group CT or physical training (PT). Physical activity and sedentary behavior were assessed with wearable accelerometers worn up to seven days pre- and post-training., Results: Patients in the CT group displayed significantly greater increases in active periods after training than patients assigned to PT. In the CT group, increases in executive functioning were associated with increases in active periods and decreases in active mean bout length after training. At pretest, reduced working memory correlated with longer sedentary mean bout length, and impairment in activities of daily living (ADL) correlated with a higher number of sedentary periods., Conclusion: Study data revealed that CT can increase physical activity in patients with PD-MCI, possibly due to effects on executive functions, which needs further investigation in larger sample sizes. Lower working memory performance and ADL impairment might be associated with a more inactive lifestyle in patients with PD-MCI., Competing Interests: Declarations of competing interest AKF and EK are co-authors of the cognitive intervention series “NEUROvitalis” but receives no corresponding honoraria. JE is an employee of McRoberts. All other co-authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: It is assumed that autoimmune limbic encephalitis (ALE) demonstrates distinct neuropsychological manifestations with differential responses to immunotherapy according to which associated autoantibody (AAB), if any, is identified. Towards investigating whether this is the case, this study aims to summarize respective findings from the primary literature on ALE with AABs binding to cell surface neural antigens and ALE with AABs against intracellular neural antigens., Methods: We chose ALE with AABs against leucine-rich, glioma inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as the most frequent cell surface membrane antigens, and ALE with AABs to Embryonic Lethal, Abnormal Vision, Like 1 (ELAVL) proteins (anti-Hu) and glutamic acid decarboxylase 65 (GAD65) as the most frequent intracellular neural antigens. The PubMed and Scopus databases were searched on March 1st, 2021 for neuropsychological test and -screening data from patients with ALE of these AAB-types. Findings were reviewed according to AAB-type and immunotherapy status and are presented in a review section and are further statistically evaluated and presented in a meta-analysis section in this publication., Results: Of the 1304 initial hits, 32 studies on ALE with AABs against LGI1, CASPR2, and GAD65 reporting cognitive screening data could be included in a review. In ALE with AABs against LGI1, CASPR2 and GAD65, memory deficits are the most frequently reported deficits. However, deficits in attention and executive functions including working memory, fluency, and psychological function have also been reported. This review shows that ALE patients with AABs against both LGI1 and CASPR2 show higher percentages of neuropsychological deficits compared to ALE patients with AABs against GAD65 before and after initiation of immunotherapy. However, the methodologies used in these studies were heterogenous, and longitudinal studies were not comparable. Moreover, 21 studies including ALE patients with AABs against LGI1 and GAD65 were also suitable for meta-analysis. No suitable study on ALE with AABs against ELAVL proteins could be identified. Meta-Analyses could be executed for cognitive screening data and only partially, due to the small number of studies. However, in statistical analysis no consistent effect of AAB or immunotherapy on performance in cognitive screening tests could be found., Conclusion: Currently, there is no definite evidence supporting the notion that different AAB-types of ALE exhibit distinct neuropsychological manifestations and respond differently to immunotherapy. Overall, we could not identify evidence for any effect of immunotherapy on cognition in ALE. More systematic, in-depth and longitudinal neuropsychological assessments of patients with different AAB-types of ALE are required in the future to investigate these aspects., Competing Interests: Competing interests The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: A brief bedside test has recently been introduced by Hoche et al. (Brain, 2018) to screen for the Cerebellar Cognitive Affective Syndrome (CCAS) in patients with cerebellar disease., Objective: This multicenter study tested the ability of the CCAS-Scale to diagnose CCAS in individual patients with common forms of hereditary ataxia., Methods: A German version of the CCAS-Scale was applied in 30 SCA3, 14 SCA6 and 20 FRDA patients, and 64 healthy participants matched for age, sex, and level of education. Based on original cut-off values, the number of failed test items was assessed, and CCAS was considered possible (one failed item), probable (two failed items) or definite (three failed items). In addition a total sum raw score was calculated., Results: On a group level, failed items were significantly higher and total sum scores were significantly lower in SCA3 patients compared to matched controls. SCA6 and FRDA patients performed numerically below controls, but respective group differences failed to reach significance. The ability of the CCAS-Scale to diagnose CCAS in individual patients was limited to severe cases failing three or more items. Milder cases failing one or two items showed a great overlap with the performance of controls exhibiting a substantial number of false-positive test results. The word fluency test items differentiated best between patients and controls., Conclusions: As a group, SCA3 patients performed below the level of SCA6 and FRDA patients, possibly reflecting additional cerebral involvement. Moreover, the application of the CCAS-Scale in its present form results in a high number of false-positive test results, that is identifying controls as patients, reducing its usefulness as a screening tool for CCAS in individual patients., (© 2022. The Author(s).)

Background: Meta-analyses indicate positive effects of cognitive training (CT) in patients with Parkinson's disease (PD), however, most previous studies had small sample sizes and did not evaluate long-term follow-up. Therefore, a multicenter randomized controlled, single-blinded trial (Train-ParC study) was conducted to examine CT effects in PD patients with mild cognitive impairment (PD-MCI). Immediately after CT, an enhancement of executive functions was demonstrated. Here, we present the long-term results 6 and 12 months after CT., Methods: At baseline, 64 PD-MCI patients were randomized to a multidomain CT group (n = 33) or to a low-intensity physical activity training control group (PT) (n = 31). Both interventions included 90 min training sessions twice a week for 6 weeks. 54 patients completed the 6 months (CT: n = 28, PT: n = 26) and 49 patients the 12 months follow-up assessment (CT: n = 25, PT: n = 24). Primary study outcomes were memory and executive functioning composite scores. Mixed repeated measures ANOVAs, post-hoc t tests and multiple regression analyses were conducted., Results: We found a significant time x group interaction effect for the memory composite score (p = 0.006, η 2  = 0.214), but not for the executive composite score (p = 0.967, η 2  = 0.002). Post-hoc t tests revealed significant verbal and nonverbal memory improvements from pre-intervention to 6 months, but not to 12 months follow-up assessment in the CT group. No significant predictors were found for predicting memory improvement after CT., Conclusions: This study provides Class 1 evidence that multidomain CT enhances memory functioning in PD-MCI after 6 months but not after 12 months, whereas executive functioning did not change in the long-term., Clinical Trial Registration: German Clinical Trials Register (ID: DRKS00010186), 21.3.2016 (The study registration is outlined as retrospective due to an administrative delay. The first patient was enrolled three months after the registration process was started. A formal confirmation of this process from the German Clinical Trials Register can be obtained from the authors.)., (© 2021. The Author(s).)

Objective: Patients with temporal lobe epilepsy caused by autoimmune limbic encephalitis (AI-TLE) clinically resemble patients with temporal lobe epilepsy with non-autoimmune etiologies (NAI-TLE) but have a different prognosis and require specific adjusted therapies. The objective of this study was to investigate whether patients with these forms of TLE can be discerned by means of neuropsychological assessment., Methods: Data from 103 patients with TLE (n = 39 with AI-TLE and n = 64 with NAI-TLE, including n = 39 with hippocampal sclerosis [HS] and n = 25 with low-grade epilepsy-associated tumors [LEAT]) and 25 healthy controls who underwent comprehensive neuropsychological assessments were analyzed retrospectively. The neuropsychological characteristics (mean z-scores) were compared between groups using one-way ANOVA, independent-samples t-tests, and discriminant function analysis (DFA)., Results: The groups of patients with TLE showed significantly lower performance in attentional, visuospatial, verbal memory, and nonverbal memory functions compared to the healthy controls. Solely in the domain of executive functions, patients with AI-TLE showed significantly lower performance compared to patients with NAI-TLE regarding cognitive flexibility (p = 0.002) and verbal fluency (p = 0.018). Moreover, the DFA identified cognitive flexibility to be most appropriate to differentiate between patients with AI-TLE and patients with HS. Group membership was correctly predicted through neuropsychological assessment alone in 66.7% of the patients using cross-validation., Significance: We were able to identify specific neuropsychological features in our sample of patients with AI-TLE. While all groups of patients with TLE showed the expected TLE-typical memory impairments, significant differences between patients with AI-TLE and NAI-TLE were present only in the cognitive domain of executive functions. This finding facilitates the choice of suitable psychometric tests in clinical routine and, thus, the clinical differential diagnosis between these entities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Depressive symptoms have a high prevalence in patients with Parkinson's disease (PD) and are associated with cognitive dysfunction. Especially in PD with mild cognitive impairment (MCI), a time-efficient and valid instrument for the assessment of depression primarily focusing on psychological symptoms and disregarding confounding somatic symptoms is needed. We performed an examination of the psychometric properties of the Beck Depression Inventory II (BDI-II) and the Beck Depression Inventory Fast Screen (BDI-FS). Methods: The sample consisted of 64 patients [22 females and 42 males, mean age: 67.27 years ( SD = 7.32)]. Depressive symptoms were measured in a cohort of PD patients with MCI. For the BDI-II and BDI-FS the psychometric concepts of internal consistency, convergent validity and diagnostic agreement were assessed. Results: Patients gave higher ratings on test items addressing somatic symptoms than those addressing non-somatic ones. The correlation between the absolute total scores of the BDI-II and the BDI-FS was significant ( r = 0.91, p < 0.001), which indicated convergent validity. The Cronbach's alpha values indicated adequate internal consistencies for both measures (BDI-II: 0.84; BDI-FS: 0.78). There was a higher than chance level agreement of diagnoses of the two questionnaires, measured by Cohen's kappa (0.58, p < 0.001). The agreements between previous diagnosis of depression and the diagnoses of the BDI-II/BDI-FS were also significantly higher than chance level (BDI-II: 0.34, p = 0.007, BDI-FS: 0.39, p = 0.002). Additional AUC analysis across different cutoffs showed that performance of BDI-FS was better than BDI-II, supporting the observation of an equivalent or better performance of BDI-FS than BDI-II. Importantly, AUC analysis confirmed that a cutoff = 4 for BDI-FS was suitable in the considered sample of patients with PD-MCI. Discussion: In a cohort of PD-MCI, the BDI-FS demonstrates adequate psychometric properties in comparison to the BDI-II and can be used as a screening measure for assessing depression in cognitively impaired PD patients, focusing solely on psychological symptoms. Still, further research is needed to validate this instrument., Competing Interests: AK-F has received a grant from the German Parkinson Society and honoraria from ProLog Wissen GmbH, Cologne, Germany, and pro audito Switzerland, Zürich, Switzerland. NS has received grants from the German Federal Ministry of Education and Research. KW has received grants for the German Research Foundation, the German Federal Ministry of Education and Research, and received speaker honoraria from BIAL, BAYER, Medtronic, Boston Scientific, Novartis, Desitin, and the German Society of Neurology. IL-S has received grants from the Parkinson Fonds Deutschland gGmbH, Janssen Pharmaceutical Companies of Johnson & Johnson, European Commission, H2020-TWINN-2015, and the Michael J. Fox Foundation. EK has received grants from the German Ministry of Education and Research, Parkinson Fonds Deutschland gGmbH, and the German Parkinson Society and honoraria from Oticon GmbH, Hamburg, Germany; Lilly Pharma GmbH, Bad Homburg, Germany; Bernafon AG, Bern, Switzerland; and Desitin GmbH, Hamburg, Germany. LW has received honoraria from Meda, Boehringer, Cephalon Pharma, TEVA, Desitin, AbbVie St. Jude Medical / Abbott, and Medtronic and grants from HHU Düsseldorf, DFG Forschergruppe (FOR 1328), ERANET Neuron/BMBF (TYMON 01EW141), German Parkinson's Disease Association (dPV), Parkinson Fonds Germany, and Hilde Ulrichs Stiftung für Parkinsonforschung. 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 Elben, Dimenshteyn, Trenado, Folkerts, Ophey, Sulzer, Becker, Schmidt, Tödt, Witt, Liepelt-Scarfone, Yilmaz, Kalbe and Wojtecki.)

Background: Meta-analyses have demonstrated cognitive training (CT) benefits in Parkinson's disease (PD) patients. However, the patients' cognitive status has only rarely been based on established criteria. Also, prediction analyses of CT success have only sparsely been conducted., Objective: To determine CT effects in PD patients with mild cognitive impairment (PD-MCI) on cognitive and noncognitive outcomes compared to an active control group (CG) and to analyze CT success predictors., Methods: Sixty-four PD-MCI patients (age: 67.61 ± 7.70; UPDRS-III: 26.58 ± 13.54; MoCA: 24.47 ± 2.78) were randomized to either a CT group or a low-intensity physical activity CG for six weeks (twice weekly, 90 minutes). Outcomes were assessed before and after training. MANOVAs with follow-up ANOVAs and multiple regression analyses were computed., Results: Both interventions were highly feasible (participation, motivation, and evaluation); the overall dropout rate was 4.7%. Time × group interaction effects favoring CT were observed for phonemic fluency as a specific executive test ( p =0.018, η p 2 =0.092) and a statistical trend for overall executive functions ( p =0.095, η p 2 =0.132). A statistical trend for a time × group interaction effect favoring CG was shown for the digit span backward as a working memory test ( p =0.098, η p 2 =0.043). Regression analyses revealed cognitive baseline levels, education, levodopa equivalent daily dose, motor scores, and ApoE status as significant predictors for CT success., Conclusions: CT is a safe and feasible therapy option in PD-MCI, yielding executive functions improvement. Data indicate that vulnerable individuals may show the largest cognitive gains. Longitudinal studies are required to determine whether CT may also attenuate cognitive decline in the long term. This trial is registered with DRKS00010186., Competing Interests: EK has received grants from the German Ministry of Education and Research, Parkinson Fonds Deutschland gGmbH, and the German Parkinson Society and honoraria from Oticon GmbH, Hamburg, Germany; Lilly Pharma GmbH, Bad Homburg, Germany; Bernafon AG, Bern, Switzerland; and Desitin GmbH, Hamburg, Germany. AKF has received a grant from the German Parkinson Society and honoraria from ProLog Wissen GmbH, Cologne, Germany, and pro audito Switzerland, Zürich, Switzerland. AFK and EK are the authors of the cognitive training program NEUROvitalis but received no corresponding honoraria. AO, SE, KD, PS, and CS declare that there are no conflicts of interest. CE has received grants from the German Research Foundation (KFO219, TP 10) and the Medical Faculty of the Philipps University Marburg, Germany, and the German Ministry of Education and Research and honoraria from AbbVie, Wiesbaden, Germany; UCB, Monheim, Germany; Daiichi Sankyo, Munich, Germany; Medtronic, Meerbusch, Germany; Bayer Vital, Leverkusen, Germany; and Bial, Mörfelden-Walldorf, Germany. NS has received grants from the German Federal Ministry of Education and Research. CS received funding from the Coppenrath-Foundation, the Parkinson Fonds Germany and honoraria from AbbVie, Wiesbaden, Germany. DB has received grants from Janssen Pharmaceutica N.V., German Parkinson's Disease Association (dPV), BMWi, BMBF, Parkinson Fonds Germany gGmbH, UCB Pharma GmbH, TEVA Pharma GmbH, EU, Novartis Pharma GmbH, Lundbeck, and Damp foundation. She received honoraria for talks or consultant work from AbbVie, Biogen, BIAL, Lundbeck, and Desitin. KW has received grants for the German Research Foundation and the German Federal Ministry of Education and Research. He received speaker honoraria from BIAL, BAYER, Medtronic, Boston Scientific, Novartis, Desitin, and the German Society of Neurology. LW has received honoraria from Meda, Boehringer, Cephalon Pharma, TEVA, Desitin, AbbVie St. Jude Medical/Abbott, and Medtronic and grants from HHU Düsseldorf, DFG Forschergruppe (FOR 1328), ERANET-Neuron/BMBF (TYMON 01EW141), German Parkinson's Disease Association (dPV), Parkinson Fonds Germany, and Hilde Ulrichs Stiftung für Parkinsonforschung. ILS reports grants from the Parkinson Fonds Deutschland gGmbH, Janssen Pharmaceutical Companies of Johnson & Johnson, European Commission, H2020-TWINN-2015, and the Michael J Fox Foundation., (Copyright © 2020 Elke Kalbe et al.)

Objective: The affection of both the peripheral (PNS) and central nervous system (CNS) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been assumed to play a direct role in the respiratory failure of patients with Corona virus disease 2019 (COVID-19) through affection of medullary cardiorespiratory centers resulting in neurological complications and sequelae. Methods: We used a multimodal electrophysiological approach combined with neuropsychological investigations to study functional alteration of both the PNS and CNS in four patients with severe COVID-19. Results: We found electrophysiological evidence for affection of both the PNS and CNS, and particularly affection of brain stem function. Furthermore, our neuropsychological investigations provide evidence of marked impairment of cognition independent of delirium, and outlasting the duration of acute infection with SARS-CoV-2. Conclusion: This case series provides first direct electrophysiological evidence for functional brain stem involvement in COVID-19 patients without evident morphological changes supporting the notion of the brain stem contributing to respiratory failure and thus promoting severe courses of the disease. Moreover, sustained neuropsychological sequelae in these patients may be of particular psychosocial and possibly also economic relevance for society., (Copyright © 2020 Groiss, Balloff, Elben, Brandenburger, Müttel, Kindgen-Milles, Vollmer, Feldt, Kunstein, Ole Jensen, Hartung, Schnitzler and Albrecht.)

Background: Target localization for deep brain stimulation (DBS) is a challenging step that determines not only the correct placement of stimulation electrodes, but also influences the success of the DBS procedure as reflected in the desired clinical outcome of a patient., Objective: We report on the feasibility of DBS target localization in the subthalamic nucleus (STN) by long-latency somatosensory evoked potentials (LL-SSEPs) (>40 msec) in Parkinson's disease (PD) patients., Methods: Micro-macroelectrode recordings were performed intraoperatively on seven PD patients (eight STN hemispheres) who underwent DBS treatment. LL-SSEPs were elicited by ipsi- and contralateral median nerve stimulation to the wrist., Results: Four distinctive LL-SSEP components were elicited ("LL-complex" consisting of P80, N100, P140, and N200). The P80 appeared as the most visible and reliable intraoperative component. Localization of the "LL-complex" within the target was approved with typical microelectrode firing activity patterns, atlas visualization of recording electrodes, and postoperative CT-based visualization of final DBS electrodes., Conclusions: LL-SSEPs represent a promising approach for DBS target localization in the STN, provided deeper understanding on their anesthesia effect is obtained. This approach is advantageous in that it does not require the patient's participation in an intraoperative setting., (© 2017 International Neuromodulation Society.)

Background: Deep brain stimulation (DBS) surgery for Parkinson's disease (PD) is usually performed as awake surgery allowing sufficient intraoperative testing. Recently, outcomes after asleep surgery have been assumed comparable. However, direct comparisons between awake and asleep surgery are scarce., Objective: To investigate the difference between awake and asleep surgery comparing motor and nonmotor outcome after subthalamic nucleus (STN)-DBS in a large single center PD population., Methods: Ninety-six patients were retrospectively matched pairwise (48 asleep and 48 awake) and compared regarding improvement of Unified PD Rating Scale Motor Score (UPDRS-III), cognitive function, Levodopa-equivalent-daily-dose (LEDD), stimulation amplitudes, side effects, surgery duration, and complication rates. Routine testing took place at three months and one year postoperatively., Results: Chronic DBS effects (UPDRS-III without medication and with stimulation on [OFF/ON]) significantly improved UPDRS-III only after awake surgery at three months and in both groups one year postoperatively. Acute effects (percentage UPDRS-III reduction after activation of stimulation) were also significantly better after awake surgery at three months but not at one year compared to asleep surgery. UPDRS-III subitems "freezing" and "speech" were significantly worse after asleep surgery at three months and one year, respectively. LEDD was significantly lower after awake surgery only one week postoperatively. The other measures did not differ between groups., Conclusions: Overall motor function improved faster in the awake surgery group, but the difference ceased after one year. However, axial subitems were worse in the asleep surgery group suggesting that worsening of axial symptoms was risked improving overall motor function. Awake surgery still seems advantageous for STN-DBS in PD, although asleep surgery may be considered with lower threshold in patients not suitable for awake surgery., (© 2018 International Neuromodulation Society.)

Deep brain stimulation (DBS) is an established therapy to treat motor symptoms in movement disorders such as Parkinson's disease (PD). The mechanisms leading to the high therapeutic effectiveness of DBS are poorly understood so far, but modulation of oscillatory activity is likely to play an important role. Thus, investigating the effect of DBS on cortical oscillatory activity can help clarifying the neurophysiological mechanisms of DBS. Here, we aimed at scrutinizing changes of cortical oscillatory activity by DBS at different frequencies using magnetoencephalography (MEG). MEG data from 17 PD patients were acquired during DBS of the subthalamic nucleus (STN) the day after electrode implantation and before implanting the pulse generator. We stimulated the STN unilaterally at two different stimulation frequencies, 130 Hz and 340 Hz using an external stimulator. Data from six patients had to be discarded due to strong artefacts and two other datasets were excluded since these patients were not able to finalize the paradigm. After DBS artefact removal, power spectral density (PSD) values of MEG were calculated for each individual patient and averaged over the group. DBS at both 130 Hz and 340 Hz led to a widespread suppression of cortical alpha/beta band activity (8-22 Hz) specifically over bilateral sensorimotor cortices. No significant differences were observed between the two stimulation frequencies. Our finding of a widespread suppression of cortical alpha/beta band activity is particularly interesting as PD is associated with pathologically increased levels of beta band activity in the basal ganglia-thalamo-cortical circuit. Therefore, suppression of such oscillatory activity might be an essential effect of DBS for relieving motor symptoms in PD and can be achieved at different stimulation frequencies above 100 Hz., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

Background: Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone., Methods: We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only., Findings: Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363·3 mg/day [SE 41·8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day [40·4]) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0·65 points [SE 0·15]) and did not change with medical therapy alone (-0·02 points [0·15]); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1·26 points [SE 0·35]) and had increased with medical therapy alone (1·12 points [0·35]); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide., Interpretation: In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications., Funding: German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Electrical median nerve somatosensory stimulation leads to a distinct modulation of cortical oscillations. Initial high frequency and gamma augmentation, as well as modulation of beta and alpha oscillations have been reported. We aimed at investigating the involvement of the subthalamic nucleus in somatosensory processing by means of local field potential recordings, since recordings during passive movements and peripheral somatosensory stimulation have suggested a prominent role., Methods: Recordings of subthalamic neuronal activity following median nerve stimulation in 11 Parkinson's disease patients were performed. Time-frequency analysis from 1 to 500 Hz was averaged and analyzed., Results: Several oscillatory components in response to somatosensory stimulation were revealed in the time-frequency analysis: (I) prolonged increase in alpha band power, followed by attenuation; (II) initial suppression of power followed by a subsequent rebound in the beta band; (III) early broad-frequency increase in gamma band power; (IV) and sustained increase of 160 Hz frequency oscillations throughout the trial., Conclusions: These results further corroborate the involvement of the subthalamic nucleus in somatosensory processing., Significance: The present results not only support the notion of somatosensory processing in the subthalamic nucleus. Moreover, an improvement of somatosensory processing during subthalamic deep brain stimulation in Parkinson's disease might be accounted for by enhancement of prevailing high frequency oscillations., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Niemann-Pick type C (NP-C) is a rare, neurodegenerative, lysosomal storage disease. Cortical excitability using different transcranial magnetic stimulation (TMS) protocols together with clinical and neuropsychological testing was longitudinally assessed in a patient with NP-C. Cerebellar inhibition, a measure for the integrity of the cerebello-thalamo-cortical network, was impaired. Short-latency afferent inhibition, a measure for cholinergic transmission, and cognitive functions were also impaired and improved under Miglustat treatment. Short interval intracortical facilitation, a marker for glutamatergic neurotransmission, was absent initially but increased after treatment with Miglustat. Our results provide new insights into pathophysiological mechanisms of NP-C and the response to Miglustat treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We investigated neurophysiological mechanisms of subthalamic nucleus involvement in verbal fluency through a verbal generation task. The subthalamic nucleus is thought to act as a behavioural go/no-go instance by means of oscillatory communication in the theta band with the prefrontal cortex. Because subthalamic alpha-theta frequency stimulation has been shown to exert beneficial effects on verbal fluency in Parkinson's disease, we hypothesized that an alpha-theta oscillatory network involving the subthalamic nucleus underlies verbal generation task performance as a gating instance for speech execution. Postoperative subthalamic local field potential recordings were performed during a verbal generation compared to a control task. Time-frequency analysis revealed a significant alpha-theta power increase and enhanced alpha-theta coherence between the subthalamic nucleus and the frontal surface EEG during the verbal generation task. Beta and gamma oscillations were not significantly modulated by the task. Power increase significantly correlated with verbal generation performance. Our results provide experimental evidence for local alpha-theta oscillatory activity in the subthalamic nucleus and coherence to frontal associative areas as a neurophysiological mechanism underlying a verbal generation task. Thus, verbal fluency improvement during subthalamic alpha-theta stimulation in Parkinson's disease is likely due to an enhancement of alpha-theta oscillatory network activity. Alpha-theta oscillations can be interpreted as the rhythmic gating signature in a speech executing subthalamic-prefrontal network., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

[This corrects the article DOI: 10.1371/journal.pone.0168151.].

Somatosensory evoked potentials (SSEPs) are a viable way to measure processing of somatosensory information. SSEPs have been described at the scalp and the cortical level by electroencephalographic, magnetoencephalographic and intracranial cortical recordings focusing on short-latency (SL; latency<40 ms) and long-latency (LL; latency>40 ms) SSEPs as well as by deep brain stimulation (DBS) electrode studies targeting SL-SSEPs. Unfortunately, LL-SSEPs have not been addressed at the subcortical level aside from the fact that studies targeting the characteristics and generators of SSEPs have been neglected for the last ten years. To cope with these issues, we investigated LL-SSEPs of the subthalamic nucleus (STN) in twelve patients with Parkinson's disease (PD) that underwent deep brain stimulation (DBS) treatment. In a postoperative setting, LL-SSEPs were elicited by median nerve stimulation (MNS) to the patient's wrists. Ipsilateral or contralateral MNS was applied with a 3 s inter-stimulus interval. Here, we report about four distinctive LL-SSEPs ("LL-complex" consisting of P80, N100, P140 and N200 component), which were recorded by using monopolar/bipolar reference and ipsi/contralateral MNS. Phase reversal and/or maximum amplitude provided support for the generation of such LL-SSEPs within the STN, which also underscores a role of this subcortical structure in sensory processing., Competing Interests: LW, JV, SJG, AS have received—unrelated to the current project—honoraria and travel expenses in the past from Inomed, Medtronic and/or St. Jude Medical and/or Boston Scientific, companies that manufacture microelectrode recordings and/or deep brain stimulation hardware. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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: Given the high prevalence of cognitive impairment in Parkinson's disease (PD), cognitive screening is important in clinical practice. The Montreal Cognitive Assessment (MoCA) is a frequently used screening test in PD to detect mild cognitive impairment (PD-MCI) and Parkinson's disease dementia (PD-D). However, the proportion in which the subtests are represented in the MoCA total score does not seem reasonable. We present the development and preliminary evaluation of an empirically based alternative scoring system of the MoCA which aims at increasing the overall diagnostic accuracy., Methods: In study 1, the MoCA was administered to 40 patients with PD without cognitive impairment (PD-N), PD-MCI, or PD-D, as defined by a comprehensive neuropsychological test battery. The new MoCA scoring algorithm was developed by defining Areas under the Curve (AUC) for MoCA subtests in a Receiver Operating Characteristic (ROC) and by weighting the subtests according to their sensitivities and specificities. In study 2, an independent sample of 24 PD patients (PD-N, PD-MCI, or PD-D) was tested with the MoCA. In both studies, diagnostic accuracy of the original and the new scoring procedure was calculated., Results: Diagnostic accuracy increased with the new MoCA scoring algorithm. In study 1, the sensitivity to detect cognitive impairment increased from 62.5% to 92%, while specificity decreased only slightly from 77.7% to 73%; in study 2, sensitivity increased from 68.8% to 81.3%, while specificity stayed stable at 75%., Conclusion: This pilot study demonstrates that the sensitivity of the MoCA can be enhanced substantially by an empirically based weighting procedure and that the proposed scoring algorithm may serve the MoCA's actual purpose as a screening tool in the detection of cognitive dysfunction in PD patients better than the original scoring of the MoCA. Further research with larger sample sizes is necessary to establish efficacy of the alternate scoring system.

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.)

In spite of the success in applying non-invasive electroencephalography (EEG), magneto-encephalography (MEG) and functional magnetic resonance imaging (fMRI) for extracting crucial information about the mechanism of the human brain, such methods remain insufficient to provide information about physiological processes reflecting cognitive and emotional functions at the subcortical level. In this respect, modern invasive clinical approaches in humans, such as deep brain stimulation (DBS), offer a tremendous possibility to record subcortical brain activity, namely local field potentials (LFPs) representing coherent activity of neural assemblies from localized basal ganglia or thalamic regions. Notwithstanding the fact that invasive approaches in humans are applied only after medical indication and thus recorded data correspond to altered brain circuits, valuable insight can be gained regarding the presence of intact brain functions in relation to brain oscillatory activity and the pathophysiology of disorders in response to experimental cognitive paradigms. In this direction, a growing number of DBS studies in patients with Parkinson's disease (PD) target not only motor functions but also higher level processes such as emotions, decision-making, attention, memory and sensory perception. Recent clinical trials also emphasize the role of DBS as an alternative treatment in neuropsychiatric disorders ranging from obsessive compulsive disorder (OCD) to chronic disorders of consciousness (DOC). Consequently, we focus on the use of combined invasive (LFP) and non-invasive (EEG) human brain recordings in assessing the role of cortical-subcortical structures in cognitive and emotional processing trough experimental paradigms (e.g. speech stimuli with emotional connotation or paradigms of cognitive control such as the Flanker task), for patients undergoing DBS treatment.