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Abstract Dystonia is a hyperkinetic movement disorder that has been associated with an imbalance towards the direct pathway between striatum and internal pallidum, but the neuronal underpinnings of this abnormal basal ganglia pathway activity remain unknown. Here, we report invasive recordings from ten dystonia patients via deep brain stimulation electrodes that allow for parallel recordings of several basal ganglia nuclei, namely the striatum, external and internal pallidum, that all displayed activity in the low frequency band (3–12 Hz). In addition to a correlation with low-frequency activity in the internal pallidum (R = 0.88, P = 0.001), we demonstrate that dystonic symptoms correlate specifically with low-frequency coupling between striatum and internal pallidum (R = 0.75, P = 0.009). This points towards a pathophysiological role of the direct striato-pallidal pathway in dystonia that is conveyed via coupling in the enhanced low-frequency band. Our study provides a mechanistic insight into the pathophysiology of dystonia by revealing a link between symptom severity and frequency-specific coupling of distinct basal ganglia pathways.

Abstract Dystonia is a neurological movement disorder characterised by abnormal involuntary movements and postures, particularly affecting the head and neck. However, current clinical assessment methods for dystonia rely on simplified rating scales which lack the ability to capture the intricate spatiotemporal features of dystonic phenomena, hindering clinical management and limiting understanding of the underlying neurobiology. To address this, we developed a visual perceptive deep learning framework that utilizes standard clinical videos to comprehensively evaluate and quantify disease states and the impact of therapeutic interventions, specifically deep brain stimulation. This framework overcomes the limitations of traditional rating scales and offers an efficient and accurate method that is rater-independent for evaluating and monitoring dystonia patients. To evaluate the framework, we leveraged semi-standardized clinical video data collected in three retrospective, longitudinal cohort studies across seven academic centres. We extracted static head angle excursions for clinical validation and derived kinematic variables reflecting naturalistic head dynamics to predict dystonia severity, subtype, and neuromodulation effects. The framework was also applied to a fully independent cohort of generalised dystonia patients for comparison between dystonia sub-types. Computer vision-derived measurements of head angle excursions showed a strong correlation with clinically assigned scores. Across comparisons, we identified consistent kinematic features from full video assessments encoding information critical to disease severity, subtype, and effects of neural circuit interventions, independent of static head angle deviations used in scoring. Our visual perceptive machine learning framework reveals kinematic pathosignatures of dystonia, potentially augmenting clinical management, facilitating scientific translation, and informing personalized precision neurology approaches.

Abstract Crowdsourcing has been used in computational pathology to generate cell and cell nuclei annotations for machine learning. Herein, we broaden its scope to the previously unsolved challenging task of glioma cell detection. This requires multiplexed immunofluorescence microscopy due to diffuse invasiveness and exceptional similarity between glioma cells and reactive astrocytes. In four pilot experiments, we iteratively developed a task design enabling high-quality annotations by crowdworkers on Amazon Mechanical Turk. We applied majority or weighted vote and validated them against ground truth in the final setting. On the base of a YOLO convolutional neural network architecture, we used these consensus labels for training with different image representations regarding colors, intensities, and immmunohistochemical marker combinations. A crowd of 712 workers defined aggregated point annotations in 235 images with an average $$F_1$$ F 1 score of 0.627 for majority vote. The networks resulted in acceptable $$F_1$$ F 1 scores up to 0.69 for YOLOv8 on average and indicated first evidence for transferability to images lacking tumor markers, especially in IDH-wildtype glioblastoma. Our work confirms feasibility of crowdsourcing to generate labels suitable for training of machine learning tools in the challenging and clinically relevant use case of glioma microenvironment.

Abstract Pathogenic germline variants in the DNA polymerase genes POLE and POLD1 cause polymerase proofreading-associated polyposis, a dominantly inherited disorder with increased risk of colorectal carcinomas and other tumors. POLE/POLD1 variants may result in high somatic mutation and neoantigen loads that confer susceptibility to immune checkpoint inhibitors (ICIs). To explore the role of POLE/POLD1 germline variants in glioma predisposition, whole-exome sequencing was applied to leukocyte DNA of glioma patients from 61 tumor families with at least one glioma case each. Rare heterozygous POLE/POLD1 missense variants predicted to be deleterious were identified in glioma patients from 10 (16%) families, co-segregating with the tumor phenotype in families with available DNA from several tumor patients. Glioblastoma patients carrying rare POLE variants had a mean overall survival of 21 months. Additionally, germline variants in POLD1, located at 19q13.33, were detected in 2/34 (6%) patients with 1p/19q-codeleted oligodendrogliomas, while POLE variants were identified in 2/4 (50%) glioblastoma patients with a spinal metastasis. In 13/15 (87%) gliomas from patients carrying POLE/POLD1 variants, features of defective polymerase proofreading, e.g. hypermutation, POLE/POLD1-associated mutational signatures, multinucleated cells, and increased intratumoral T cell response, were observed. In a CRISPR/Cas9-derived POLE-deficient LN-229 glioblastoma cell clone, a mutator phenotype and delayed S phase progression were detected compared to wildtype POLE cells. Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy.

Background: In children, hearing loss has been associated with hyperactivity, disturbed social interaction, and risk of cognitive disturbances. Mechanistic explanations of these relations sometimes involve language. To investigate the effect of hearing loss on behavioral deficits in the absence of language, we tested the impact of hearing loss in juvenile rats on motor, social, and cognitive behavior and on physiology of prefrontal cortex. Methods: Hearing loss was induced in juvenile (postnatal day 14) male Sprague-Dawley rats by intracochlear injection of neomycin under general anesthesia. Sham-operated and non-operated hearing rats served as controls. One week after surgery auditory brainstem response (ABR) measurements verified hearing loss or intact hearing in sham-operated and non-operated controls. All rats were then tested for locomotor activity (open field), coordination (Rotarod), and for social interaction during development in weeks 1, 2, 4, 8, 16, and 24 after surgery. From week 8 on, rats were trained and tested for spatial learning and memory (4-arm baited 8-arm radial maze test). In a final setting, neuronal activity was recorded in the medial prefrontal cortex (mPFC). Results: In the open field deafened rats moved faster and covered more distance than sham-operated and non-operated controls from week 8 on (both p 0.05), but rats used less next-arm entries than other groups indicating impaired concept learning (p

Abstract Pathologically increased beta power has been described as a biomarker for Parkinson’s disease (PD) and related to prolonged bursts of subthalamic beta synchronization. Here, we investigate the association between subthalamic beta dynamics and motor impairment in a cohort of 106 Parkinson’s patients in the ON- and OFF-medication state, using two different methods of beta burst determination. We report a frequency-specific correlation of low beta power and burst duration with motor impairment OFF dopaminergic medication. Furthermore, reduction of power and burst duration correlated significantly with symptom alleviation through dopaminergic medication. Importantly, qualitatively similar results were yielded with two different methods of beta burst definition. Our findings validate the robustness of previous results on pathological changes in subcortical oscillations both in the frequency- as well as in the time-domain in the largest cohort of PD patients to date with important implications for next-generation adaptive deep brain stimulation control algorithms.

Abstract Background A reliable assessment of the functional abilities of patients after severe brain damage is crucial for valid prognostication and treatment decisions, but most clinical scales are of limited use among this specific group of patients. Aim The present study investigates the usefulness of the Early Functional Ability (EFA) scale, which determines the functional abilities of severely impaired patients. Methods Critically ill patients consecutively admitted to early neurological rehabilitation were screened for eligibility. We assessed the correlation between the EFA scale and (i) the Early Rehabilitation Barthel Index (ERBI), and (ii) the Coma Recovery Scale-Revised (CRS-R). The 1-year outcome on the Glasgow Outcome Scale-extended (GOSE) was used to examine the predictive validity. Demographical and medical variables were entered into univariate and multivariate binary regression models to identify independent predictors of 1-year outcome. Results Two hundred fifty-seven patients (168 men) with a median age of 62 years (IQR = 51–75) were enrolled. The correlation of the EFA scale with the CRS-R was high but low with the ERBI upon admission. Multivariate regression analysis yielded the vegetative subscale of the EFA scale as the only independent predictor for the 1-year outcome of patients admitted to early neurological rehabilitation. Conclusions This study shows a high correlation of the EFA scale with the CRS-R but a weak correlation with the ERBI in patients with low functional abilities. With improving patient abilities, these correlations were partly reversed. Thus, the EFA scale is a useful tool to assess the functional abilities and the prognosis of critically ill patients adequately and may be more feasible than other scales.

Abstract Adaptive deep brain stimulation (aDBS) is a promising concept for feedback-based neurostimulation, with the potential of clinical implementation with the sensing-enabled Percept neurostimulator. We aim to characterize chronic electrophysiological activity during stimulation and to validate beta-band activity as a biomarker for bradykinesia. Subthalamic activity was recorded during stepwise stimulation amplitude increase OFF medication in 10 Parkinson’s patients during rest and finger tapping. Offline analysis of wavelet-transformed beta-band activity and assessment of inter-variable relationships in linear mixed effects models were implemented. There was a stepwise suppression of low-beta activity with increasing stimulation intensity (p = 0.002). Low-beta power was negatively correlated with movement speed and predictive for velocity improvements (p

Abstract Gait issues in Parkinson’s disease (PD) are common and can be highly disabling. Although levodopa and deep brain stimulation (DBS) of the subthalamic nucleus and the globus pallidus internus have been established therapies for addressing the motor symptoms of PD, their effects on gait are less predictable and not well sustained with disease progression. Given the high prevalence of gait impairment in PD and the limitations in currently approved therapies, there has been considerable interest in alternative neuromodulation targets and techniques. These have included DBS of pedunculopontine nucleus and substantia nigra pars reticulata, spinal cord stimulation, non-invasive modulation of cortical regions and, more recently, vagus nerve stimulation. However, successes and failures have also emerged with these approaches. Current gaps and controversies are related to patient selection, optimal electrode placement within the target, placebo effects and the optimal programming parameters. Additionally, recent advances in pathophysiology of oscillation dynamics have driven new models of closed-loop DBS systems that may or may not be applicable to gait issues. Our aim is to describe approaches, especially neuromodulation procedures, and emerging challenges to address PD gait issues beyond subthalamic nucleus and the globus pallidus internus stimulation.

Abstract Background The present study intended to analyze the outcome of patients with severe brain injury one-year after discharge from early rehabilitation. Methods Early neurological rehabilitation patients admitted to intensive or intermediate care units and discharged between June 2018 and May 2020 were screened for eligibility. The level of consciousness was evaluated using the Coma Recovery Scale-Revised (CRS-R) upon admission and at discharge. At one-year follow-up, the outcome was assessed with the Glasgow Outcome Scale-extended (GOSE). Demographical and clinical data collected during inpatient rehabilitation were used to predict the outcome 1 year after discharge. Results Two hundred sixty-four patients (174 males, 90 females) with a median age of 62 years (IQR = 51–75) and a median duration of their disease of 18 days (IQR = 12–28) were included in the study. At follow-up, the mortality rate was 27% (n = 71). Age and discharge CRS-R total score were independent predictors in a Cox proportional hazards model with death (yes/no) as the dependent variable. According to the GOSE interviews, most patients were either dead (n = 71; 27%), in a vegetative state (n = 28; 11%) or had a severe disability (n = 124; 47%), whereas only a few patients showed a moderate disability (n = 18; 7%) or a good recovery (n = 23; 9%) 1 year after discharge. Age, non-traumatic etiology, discharge CRS-R total score and length of stay independently predicted whether the outcome was good or poor at follow-up. Conclusion Age was an important predictor for outcome at one-year follow-up, which might be due to altered brain plasticity and more comorbidities in elderly subjects. In addition, the present study demonstrated that the CRS-R total score at discharge might be more important for the prediction of one-year outcome than the initial assessment upon admission.

Introduction: Deep brain stimulation (DBS) is an established treatment in patients of various ages with pharmaco-resistant neurological disorders. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures, and on electrode connectivity to a specific distribution pattern within brain networks. Such information is usually collected using group-level analysis, which relies on the availability of normative imaging resources (atlases and connectomes). Analysis of DBS data in children with debilitating neurological disorders such as dystonia would benefit from such resources, especially given the developmental differences in neuroimaging data between adults and children. We assembled pediatric normative neuroimaging resources from open-access datasets in order to comply with age-related anatomical and functional differences in pediatric DBS populations. We illustrated their utility in a cohort of children with dystonia treated with pallidal DBS. We aimed to derive a local pallidal sweetspot and explore a connectivity fingerprint associated with pallidal stimulation to exemplify the utility of the assembled imaging resources. Methods: An average pediatric brain template (the MNI brain template 4.5–18.5 years) was implemented and used to localize the DBS electrodes in 20 patients from the GEPESTIM registry cohort. A pediatric subcortical atlas, analogous to the DISTAL atlas known in DBS research, was also employed to highlight the anatomical structures of interest. A local pallidal sweetspot was modeled, and its degree of overlap with stimulation volumes was calculated as a correlate of individual clinical outcomes. Additionally, a pediatric functional connectome of 100 neurotypical subjects from the Consortium for Reliability and Reproducibility was built to allow network-based analyses and decipher a connectivity fingerprint responsible for the clinical improvements in our cohort. Results: We successfully implemented a pediatric neuroimaging dataset that will be made available for public use as a tool for DBS analyses. Overlap of stimulation volumes with the identified DBS-sweetspot model correlated significantly with improvement on a local spatial level (R = 0.46, permuted p = 0.019). The functional connectivity fingerprint of DBS outcomes was determined to be a network correlate of therapeutic pallidal stimulation in children with dystonia (R = 0.30, permuted p = 0.003). Conclusions: Local sweetspot and distributed network models provide neuroanatomical substrates for DBS-associated clinical outcomes in dystonia using pediatric neuroimaging surrogate data. Implementation of this pediatric neuroimaging dataset might help to improve the practice and pave the road towards a personalized DBS-neuroimaging analyses in pediatric patients.

ObjectivesTardive dystonia/dyskinesia (TDD) occurs as a side effect of anti-dopaminergic drugs, including metoclopramide, and is often refractory to medication. While pallidal deep brain stimulation (DBS) has become an accepted treatment for TDD secondary to neuroleptic medication, there is much less knowledge about its effects on metoclopramide-induced TDD.MethodsWe present the case of a woman with metoclopramide-induced TDD, whose symptoms were initially misjudged as “functional.” After 8 years of ineffective medical treatments, she received bilateral implantation of quadripolar electrodes into the posteroventral lateral globus pallidus internus (GPi).ResultsGPi DBS led to significant symptom reduction [Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) motor score 24/44 at admission and 7/44 at discharge]. Chronic stimulation led to full recovery from TDD symptoms 9 years after surgery. The BFMDRS motor score decreased to 0.5 (98% improvement).DiscussionPallidal DBS may result in sustained improvement of TDD secondary to chronic metoclopramide intake in the long term.

Background: Brain sensing devices are approved today for Parkinson's, essential tremor, and epilepsy therapies. Clinical decisions for implants are often influenced by the premise that patients will benefit from using sensing technology. However, artifacts, such as ECG contamination, can render such treatments unreliable. Therefore, clinicians need to understand how surgical decisions may affect artifact probability. Objectives: Investigate neural signal contamination with ECG activity in sensing enabled neurostimulation systems, and in particular clinical choices such as implant location that impact signal fidelity. Methods: Electric field modeling and empirical signals from 85 patients were used to investigate the relationship between implant location and ECG contamination. Results: The impact on neural recordings depends on the difference between ECG signal and noise floor of the electrophysiological recording. Empirically, we demonstrate that severe ECG contamination was more than 3.2x higher in left-sided subclavicular implants (48.3%), when compared to right-sided implants (15.3%). Cranial implants did not show ECG contamination. Conclusions: Given the relative frequency of corrupted neural signals, we conclude that implant location will impact the ability of brain sensing devices to be used for “closed-loop” algorithms. Clinical adjustments such as implant location can significantly affect signal integrity and need consideration.

BackgroundHearing loss was proposed as a factor affecting development of cognitive impairment in elderly. Deficits cannot be explained primarily by dysfunctional neuronal networks within the central auditory system. We here tested the impact of hearing loss in adult rats on motor, social, and cognitive function. Furthermore, potential changes in the neuronal activity in the medial prefrontal cortex (mPFC) and the inferior colliculus (IC) were evaluated.Materials and methodsIn adult male Sprague Dawley rats hearing loss was induced under general anesthesia with intracochlear injection of neomycin. Sham-operated and naive rats served as controls. Postsurgical acoustically evoked auditory brainstem response (ABR)-measurements verified hearing loss after intracochlear neomycin-injection, respectively, intact hearing in sham-operated and naive controls. In intervals of 8 weeks and up to 12 months after surgery rats were tested for locomotor activity (open field) and coordination (Rotarod), for social interaction and preference, and for learning and memory (4-arms baited 8-arms radial maze test). In a final setting, electrophysiological recordings were performed in the mPFC and the IC.ResultsLocomotor activity did not differ between deaf and control rats, whereas motor coordination on the Rotarod was disturbed in deaf rats (P < 0.05). Learning the concept of the radial maze test was initially disturbed in deaf rats (P < 0.05), whereas retesting every 8 weeks did not show long-term memory deficits. Social interaction and preference was also not affected by hearing loss. Final electrophysiological recordings in anesthetized rats revealed reduced firing rates, enhanced irregular firing, and reduced oscillatory theta band activity (4–8 Hz) in the mPFC of deaf rats as compared to controls (P < 0.05). In the IC, reduced oscillatory theta (4–8 Hz) and gamma (30–100 Hz) band activity was found in deaf rats (P < 0.05).ConclusionMinor and transient behavioral deficits do not confirm direct impact of long-term hearing loss on cognitive function in rats. However, the altered neuronal activities in the mPFC and IC after hearing loss indicate effects on neuronal networks in and outside the central auditory system with potential consequences on cognitive function.

Abstract Background The aim of the study was to determine the role of the Coma Recovery Scale-Revised (CRS-R) in the prediction of functional status at the end of neurological early rehabilitative treatment. Methods Patients consecutively admitted to intensive or intermediate care units of a neurological rehabilitation center were enrolled in the study. Consciousness and functional status were assessed with the Coma Recovery Scale-Revised (CRS-R) and the Early Rehabilitation Barthel Index (ERBI), respectively. Both assessments were carried out weekly within the first month and at the end of early rehabilitation. Patient and clinical data were entered into a binary logistic regression model to predict functional status at discharge. Results 327 patients (112 females, 215 males) with a median age of 63 years (IQR = 53–75) and a median disease duration of 18 days (IQR = 12–28) were included. Most patients suffered from stroke (59 %), followed by traumatic brain injury (31 %), and hypoxic ischemic encephalopathy (10 %). Upon admission, 12 % were diagnosed as comatose, 31 % as unresponsive wakefulness syndrome (UWS), 35 % as minimally conscious state (MCS) and 22 % already emerged from MCS (eMCS). Of all patients undergoing complete early rehabilitative treatment (n = 180), 72 % showed improvements in level of consciousness (LOC). In this group, age, initial CRS-R score and gains in CRS-R score after four weeks independently predicted functional outcome at discharge. Conclusions The study confirms the relevance of the CRS-R score for functional outcome prediction. High CRS-R scores and young age facilitate functional improvements and increase the probability to continue treatment in subsequent rehabilitation phases. Moreover, results indicate that recovery might occur over a period of time that extends beyond acute care.

Improved care for people with dystonia presents a number of challenges. Major gaps in knowledge exist with regard to how to optimize the diagnostic process, how to leverage discoveries in pathophysiology into biomarkers, and how to develop an evidence base for current and novel treatments. These challenges are made greater by the realization of the wide spectrum of symptoms and difficulties faced by people with dystonia, which go well-beyond motor symptoms. A network of clinicians, scientists, and patients could provide resources to facilitate information exchange at different levels, share mutual experiences, and support each other's innovative projects. In the past, collaborative initiatives have been launched, including the American Dystonia Coalition, the European Cooperation in Science and Technology (COST—which however only existed for a limited time), and the Dutch DystonieNet project. The European Reference Network on Rare Neurological Diseases includes dystonia among other rare conditions affecting the central nervous system in a dedicated stream. Currently, we aim to broaden the scope of these initiatives to a comprehensive European level by further expanding the DystoniaNet network, in close collaboration with the ERN-RND. In line with the ERN-RND, the mission of DystoniaNet Europe is to improve care and quality of life for people with dystonia by, among other endeavors, facilitating access to specialized care, overcoming the disparity in education of medical professionals, and serving as a solid platform to foster international clinical and research collaborations. In this review, both professionals within the dystonia field and patients and caregivers representing Dystonia Europe highlight important unsolved issues and promising new strategies and the role that a European network can play in activating them.

Abstract Background Rising evidence indicate that oxytocin and IL-1β impact trigemino-nociceptive signaling. Current perspectives on migraine physiopathology emphasize a cytokine bias towards a pro-inflammatory status. The anti-nociceptive impact of oxytocin has been reported in preclinical and human trials. Cervical non-invasive vagus nerve stimulation (nVNS) emerges as an add-on treatment for the preventive and abortive use in migraine. Less is known about its potential to modulate saliva inflammatory signaling in migraine patients. The rationale was to perform inter-ictal saliva measures of oxytocin and IL-1ß along with headache assessment in migraine patients with 10 weeks adjunctive nVNS compared to healthy controls. Methods 12 migraineurs and 12 suitably matched healthy control were studied with inter-ictal saliva assay of pro- and anti-neuroinflammatory cytokines using enzyme-linked immuno assay techniques along with assessment of headache severity/frequency and associated functional capacity at baseline and after 10 weeks adjunctive cervical nVNS. Results nVNS significantly reduced headache severity (VAS), frequency (headache days and total number of attacks) and significantly improved sleep quality compared to baseline (p

Passive listening to music is associated with several psychological and physical benefits in both, healthy and diseased populations. In this fMRI study, we examined whether preferred music has effects on the functional connectivity within resting-state networks related to consciousness. Thirteen patients in unresponsive wakefulness syndrome (UWS) and 18 healthy controls (HC) were enrolled. Both groups were exposed to different auditory stimulation (scanner noise, preferred music, and aversive auditory stimulation). Functional connectivity was analyzed using a seed-based approach. In HC, no differences were found between the three conditions, indicating that their networks are already working at high level. UWS patients showed impaired functional connectivity within all resting-state networks. In addition, functional connectivity of the auditory network was modulated by preferred music and aversive auditory stimulation. Hence, both conditions have the potential to modulate brain activity of UWS patients.

Studies with non-human primates have suggested an excitatory influence of the thalamus on the cerebral cortex, with the centromedian-parafascicular complex (CM-Pf) being particularly involved in processes of sensory event-driven attention and arousal. To define the involvement of the human CM-Pf in bottom-up and top-down auditory attention, we simultaneously recorded cortical EEG activity and intracranial local field potentials (LFPs) via electrodes implanted for deep brain stimulation for the treatment of neuropathic pain. The patients (N ​= ​6) performed an auditory three-class oddball paradigm with frequent standard stimuli and two types of infrequent deviant stimuli (target and distractor). We found a parietal P3b to targets and a central P3a to distractors at the scalp level. Subcortical recordings in the CM-Pf revealed enhanced activation to targets compared to standards. Interarea-correlation analyses showed that activation in the CM-Pf predicted the generation of longer latency P3b scalp potentials specifically in the target condition. Our results provide first direct human evidence for a functional temporal relationship between target-related activation in the CM-Pf and an enhanced cortical target response. These results corroborate the hypothetical model of a cortico-basal ganglia loop system that switches from top-down to bottom-up mode in response to salient, task-relevant external events that are not predictable.

Abstract Background Cerebrospinal fluid (CSF) circulation disturbances may occur during the course of disease in patients with glioblastoma. Ventriculoperitoneal shunting has generally been recommended to improve symptoms in glioblastoma patients. Shunt implantation for patients with glioblastoma, however, presents as a complex situation and produces different problems to shunting in other contexts. Information on complications of shunting glioma patients has rarely been the subject of investigation. In this retrospective study, we analysed restropectively the course and outcome of glioblastoma-related CSF circulation disturbances after shunt management in a consecutive series of patients within a period of over a decade. Methods Thirty of 723 patients with histopathologically-confirmed glioblastoma diagnosed from 2002 to 2016 at the Department of Neurosurgery, Hannover Medical School, underwent shunting for CSF circulation disorders. Treatment history of glioblastoma and all procedures associated with shunt implementation were analyzed. Data on follow-up, time to progression and survival rates were obtained by review of hospital charts and supplemented by phone interviews with the patients, their relations or the primary physicians. Results Mean age at the time of diagnosis of glioblastoma was 43 years. Five types of CSF circulation disturbances were identified: obstructive hydrocephalus (n = 9), communicating hydrocephalus (n = 15), external hydrocephalus (n = 3), trapped lateral ventricle (n = 1), and expanding fluid collection in the resection cavity (n = 2). All patients showed clinical deterioration. Procedures for CSF diversion were ventriculoperitoneal shunt (n = 21), subduroperitoneal shunt (n = 3), and cystoperitoneal shunt (n = 2). In patients with lower Karnofsky Performance Score (KPS) (

Background: DYT6 dystonia can have an unpredictable clinical course and the result of deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi) is known to be less robust than in other forms of autosomal dominant dystonia. Patients who had previous stereotactic surgery with insufficient clinical benefit form a particular challenge with very limited other treatment options available. Case Report: A pediatric DYT6 patient unexpectedly deteriorated to status dystonicus 1 year after GPi DBS implantation with good initial clinical response. After repositioning the DBS electrodes the status dystonicus resolved. Discussion: This case study demonstrates that medication-resistant status dystonicus in DYT6 dystonia can be reversed by relocation of pallidal electrodes. This case highlights that repositioning of DBS electrodes may be considered in patients with status dystonicus, especially when the electrode position is not optimal, even after an initial clinical response to DBS.

Background: Detection of defective deep brain stimulation (DBS) contacts/electrodes is sometimes challenging. Case Report: We report a patient with Tourette syndrome (TS), who presented with abrupt tic increase and mild generalized headache 9 years after DBS implantation. On the suspicion of a hardware defect, a fracture of the DBS electrode and extension lead was ruled out by radiography and standard implantable pulse generator readouts. Further investigation revealed position-dependent modifiable therapeutic impedances, suggesting an impaired contact of the extension lead/adaptor. After replacement normal impedances were recorded, and the patient fully recovered. Discussion: In DBS dysfunction with inconspicuous hardware check, position-dependent defects might be suspected.

Introduction: The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Methods: Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian–parafascicular (CM–Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores (maximum, minimum, average pain, pain at presentation, allodynia). Results: The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM–Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3–180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM–Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain (except thalamic pain), or brachial plexus injury, while patients with thalamic lesions had the least benefit. Conclusion: Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain.

IntroductionThe neurobiological mechanisms underlying the clinical effects of psychotherapy are scarcely understood. In particular, the modifying effects of psychotherapy on neuronal activity are largely unknown. We here present data from an innovative experimental paradigm using the example of a patient with treatment resistant obsessive-compulsive disorder (trOCD) who underwent implantation of bilateral electrodes for deep brain stimulation (DBS). The aim of the paradigm was to examine the short term effect of metacognitive therapy (MCT) on neuronal local field potentials (LFP) before and after 5 MCT sessions.MethodsDBS electrodes were implanted bilaterally with stereotactic guidance in the bed nucleus of the stria terminalis/ internal capsule (BNST/IC). The period between implantation of the electrodes and the pacemaker was used for the experimental paradigm. DBS electrodes were externalized via extension cables, yielding the opportunity to record LFP directly from the BNST/IC. The experimental paradigm was designed as follows: (a) baseline recording of LFP from the BNST/IC, (b) application of 5 MCT sessions over 3 days, (c) post-MCT recording from the BNST/IC. The Obsessive-Compulsive Disorder- scale (OCD-S) was used to evaluate OCD symptoms.ResultsOCD symptoms decreased after MCT. These reductions were accompanied by a decrease of the relative power of theta band activity, while alpha, beta, and gamma band activity was significantly increased after MCT. Further, analysis of BNST/IC LFP and frontal cortex EEG coherence showed that MCT decreased theta frequency band synchronization.DiscussionImplantation of DBS electrodes for treating psychiatric disorders offers the opportunity to gather data from neuronal circuits, and to compare effects of therapeutic interventions. Here, we demonstrate direct effects of MCT on neuronal oscillatory behavior, which may give possible cues for the neurobiological changes associated with psychotherapy.

Patients with dystonia experience unusual postures and disfigurement. The aim of the study was to examine changes in the body concept in relation to quality of life and severity of dystonia. Our cohort consisted of 20 patients with idiopathic dystonia resistant to medical therapy who were planned for pallidal deep brain stimulation. The results were compared to 25 healthy controls. The patients were assessed with Frankfurt Body Concept Scale, Short Form 36 (SF-36) Health Survey, Hamilton Depression Scale, Beck Depression Inventory, Social Phobia Inventory and Social Interaction Anxiety Scale. The disease severity was evaluated with Burke–Fahn–Marsden Dystonia Rating Scale and Toronto Western Spasmodic Torticollis Rating Scale. Patients with dystonia had a significantly impaired body concept in eight out of nine subscales in comparison to healthy controls. The differences were most pronounced for the subscales general health, body care, physical efficacy, sexuality and physical appearance (p < 0.001). Furthermore, all eight subscales of SF-36 exhibited significantly lower values in patients with dystonia compared to controls. We also found significant positive correlations between SF-36 and body concept subscales. Impairment of body concept was not associated with disease severity or levels of social anxiety symptoms. However, there was a significant association between self-rated depression and disease severity. Our patients suffered from increased depression and social anxiety symptoms except social interaction anxiety. We conclude that patients with dystonia have significant body concept impairment that interferes with quality of life in both physical and emotional domains. Future studies should focus on assessing these symptoms after adequate therapeutic management of motor symptoms.

Background: The dentatothalamic tract connects the dentate nucleus of the cerebellum with the contralateral thalamus and plays a major role in the pathogenesis of tremor. Unilateral lesions of the dentatothalamic pathway may affect its ipsilateral predecussational or its contralateral postdecussational course, which results either in ipsilateral or in contralateral tremor.Case Report: Here, we present two patients with a unilateral midbrain lesion resulting in bilateral tremor. Both patients presented with severe kinetic tremor.Discussion: The corresponding unilateral mesencephalic lesion affected both the ipsilateral predecussational and the ipsilateral postdecussational dentatothalamic tract originating from the contralateral dentate nucleus, which is very unusual and has not been outlined clearly before.

Abnormalities in the somatosensory system are increasingly being recognized in patients with dystonia. The aim of this study was to investigate whether sensory abnormalities are confined to the dystonic body segments or whether there is a wider involvement in patients with idiopathic dystonia. For this purpose, we recruited 20 patients, 8 had generalized, 5 had segmental dystonia with upper extremity involvement, and 7 had cervical dystonia. In total, there were 13 patients with upper extremity involvement. We used Quantitative Sensory Testing (QST) at the back of the hand in all patients and at the shoulder in patients with cervical dystonia. The main finding on the hand QST was impaired cold detection threshold (CDT), dynamic mechanical allodynia (DMA), and thermal sensory limen (TSL). The alterations were present on both hands, but more pronounced on the side more affected with dystonia. Patients with cervical dystonia showed a reduced CDT and hot detection threshold (HDT), enhanced TSL and DMA at the back of the hand, whereas the shoulder QST only revealed increased cold pain threshold and DMA. In summary, QST clearly shows distinct sensory abnormalities in patients with idiopathic dystonia, which may also manifest in body regions without evident dystonia. Further studies with larger groups of dystonia patients are needed to prove the consistency of these findings.

Background: Chronic deep brain stimulation (DBS) of the globus pallidus internus (GPi) has become an established treatment for dystonia. While bradykinetic symptoms may occur on chronic stimulation, the appearance of hyperkinetic movements has not been well characterized.Case Report: We report on the development of hyperkinesias after more than 10 years of GPi DBS.Discussion: Hyperkinesias may evolve upon long-term GPi DBS in dystonia. This might be related to a combined effect consisting of a reduced threshold for effective GPi stimulation for dystonia and spread of current to the globus pallidus externus.

Dopamine (DA) depletion in the nigrostriatal system leads to basal ganglia dysfunction both in Parkinson's disease (PD) and in 6-hydroxy dopamine (6-OHDA)-lesioned rats with neuronal hyperactivity in the subthalamic nucleus (STN), i.e. increased firing rate and burst activity, together with enhanced beta oscillatory activity. Moreover, intrastriatal transplantation of DA neurons has been shown to functionally re-innervate the host striatum and restore DA input.However, the effects of those transplanted cells on the STN are not well characterized. Therefore, we transplanted cells, derived from the ventral mesencephalon of E12 rat embryos, intrastriatally in the unilateral 6-OHDA-lesioned rat model of PD. We combined behavioral and histological findings with electrophysiological extracellular recordings in the STN, as well as qRT-PCR analyses of dopaminergic, GABAergic, and glutamatergic transporter and receptor genes in the striatum and the STN. Transplanted animals displayed improved rotational behavior after amphetamine injection by 50% in rats with small grafts (586 ± 109 SEM dopamine cells), or even overcompensation by 116% in rats with large grafts (3486 ± 548 SEM dopamine cells). Electrophysiological measurements revealed, that in rats with large grafts burst activity was not affected, while STN neuronal firing rate, as well as beta oscillatory activity was alleviated, whereas small grafts had less impact. Interestingly, both behavioral and electrophysiological measures were dependent on the number of surviving tyrosine hydroxylase positive cells. Although grafted rats displayed restored expression of the GABA synthesizing enzymes Gad65 and Gad67 in the striatum compared to naive rats, the grafts induced a decreased mRNA expression of dopamine receptor Drd2, glutamate receptors AMPA3, NMDA2A, and NMDA2B, and glutamate transporter Eaat3. Interestingly, the NMDA receptor subunit 2B and glutamate transporter Eaat3 were also less expressed in the STN of grafted animals compared to naive rats.In summary, DA grafts restore functional deficits and cause partial improvement of subthalamic neuronal activity. Incomplete recovery, however, may be due to decreased receptor gene expression induced by DA grafts in the striatum and in the STN.

Deficient prepulse inhibition (PPI) of startle reflects disturbed sensorimotor gating found in certain neuropsychiatric disorders, such as Tourette's syndrome, ADHD, Huntington's and schizophrenia. We here tested, whether lesions of the entopeduncular nucleus (EPN) would improve a PPI-deficit induced by selective breeding. Rats with breeding induced high and low expression of PPI were stereotaxically microinjected with ibotenate (0.2 μg in 0.3 μl phosphate buffered saline) or vehicle into the EPN and two weeks later tested for PPI of the acoustic startle response (ASR) and motor activity. Lesions of the EPN counteracted the breeding-induced PPI-deficit and reduced ASR in the PPI low group without affecting their motor activity. In the PPI high group EPN lesions did not affect PPI, ASR, and motor activity. This work indicates an important role of the EPN in the modulation of sensorimotor gating. Additionally, PPI low rats may provide a non-pharmacological model that can be used to develop new therapeutic strategies for neuropsychiatric disorders.

The pathophysiological mechanisms of primary dystonia have largely remained obscure. Yet there is one undeniable observation: lesioning or high-frequency stimulation of the internal segment of the globus pallidus (GP) ameliorates dystonic symptoms. The latter observation implicates abnormal pallidal activity in the genesis of primary dystonia. Recently, excessive oscillatory pallidal activity in the 3–10 Hz frequency range, synchronized with dystonic EMG, has been related to the occurrence of involuntary muscle activity in these patients. However, it is unclear whether this pathological synchronization is driven by GP, caused by re-afference from dystonic muscle, or due to a combination of these two processes. Here we used the Directed Transfer Function as a spectral measure to identify the degree and direction of coupling across time between GP and muscle in seven patients with primary dystonia. We show that pallidal local field potential activity ≤ 10 Hz is coherent with dystonic movements, and that although the coupling between GP and activity in the sternocleidomastoid muscle is bidirectional, the drive from GP to muscle significantly outweighs that from muscle to GP. In addition, the net GP drive to muscle is not stable but fluctuates across time, in keeping with the dynamic nature of dystonic muscle activity. [ABSTRACT FROM AUTHOR]

Gamma synchronization increases during movement and scales with kinematic parameters. Here, disease-specific characteristics of this synchronization and the dopamine-dependence of its scaling in Parkinson’s disease are investigated. In 16 patients undergoing deep brain stimulation surgery, movements of different velocities revealed that subthalamic gamma power peaked in the sensorimotor part of the subthalamic nucleus, correlated positively with maximal velocity and negatively with symptom severity. These effects relied on movement-related bursts of transient synchrony in the gamma band. The gamma burst rate highly correlated with averaged power, increased gradually with larger movements and correlated with symptom severity. In the dopamine-depleted state, gamma power and burst rate significantly decreased, particularly when peak velocity was slower than ON medication. Burst amplitude and duration were unaffected by the medication state. We propose that insufficient recruitment of fast gamma bursts during movement may underlie bradykinesia as one of the cardinal symptoms in Parkinson’s disease.

Supratentorial pneumocephalus after posterior fossa surgery in the semisitting position may lead to decreased alertness and other symptoms. We here aimed to prove the efficacy of normobaric hyperoxia on the absorption of postoperative pneumocephalus according to a standardized treatment protocol.We enrolled 44 patients with postoperative supratentorial pneumocephalus (> 30 ml) after posterior fossa surgery in a semisitting position. After randomisation procedure, patients received either normobaric hyperoxia at FiO2 100% over an endotracheal tube for 3 hours (treatment arm) or room air (control arm). Routine cranial CT scans were performed immediately (CT1) and 24 hours (CT2) after completion of surgery and were rated without knowledge of the therapy arm. Two co-primary endpoints were assessed: (i) mean change of pneumocephalus volume, and (ii) air resorption rate in 24 hours. Secondary endpoints were subjective alertness (Stanford Sleepiness Scale) postoperatively and attention (Stroop test), which were evaluated preoperatively and 24 hours after surgery. The mean change in pneumocephalus volume was higher in patients in the treatment arm as compared to patients in the control arm (p = 0.001). The air resorption rate was higher in patients in the treatment arm as compared to patients in the control arm (p = 0.0015). Differences were more pronounced in patients aged 52 years and older. No difference between patients in treatment arm and control arm was observed for the Stroop test. The distribution of scores in the Stanford Sleepiness Scale differed in the treatment arm as compared to the control arm, and there was a difference in mean values (p = 0.015).Administration of normobaric hyperoxia at FiO2 100% via an endotracheal tube for 3 hours is safe and efficacious in the treatment of pneumocephalus after posterior fossa surgery in the semisitting position. Largest benefit was found in elderly patients and particularly in older men.German Clinical Trials Register DRKS00006273.