Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis-A real-world case series.

BACKGROUND AND AIMS: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis. APPROACH AND RESULTS: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9-17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12). CONCLUSIONS: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis.

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

Motor learning is independent of effects of subthalamic deep brain stimulation on motor execution.

Motor learning is defined as an improvement in performance through practice. The ability to learn new motor skills may be particularly challenged in patients with Parkinson's disease, in whom motor execution is impaired by the disease-defining motor symptoms such as bradykinesia. Subthalamic deep brain stimulation is an effective treatment in advanced Parkinson's disease, and its beneficial effects on Parkinsonian motor symptoms and motor execution have been widely demonstrated. Much less is known about whether deep brain stimulation directly interacts with motor learning independent of modulation of motor execution. We investigated motor sequence learning in 19 patients with Parkinson's disease treated with subthalamic deep brain stimulation and 19 age-matched controls. In a cross-over design, patients performed an initial motor sequence training session with active and inactive stimulation, respectively (experiments separated by ≥14 days). Performance was retested after 5 min and after a 6 h consolidation interval with active stimulation. Healthy controls performed a similar experiment once. We further investigated neural correlates underlying stimulation-related effects on motor learning by exploring the association of normative subthalamic deep brain stimulation functional connectivity profiles with stimulation-related differences in performance gains during training. Pausing deep brain stimulation during initial training resulted in the inhibition of performance gains that could have been indicative of learning at the behavioural level. Task performance improved significantly during training with active deep brain stimulation, but did not reach the level of learning dynamics of healthy controls. Importantly, task performance after the 6 h consolidation interval was similar across patients with Parkinson's disease independent of whether the initial training session had been performed with active or inactive deep brain stimulation. This indicates that early learning and subsequent consolidation were relatively intact despite severe impairments of motor execution during training with inactive deep brain stimulation. Normative connectivity analyses revealed plausible and significant connectivity of volumes of tissue activated by deep brain stimulation with several cortical areas. However, no specific connectivity profiles were associated with stimulation-dependent differences in learning during initial training. Our results show that motor learning in Parkinson's disease is independent of modulation of motor execution by subthalamic deep brain stimulation. This indicates an important role of the subthalamic nucleus in regulating general motor execution, whereas its role in motor learning appears negligible. Because longer-term outcomes were independent of performance gains during initial training, patients with Parkinson's disease may not need to wait for an optimal motor state to practice new motor skills.

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA.

Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+-taurocholate co-transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines. We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks. ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment Week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at Week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p = .0029) and evidence of portal hypertension (p = .0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at Week 24 (rho = -0.577; p = .0078; rho = -0.635, p = .0026; rho = -0.577, p = .0077; rho = -0.519, p = .0191; rho = -0.564, p = .0119 and rho = -0.393, p = .087 at treatment Weeks 2, 8, 12, 16, 20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points. BLV-induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed.

Cross-frequency phase-amplitude coupling in repetitive movements in patients with Parkinson's disease.

Bradykinesia is a cardinal motor symptom in Parkinson's disease (PD), the pathophysiology of which is not fully understood. We analyzed the role of cross-frequency coupling of oscillatory cortical activity in motor impairment in patients with PD and healthy controls. High-density EEG signals were recorded during various motor activities and at rest. Patients performed a repetitive finger-pressing task normally, but were slower than controls during tapping. Phase-amplitude coupling (PAC) between ß (13-30 Hz) and broadband γ (50-150 Hz) was computed from individual EEG source signals in the premotor, primary motor, and primary somatosensory cortices, and the primary somatosensory complex. In all four regions, averaging the entire movement period resulted in higher PAC in patients than in controls for the resting condition and the pressing task (similar performance between groups). However, this was not the case for the tapping tasks where patients performed slower. This suggests the strength of state-related ß-γ PAC does not determine Parkinsonian bradykinesia. Examination of the dynamics of oscillatory EEG signals during motor transitions revealed a distinctive motif of PAC rise and decay around press onset. This pattern was also present at press offset and slow tapping onset, linking such idiosyncratic PAC changes to transitions between different movement states. The transition-related PAC modulation in patients was similar to controls in the pressing task but flattened during slow tapping, which related to normal and abnormal performance, respectively. These findings suggest that the dysfunctional evolution of neuronal population dynamics during movement execution is an important component of the pathophysiology of Parkinsonian bradykinesia.NEW & NOTEWORTHY Our findings using noninvasive EEG recordings provide evidence that PAC dynamics might play a role in the physiological cortical control of movement execution and may encode transitions between movement states. Results in patients with Parkinson's disease suggest that bradykinesia is related to a deficit of the dynamic regulation of PAC during movement execution rather than its absolute strength. Our findings may contribute to the development of a new concept of the pathophysiology of bradykinesia.

Support Vector Machine Classifiers Show High Generalizability in Automatic Fall Detection in Older Adults.

Falls are a major cause of morbidity and mortality in neurological disorders. Technical means of detecting falls are of high interest as they enable rapid notification of caregivers and emergency services. Such approaches must reliably differentiate between normal daily activities and fall events. A promising technique might be based on the classification of movements based on accelerometer signals by machine-learning algorithms, but the generalizability of classifiers trained on laboratory data to real-world datasets is a common issue. Here, three machine-learning algorithms including Support Vector Machine (SVM), k-Nearest Neighbors (kNN), and Random Forest (RF) were trained to detect fall events. We used a dataset containing intentional falls (SisFall) to train the classifier and validated the approach on a different dataset which included real-world accidental fall events of elderly people (FARSEEING). The results suggested that the linear SVM was the most suitable classifier in this cross-dataset validation approach and reliably distinguished a fall event from normal everyday activity at an accuracy of 93% and similarly high sensitivity and specificity. Thus, classifiers based on linear SVM might be useful for automatic fall detection in real-world applications.

Differentiating neurodegenerative parkinsonian syndromes using vestibular evoked myogenic potentials and balance assessment.

OBJECTIVE: Vestibular evoked myogenic potentials (VEMP) were investigated to differentiate between parkinsonian syndromes. We correlated balance and VEMP parameters to investigate the VEMP brainstem circuits as possible origin for postural instability. METHODS: We assessed clinical status, ocular and cervical VEMP (oVEMP, cVEMP) and conducted a balance assessment (posturography, Activities-specific Balance Confidence Scale, Berg Balance Scale, modified Barthel Index) in 76 subjects: 30 with Parkinson's disease (PD), 16 with atypical parkinsonism (AP) and 30 healthy controls. VEMP were elicited by using a mini-shaker on the forehead. RESULTS: Patients with PD had a prolonged oVEMP n10 in comparison to controls and prolonged p15 compared to controls and AP. Patients with AP showed reduced oVEMP amplitudes compared to PD and controls. CVEMP did not differ between groups. Postural impairment was higher in AP compared to controls and PD, particularly in the rating scales. No correlations between VEMP and posturography were found. A support vector machine classifier was able to automatically classify controls and patient subgroups with moderate to good accuracy based on oVEMP latencies and balance questionnaires. CONCLUSIONS: Both oVEMP and posturography, but not cVEMP, may be differentially affected in PD and AP. We did not find evidence that impairment of the cVEMP or oVEMP pathways is directly related to postural impairment. SIGNIFICANCE: OVEMP and balance assessment could be implemented in the differential diagnostic work-up of parkinsonian syndromes.

Evaluation of Three Machine Learning Algorithms for the Automatic Classification of EMG Patterns in Gait Disorders.

Gait disorders are common in neurodegenerative diseases and distinguishing between seemingly similar kinematic patterns associated with different pathological entities is a challenge even for the experienced clinician. Ultimately, muscle activity underlies the generation of kinematic patterns. Therefore, one possible way to address this problem may be to differentiate gait disorders by analyzing intrinsic features of muscle activations patterns. Here, we examined whether it is possible to differentiate electromyography (EMG) gait patterns of healthy subjects and patients with different gait disorders using machine learning techniques. Nineteen healthy volunteers (9 male, 10 female, age 28.2 ± 6.2 years) and 18 patients with gait disorders (10 male, 8 female, age 66.2 ± 14.7 years) resulting from different neurological diseases walked down a hallway 10 times at a convenient pace while their muscle activity was recorded via surface EMG electrodes attached to 5 muscles of each leg (10 channels in total). Gait disorders were classified as predominantly hypokinetic (n = 12) or ataxic (n = 6) gait by two experienced raters based on video recordings. Three different classification methods (Convolutional Neural Network-CNN, Support Vector Machine-SVM, K-Nearest Neighbors-KNN) were used to automatically classify EMG patterns according to the underlying gait disorder and differentiate patients and healthy participants. Using a leave-one-out approach for training and evaluating the classifiers, the automatic classification of normal and abnormal EMG patterns during gait (2 classes: "healthy" and "patient") was possible with a high degree of accuracy using CNN (accuracy 91.9%), but not SVM (accuracy 67.6%) or KNN (accuracy 48.7%). For classification of hypokinetic vs. ataxic vs. normal gait (3 classes) best results were again obtained for CNN (accuracy 83.8%) while SVM and KNN performed worse (accuracy SVM 51.4%, KNN 32.4%). These results suggest that machine learning methods are useful for distinguishing individuals with gait disorders from healthy controls and may help classification with respect to the underlying disorder even when classifiers are trained on comparably small cohorts. In our study, CNN achieved higher accuracy than SVM and KNN and may constitute a promising method for further investigation.

Spatiotemporal features of ß-γ phase-amplitude coupling in Parkinson's disease derived from scalp EEG.

Abnormal phase-amplitude coupling between ß and broadband-γ activities has been identified in recordings from the cortex or scalp of patients with Parkinson's disease. While enhanced phase-amplitude coupling has been proposed as a biomarker of Parkinson's disease, the neuronal mechanisms underlying the abnormal coupling and its relationship to motor impairments in Parkinson's disease remain unclear. To address these issues, we performed an in-depth analysis of high-density EEG recordings at rest in 19 patients with Parkinson's disease and 20 age- and sex-matched healthy control subjects. EEG signals were projected onto the individual cortical surfaces using source reconstruction techniques and separated into spatiotemporal components using independent component analysis. Compared to healthy controls, phase-amplitude coupling of Parkinson's disease patients was enhanced in dorsolateral prefrontal cortex, premotor cortex, primary motor cortex and somatosensory cortex, the difference being statistically significant in the hemisphere contralateral to the clinically more affected side. ß and γ signals involved in generating abnormal phase-amplitude coupling were not strictly phase-phase coupled, ruling out that phase-amplitude coupling merely reflects the abnormal activity of a single oscillator in a recurrent network. We found important differences for couplings between the ß and γ signals from identical components as opposed to those from different components (originating from distinct spatial locations). While both couplings were abnormally enhanced in patients, only the latter were correlated with clinical motor severity as indexed by part III of the Movement Disorder Society Unified Parkinson's Disease Rating Scale. Correlations with parkinsonian motor symptoms of such inter-component couplings were found in premotor, primary motor and somatosensory cortex, but not in dorsolateral prefrontal cortex, suggesting motor domain specificity. The topography of phase-amplitude coupling demonstrated profound differences in patients compared to controls. These findings suggest, first, that enhanced phase-amplitude coupling in Parkinson's disease patients originates from the coupling between distinct neural networks in several brain regions involved in motor control. Because these regions included the somatosensory cortex, abnormal phase-amplitude coupling is not exclusively tied to the hyperdirect tract connecting cortical regions monosynaptically with the subthalamic nucleus. Second, only the coupling between ß and γ signals from different components appears to have pathophysiological significance, suggesting that therapeutic approaches breaking the abnormal lateral coupling between neuronal circuits may be more promising than targeting phase-amplitude coupling per se.

Long-term cognitive impairment after ICU treatment: a prospective longitudinal cohort study (Cog-I-CU).

In this prospective cohort study we aimed to investigate the trajectory of the cognitive performance of patients after discharge from an intensive care unit (ICU). Special consideration was given to patients with suspected premorbid cognitive impairment who might be at risk for the development of dementia. Clinical characteristics were collected until discharge. The premorbid cognitive state was estimated by a structured interview with a close relative. Cognitive outcome was assessed using the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) Plus battery and the Stroop Color and Word Test at the time of discharge from ICU and 9 months later. The results of the study group were compared to an established healthy control group and to normative data. A total number of 108 patients were finally included. At the time of discharge, patients underperformed the healthy control group. In linear regression models, delirium during the ICU stay and the factor premorbid cognitive impairment were associated with poorer cognitive outcome (p = 0.047 and p = 0.001). After 9 months, in 6% of patients without evidence of premorbid cognitive impairment long-lasting deficits were found. In patients with suspected premorbid cognitive impairment, performance in tests of executive function failed to improve.

Motor Performance But Neither Motor Learning Nor Motor Consolidation Are Impaired in Chronic Cerebellar Stroke Patients.

The capacity to acquire and retain new motor skills is essential for everyday behavior and a prerequisite to regain functional independence following impairments of motor function caused by brain damage, e.g., ischemic stroke. Learning a new motor skill requires repeated skill practice and passes through different online and offline learning stages that are mediated by specific dynamic interactions between distributed brain regions including the cerebellum. Motor sequence learning is an extensively studied paradigm of motor skill learning, yet the role of the cerebellum during online and offline stages remains controversial. Here, we studied patients with chronic cerebellar stroke and healthy control participants to further elucidate the role of the cerebellum during acquisition and consolidation of sequential motor skills. Motor learning was assessed by an ecologically valid explicit sequential finger tapping paradigm and retested after an interval of 8 h to assess consolidation. Compared to healthy controls, chronic cerebellar stroke patients displayed significantly lower motor sequence performance independent of whether the ipsilesional or contralesional hand was used for task execution. However, the ability to improve performance during training (i.e., online learning) and to consolidate training-induced skill formation was similar in patients and controls. Findings point to an essential role of the cerebellum in motor sequence production that cannot be compensated, while its role in online and offline motor sequence learning seems to be either negligible or amenable to compensatory mechanisms. This further suggests that residual functional impairments caused by cerebellar stroke may be mitigated even months later by additional skill training.

Linking Individual Movements to a Skilled Repertoire: Fast Modulation of Motor Synergies by Repetition of Stereotyped Movements.

Motor skills emerge when practicing individual movements enables the motor system to extract building instructions that facilitate the generation of future diverse movements. Here we asked how practicing stereotyped movements for minutes affects motor synergies that encode human motor skills acquired over years of training. Participants trained a kinematically highly constrained combined index-finger and thumb movement. Before and after training, finger movements were evoked at rest by transcranial magnetic stimulation (TMS). Post-training, the angle between posture vectors describing TMS-evoked movements and the training movements temporarily decreased, suggesting the presence of a short-term memory for the trained movement. Principal component analysis was used to identify joint covariance patterns in TMS-evoked movements. The quality of reconstruction of training or grasping movements from linear combinations of a small subset of these TMS-derived synergies was used as an index of neural efficiency of movement generation. The reconstruction quality increased for the trained movement but remained constant for grasping movements. These findings suggest that the motor system rapidly reorganizes to enhance the coding efficiency of a difficult movement without compromising the coding efficiency of overlearned movements. Practice of individual movements may drive an unsupervised bottom-up process that ultimately shapes synergistic neuronal organization by constant competition of action memories.

Interleaving Motor Sequence Training With High-Frequency Repetitive Transcranial Magnetic Stimulation Facilitates Consolidation.

The acquisition of novel motor skills is a fundamental process of lifelong learning and crucial for everyday behavior. Performance gains acquired by training undergo a transition from an initially labile state to a state that is progressively robust towards interference, a phenomenon referred to as motor consolidation. Previous work has demonstrated that the primary motor cortex (M1) is a neural key region for motor consolidation. However, it remains unknown whether physiological processes underlying posttraining motor consolidation in M1 are active already during an ongoing training phase or only after completion of the training. We examined whether 10-Hz interleaved repetitive transcranial magnetic stimulation (i-rTMS) of M1 during rest periods between active motor training in an explicit motor learning task affects posttraining offline consolidation. Relative to i-rTMS to the vertex (control region), i-rTMS to the M1hand area of the nondominant hand facilitated posttraining consolidation assessed 6 h after training without affecting training performance. This facilitatory effect generalized to delayed performance of the mirror-symmetric sequence with the untrained (dominant) hand. These findings indicate that posttraining consolidation can be facilitated independently from training-induced performance increments and suggest that consolidation is initiated already during offline processing in short rest periods between active training phases.

Posttraining Alpha Transcranial Alternating Current Stimulation Impairs Motor Consolidation in Elderly People.

The retention of a new sequential motor skill relies on repeated practice and subsequent consolidation in the absence of active skill practice. While the early phase of skill acquisition remains relatively unaffected in older adults, posttraining consolidation appears to be selectively impaired by advancing age. Motor learning is associated with posttraining changes of oscillatory alpha and beta neuronal activities in the motor cortex. However, whether or not these oscillatory dynamics relate to posttraining consolidation and how they relate to the age-specific impairment of motor consolidation in older adults remains elusive. Transcranial alternating current stimulation (tACS) is a noninvasive brain stimulation technique capable of modulating such neuronal oscillations. Here, we examined whether tACS targeting M1 immediately following explicit motor sequence training is capable of modulating motor skill consolidation in older adults. In two sets of double-blind, sham-controlled experiments, tACS targeting left M1 was applied at either 10 Hz (alpha-tACS) or 20 Hz (beta-tACS) immediately after termination of a motor sequence training with the right (dominant) hand. Task performance was retested after an interval of 6 hours to assess consolidation of the training-acquired skill. EEG was recorded over left M1 to be able to detect local after-effects on oscillatory activity induced by tACS. Relative to the sham intervention, consolidation was selectively disrupted by posttraining alpha-tACS of M1, while posttraining beta-tACS of M1 had no effect on delayed retest performance compared to the sham intervention. No significant postinterventional changes of oscillatory activity in M1 were detected following alpha-tACS or beta-tACS. Our findings point to a frequency-specific interaction of tACS with posttraining motor memory processing and may suggest an inhibitory role of immediate posttraining alpha oscillations in M1 with respect to motor consolidation in healthy older adults.

Fluid Balance Variations During the Early Phase of Large Hemispheric Stroke Are Associated With Patients' Functional Outcome.

Background: From the variety of factors underlying the ischemia-associated edema formation in large hemispheric stroke (LHS), an increased brain water content during the early phase seems to have a pivotal role for long-lasting tissue damage. However, the importance of the fluid management during the acute phase of LHS has so far not been adequately studied. Therefore, this study explored the association between the fluid balance and functional outcome in patients suffering from LHS. Methods: We analyzed hospital-based medical records of 39 consecutive patients with LHS and decompressive hemicraniectomy. Over the first 10 days after admission, the volumes of all administered fluids were assessed daily and corrected for daily urinary output and insensible loss. Functional outcome at 3 months was assessed with the modified Rankin Scale (mRS) and dichotomized into an acceptable (mRS ≤ 4) vs. a poor outcome (mRS ≥ 5). Results: Compared to patients with a poor functional outcome (n = 19), those with an acceptable outcome (n = 20) were characterized by a significantly lower cumulative net fluid balance at day 5 (1.6 ± 2.5 vs. 3.4 ± 4.4 l), day 7 (2.0 ± 2.9 vs. 4.6 ± 5.2 l), and day 10 (0 ± 2.5 vs. 5.6 ± 6.2 l). In addition to age, only the cumulative net fluid balance at day 10 served as an independent factor for poor functional outcome in multiple regression analyses. Conclusion: These data provide evidence for a critical role of the early phase net fluid balance with respect to the functional outcome after LHS. This observation leads to the hypothesis that patients with LHS might benefit from a more restrictive volume therapy. However, prospective studies are warranted to establish a causal relationship and recommendations for treatment strategies.

Dual-Site Transcranial Magnetic Stimulation for the Treatment of Parkinson's Disease.

Abnormal oscillatory activity in the subthalamic nucleus (STN) may be relevant for motor symptoms in Parkinson's disease (PD). Apart from deep brain stimulation, transcranial magnetic stimulation (TMS) may be suitable for altering these oscillations. We speculated that TMS to different cortical areas (primary motor cortex, M1, and dorsal premotor cortex, PMd) may activate neuronal subpopulations within the STN via corticofugal neurons projecting directly to the nucleus. We hypothesized that PD symptoms can be ameliorated by a lasting decoupling of STN neurons by associative dual-site repetitive TMS (rTMS). Associative dual-site rTMS (1 Hz) directed to PMd and M1 ("ADS-rTMS") was employed in 20 PD patients treated in a blinded, placebo-controlled cross-over design. Results: No adverse events were noted. We found no significant improvement in clinical outcome parameters (videography of MDS-UPDRS-III, finger tapping, spectral tremor power). Variation of the premotor stimulation site did not induce beneficial effects either. A single session of ADS-rTMS was tolerated well, but did not produce a clinically meaningful benefit on Parkinsonian motor symptoms. Successful treatment using TMS targeting subcortical nuclei may require an intervention over several days or more detailed physiological information about the individual brain state and stimulation-induced subcortical effects.

Assessing blink reflex circuits by three different afferent routes in Parkinson's disease.

OBJECTIVE: Degeneration of nuclei of the brainstem, especially parts of the vagal nuclei complex and the reticular formation, in Parkinson's disease (PD) may in part be responsible for nonmotor signs like obstipation, cardiac dysfunction and rapid eye movement sleep behavior disorder (RBD). The aim of the study was to establish a new blink reflex (BR) variant involving the vagal nuclei complex and the reticular formation and to investigate BR comprehensively using 3 different afferent routes in PD. METHODS: In this cross-sectional observational study in 30 PD patients and 30 age and sex matched healthy controls, BR was elicited by stimulation of the auricular branch of the vagus nerve (ABVN) and compared to conventional BR variants evoked by the trigeminal and median nerve. RESULTS: BRs could be elicited reliably by stimulation of ABVN in both groups. In none of the three BR variants, latencies or amplitudes differed between PD patients and controls. In PD, BR parameters were not related to cognition or presence of RBD. CONCLUSION: The present study did not provide evidence for malfunctioning of neural circuits subserving BRs elicited by three different afferents in PD. SIGNIFICANCE: Brainstem circuits mediating these BR variants may be spared from neurodegeneration in PD.

Axonal Degeneration of the Vagus Nerve in Parkinson's Disease-A High-Resolution Ultrasound Study.

Background: Recent histopathological studies revealed degeneration of the dorsal motor nucleus early in the course of Parkinson's disease (PD). Degeneration of the vagus nerve (VN) axons following neurodegeneration of brainstem vagal nuclei should be detectable by high-resolution ultrasound (HRUS) as a thinning of the VNs. Methods: We measured both VNs cross-sectional area (VN-CSA) of 35 patients with PD and 35 age- and sex-matched healthy controls at the level of the thyroid gland using HRUS. Results: On both sides, the VN-CSA was significantly smaller in PD patients than in controls (right: 2.1 ± 0.4 vs. 2.3 ± 0.5 mm2, left 1.5 ± 0.4 vs. 1.8 ± 0.4 mm2; both p < 0.05). There was no correlation between the right or left VN-CSA and age, the Hoehn & Yahr stage, disease duration, the motor part of the Unified Parkinson's Disease Rating Scale score, the Montreal Cognitive Assessment score, or the Non-motor Symptoms Questionnaire, and Scale for Parkinson's disease score including its gastrointestinal domain. Conclusions: These findings provide evidencethat atrophy of the VNs in PD patients can be detected in-vivo by HRUS.