Translational Neuromodulation Group
Institution: Charité Universitätsmedizin Berlin
About the lab
We are interested in understanding the neural control of movement and how distortions in network communication explain motor impairment in neurological disorders. Therefore, our interdisciplinary team combines methods from molecular biology, optogenetics, electrophysiology, kinematic analysis, closed-loop neuromodulation, and brain-computer-interfacing. In particular, our research focuses on the development of novel neuroprosthetic technologies for the restoration of movement in Parkinson’s disease and stroke. We are working both in animal models and humans with the translational aim to innovate future treatments for neurological disorders.
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Featured research (9)
The understanding of locomotion in neurological disorders requires technologies for quantitative gait analysis. Numerous modalities are available today to objectively capture spatiotemporal gait and postural control features. Nevertheless, many obstacles prevent the application of these technologies to their full potential in neurological research and especially clinical practice. These include the required expert knowledge, time for data collection, and missing standards for data analysis and reporting. Here, we provide a technological review of wearable and vision-based portable motion analysis tools that emerged in the last decade with recent applications in neurological disorders such as Parkinson's disease and Multiple Sclerosis. The goal is to enable the reader to understand the available technologies with their individual strengths and limitations in order to make an informed decision for own investigations and clinical applications. We foresee that ongoing developments toward user-friendly automated devices will allow for closed-loop applications, long-term monitoring, and telemedical consulting in real-life environments.
Gait impairments in Parkinson's disease remain a scientific and therapeutic challenge. The advent of new deep brain stimulation (DBS) devices capable of recording brain activity from chronically implanted electrodes has fostered new studies of gait in freely moving patients. The hope is to identify gait-related neural biomarkers and improve therapy using closed-loop DBS. In this context, animal models offer the opportunity to investigate gait network activity at multiple biological scales and address unresolved questions from clinical research. Yet, the contribution of rodent models to the development of future neuromodulation therapies will rely on translational validity. In this review, we summarize the most effective strategies to model parkinsonian gait in rodents. We discuss how clinical observations have inspired targeted brain lesions in animal models, and whether resulting motor deficits and network oscillations match recent findings in humans. Gait impairments with hypo-, bradykinesia and altered limb rhythmicity were successfully modelled in rodents. However, clear evidence for the presence of freezing of gait was missing. The identification of reliable neural biomarkers for gait impairments has remained challenging in both animals and humans. Moving forward, we expect that the ongoing investigation of circuit specific neuromodulation strategies in animal models will lead to future optimizations of gait therapy in Parkinson's disease.
Parkinson's disease is the second most common neurodegenerative disease worldwide reducing cognitive and motoric abilities of affected persons. Freezing of Gait (FoG) is one of the severe symptoms that is observed in the late stages of the disease and considerably impairs the mobility of the person and raises the risk of falls. Due to the pathology and heterogeneity of the Parkinsonian gait cycle, especially in the case of freezing episodes, the detection of the gait phases with wearables is challenging in Parkinson's disease. This is addressed by introducing a state-automaton-based algorithm for the detection of the foot's motion phases using a shoe-placed inertial sensor. Machine-learning-based methods are investigated to classify the actual motion phase as normal or FoG-affected and to predict the outcome for the next motion phase. For this purpose, spatio-temporal gait and signal parameters are determined from the segmented movement phases. In this context, inertial sensor fusion is applied to the foot's 3D acceleration and rate of turn. Support Vector Machine (SVM) and AdaBoost classifiers have been trained on the data of 16 Parkinson's patients who had shown FoG episodes during a clinical freezing-provoking assessment course. Two clinical experts rated the video-recorded trials and marked episodes with festination, shank trembling, shuffling, or akinesia. Motion phases inside such episodes were labeled as FoG-affected. The classifiers were evaluated using leave-one-patient-out cross-validation. No statistically significant differences could be observed between the different classifiers for FoG detection (p>0.05). An SVM model with 10 features of the actual and two preceding motion phases achieved the highest average performance with 88.5 ± 5.8% sensitivity, 83.3 ± 17.1% specificity, and 92.8 ± 5.9% Area Under the Curve (AUC). The performance of predicting the behavior of the next motion phase was significantly lower compared to the detection classifiers. No statistically significant differences were found between all prediction models. An SVM-predictor with features from the two preceding motion phases had with 81.6 ± 7.7% sensitivity, 70.3 ± 18.4% specificity, and 82.8 ± 7.1% AUC the best average performance. The developed methods enable motion-phase-based FoG detection and prediction and can be utilized for closed-loop systems that provide on-demand gait-phase-synchronous cueing to mitigate FoG symptoms and to prevent complete motoric blockades.
Transcutaneous spinal cord stimulation (tSCS) is a promising intervention that can benefit spasticity control and augment voluntary movement in spinal cord injury (SCI) and multiple sclerosis. Current applications require expert knowledge and rely on the thorough visual analysis of elec-tromyographic (EMG) responses from lower-limb muscles to optimize attainable treatment effects. Here, we devised an automated tSCS setup by combining an electrode array placed over low-thoracic to mid-lumbar vertebrae, synchronized EMG recordings, and a self-operating stimulation protocol to systematically test various stimulation sites and amplitudes. A built-in calibration procedure classifies the evoked responses as reflexes or direct motor responses and identifies stimulation thresholds as recommendations for tSCS therapy. We tested our setup in 15 individuals (five neurologically intact, five SCI, and five Parkinson's disease) and validated the results against blinded ratings from two clinical experts. Congruent results were obtained in 13 cases for electrode positions and in eight for tSCS amplitudes, with deviations of a maximum of one position and 5 to 10 mA in amplitude in the remaining cases. Despite these minor deviations, the calibration found clinically suitable tSCS settings in 13 individuals. In the remaining two cases, the automatic setup and both experts agreed that no reflex responses could be detected. The presented technological developments may facilitate the dissemination of tSCS into non-academic environments and broaden its use for diagnostic and therapeutic purposes.
Deep brain stimulation (DBS) is the preferred treatment for therapy-resistant movement disorders such as dystonia and Parkinson's disease (PD), mostly in advanced disease stages. Although DBS is already in clinical use for ~30 years and has improved patients' quality of life dramatically, there is still limited understanding of the underlying mechanisms of action. Rodent models of PD and dystonia are essential tools to elucidate the mode of action of DBS on behavioral and multiscale neurobiological levels. Advances have been made in identifying DBS effects on the central motor network, neuroprotection and neuroinflammation in DBS studies of PD rodent models. The phenotypic dtsz mutant hamster and the transgenic DYT-TOR1A (ΔETorA) rat proved as valuable models of dystonia for preclinical DBS research. In addition, continuous refinements of rodent DBS technologies are ongoing and have contributed to improvement of experimental quality. We here review the currently existing literature on experimental DBS in PD and dystonia models regarding the choice of models, experimental design, neurobiological readouts, as well as methodological implications. Moreover, we provide an overview of the technical stage of existing DBS devices for use in rodent studies.