@article{SteigerwaldTimmermannKuehnetal.2018, author = {Steigerwald, Frank and Timmermann, Lars and K{\"u}hn, Andrea and Schnitzler, Alfons and Reich, Martin M. and Kirsch, Anna Dalal and Barbe, Michael Thomas and Visser-Vandewalle, Veerle and H{\"u}bl, Julius and van Riesen, Christoph and Groiss, Stefan Jun and Moldovan, Alexia-Sabine and Lin, Sherry and Carcieri, Stephen and Manola, Ljubomir and Volkmann, Jens}, title = {Pulse duration settings in subthalamic stimulation for Parkinson's disease}, series = {Movement Disorders}, volume = {33}, journal = {Movement Disorders}, doi = {10.1002/mds.27238}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239402}, pages = {165-169}, year = {2018}, abstract = {Background Stimulation parameters in deep brain stimulation (DBS) of the subthalamic nucleus for Parkinson's disease (PD) are rarely tested in double-blind conditions. Evidence-based recommendations on optimal stimulator settings are needed. Results from the CUSTOM-DBS study are reported, comparing 2 pulse durations. Methods A total of 15 patients were programmed using a pulse width of 30 µs (test) or 60 µs (control). Efficacy and side-effect thresholds and unified PD rating scale (UPDRS) III were measured in meds-off (primary outcome). The therapeutic window was the difference between patients' efficacy and side effect thresholds. Results The therapeutic window was significantly larger at 30 µs than 60 µs (P = ·0009) and the efficacy (UPDRS III score) was noninferior (P = .00008). Interpretation Subthalamic neurostimulation at 30 µs versus 60 µs pulse width is equally effective on PD motor signs, is more energy efficient, and has less likelihood of stimulation-related side effects. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.}, language = {en} } @article{KirschHassinBaerMatthiesetal.2018, author = {Kirsch, Anna Dalal and Hassin-Baer, Sharon and Matthies, Cordula and Volkmann, Jens and Steigerwald, Frank}, title = {Anodic versus cathodic neurostimulation of the subthalamic nucleus: A randomized-controlled study of acute clinical effects}, series = {Parkinsonism and Related Disorders}, volume = {55}, journal = {Parkinsonism and Related Disorders}, doi = {10.1016/j.parkreldis.2018.05.015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325820}, pages = {61-67}, year = {2018}, abstract = {Introduction Stimulation settings of deep brain stimulation (DBS) have evolved empirically within a limited parameter space dictated by first generation devices. There is a need for controlled clinical studies, which evaluate efficacy and safety of established programming practice against novel programming options provided by modern neurostimulation devices. Methods Here, we tested a polarity reversal from conventional monopolar cathodic to anodic stimulation in an acute double-blind, randomized, cross-over study in patients with PD implanted with bilateral STN DBS. The primary outcome measure was the difference between efficacy and side-effect thresholds (current amplitude, mA) in a monopolar review and the severity of motor symptoms (as assessed by MDS-UPDRS III ratings) after 30 min of continuous stimulation in the medication off-state. Results Effect and side effect thresholds were significantly higher with anodic compared to cathodic stimulation (3.36 ± 1.58 mA vs. 1.99 ± 1.37 mA; 6.05 ± 1.52 mA vs. 4.15 ± 1.13 mA; both p < 0.0001). However, using a predefined amplitude of 0.5 mA below the respective adverse effect threshold, blinded MDS-UPDRS-III-ratings were significantly lower with anodic stimulation (anodic: median 17 [min: 12, max: 25]; cathodic: 23 [12, 37]; p < 0.005). Conclusion Effective anodic stimulation requires a higher charge injection into the tissue, but may provide a better reduction of off-period motor symptoms within the individual therapeutic window. Therefore, a programming change to anodic stimulation may be considered in patients suffering from residual off-period motor symptoms of PD despite reaching the adverse effect threshold of cathodic stimulation in the subthalamic nucleus.}, language = {en} } @article{OdorferVolkmann2023, author = {Odorfer, Thorsten M. and Volkmann, Jens}, title = {Deep brain stimulation for focal or segmental craniocervical dystonia in patients who have failed botulinum neurotoxin therapy - a narrative review of the literature}, series = {Toxins}, volume = {15}, journal = {Toxins}, number = {10}, issn = {2072-6651}, doi = {10.3390/toxins15100606}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357707}, year = {2023}, abstract = {(1) Background: The first-line treatment for patients with focal or segmental dystonia with a craniocervical distribution is still the intramuscular injection of botulinum neurotoxin (BoNT). However, some patients experience primary or secondary treatment failure from this potential immunogenic therapy. Deep brain stimulation (DBS) may then be used as a backup strategy in this situation. (2) Methods: Here, we reviewed the current study literature to answer a specific question regarding the efficacy and safety of the use of DBS, particularly for cervical dystonia (CD) and Meige syndrome (MS) in patients with documented treatment failure under BoNT. (3) Results: There are only two studies with the highest level of evidence in this area. Despite this clear limitation, in the context of the narrowly defined research question of this paper, it is possible to report 161 patients with CD or MS who were included in studies that were able to show a statistically significant reduction in dystonic symptoms using DBS. Safety and tolerability data appeared adequate. However, much of the information is based on retrospective observations. (4) Conclusions: The evidence base in this area is in need of further scientific investigation. Most importantly, more randomized, controlled and double-blind trials are needed, possibly including a head-to-head comparison of DBS and BoNT.}, language = {en} } @article{BinderLangePozzietal.2023, author = {Binder, Tobias and Lange, Florian and Pozzi, Nicol{\`o} and Musacchio, Thomas and Daniels, Christine and Odorfer, Thorsten and Fricke, Patrick and Matthies, Cordula and Volkmann, Jens and Capetian, Philipp}, title = {Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson's disease: a comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial}, series = {Brain Stimulation}, volume = {16}, journal = {Brain Stimulation}, number = {5}, doi = {10.1016/j.brs.2023.08.017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350280}, pages = {1243-1251}, year = {2023}, abstract = {Highlights • Beta-Guided programming is an innovative approach that may streamline the programming process for PD patients with STN DBS. • While preliminary findings from our study suggest that Beta Titration may potentially mitigate STN overstimulation and enhance symptom control, • Our results demonstrate that beta-guided programming significantly reduces programming time, suggesting it could be efficiently integrated into routine clinical practice using a commercially available patient programmer. Background Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. Objective To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. Methods We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). Results All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). Conclusion Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice.}, language = {en} } @phdthesis{Knorr2024, author = {Knorr, Susanne}, title = {Pathophysiology of early-onset isolated dystonia in a DYT-TOR1A rat model with trauma-induced dystonia-like movements}, doi = {10.25972/OPUS-20609}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206096}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Early-onset torsion dystonia (DYT-TOR1A, DYT1) is an inherited hyperkinetic movement disorder caused by a mutation of the TOR1A gene encoding the torsinA protein. DYT-TOR1A is characterized as a network disorder of the central nervous system (CNS), including predominantly the cortico-basal ganglia-thalamo-cortical loop resulting in a severe generalized dystonic phenotype. The pathophysiology of DYTTOR1A is not fully understood. Molecular levels up to large-scale network levels of the CNS are suggested to be affected in the pathophysiology of DYT-TOR1A. The reduced penetrance of 30\% - 40\% indicates a gene-environmental interaction, hypothesized as "second hit". The lack of appropriate and phenotypic DYT-TOR1A animal models encouraged us to verify the "second hit" hypothesis through a unilateral peripheral nerve trauma of the sciatic nerve in a transgenic asymptomatic DYT-TOR1A rat model (∆ETorA), overexpressing the human mutated torsinA protein. In a multiscale approach, this animal model was characterized phenotypically and pathophysiologically. Nerve-injured ∆ETorA rats revealed dystonia-like movements (DLM) with a partially generalized phenotype. A physiomarker of human dystonia, describing increased theta oscillation in the globus pallidus internus (GPi), was found in the entopeduncular nucleus (EP), the rodent equivalent to the human GPi, of nerve-injured ∆ETorA rats. Altered oscillation patterns were also observed in the primary motor cortex. Highfrequency stimulation (HFS) of the EP reduced DLM and modulated altered oscillatory activity in the EP and primary motor cortex in nerve-injured ∆ETorA rats. Moreover, the dopaminergic system in ∆ETorA rats demonstrated a significant increased striatal dopamine release and dopamine turnover. Whole transcriptome analysis revealed differentially expressed genes of the circadian clock and the energy metabolism, thereby pointing towards novel, putative pathways in the pathophysiology of DYTTOR1A dystonia. In summary, peripheral nerve trauma can trigger DLM in genetically predisposed asymptomatic ΔETorA rats leading to neurobiological alteration in the central motor network on multiple levels and thereby supporting the "second hit" hypothesis. This novel symptomatic DYT-TOR1A rat model, based on a DYT-TOR1A genetic background, may prove as a valuable chance for DYT-TOR1A dystonia, to further investigate the pathomechanism in more detail and to establish new treatment strategies.}, subject = {Dystonie}, language = {en} } @article{DelVecchioHanafiPozzietal.2023, author = {Del Vecchio, Jasmin and Hanafi, Ibrahem and Pozzi, Nicol{\´o} Gabriele and Capetian, Philipp and Isaias, Ioannis U. and Haufe, Stefan and Palmisano, Chiara}, title = {Pallidal recordings in chronically implanted dystonic patients: mitigation of tremor-related artifacts}, series = {Bioengineering}, volume = {10}, journal = {Bioengineering}, number = {4}, issn = {2306-5354}, doi = {10.3390/bioengineering10040476}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313498}, year = {2023}, abstract = {Low-frequency oscillatory patterns of pallidal local field potentials (LFPs) have been proposed as a physiomarker for dystonia and hold the promise for personalized adaptive deep brain stimulation. Head tremor, a low-frequency involuntary rhythmic movement typical of cervical dystonia, may cause movement artifacts in LFP signals, compromising the reliability of low-frequency oscillations as biomarkers for adaptive neurostimulation. We investigated chronic pallidal LFPs with the Percept\(^{TM}\) PC (Medtronic PLC) device in eight subjects with dystonia (five with head tremors). We applied a multiple regression approach to pallidal LFPs in patients with head tremors using kinematic information measured with an inertial measurement unit (IMU) and an electromyographic signal (EMG). With IMU regression, we found tremor contamination in all subjects, whereas EMG regression identified it in only three out of five. IMU regression was also superior to EMG regression in removing tremor-related artifacts and resulted in a significant power reduction, especially in the theta-alpha band. Pallido-muscular coherence was affected by a head tremor and disappeared after IMU regression. Our results show that the Percept PC can record low-frequency oscillations but also reveal spectral contamination due to movement artifacts. IMU regression can identify such artifact contamination and be a suitable tool for its removal.}, language = {en} } @article{FriedrichEldebakeyRoothansetal.2022, author = {Friedrich, Maximilian U. and Eldebakey, Hazem and Roothans, Jonas and Capetian, Philipp and Zwergal, Andreas and Volkmann, Jens and Reich, Martin}, title = {Current-dependent ocular tilt reaction in deep brain stimulation of the subthalamic nucleus: Evidence for an incerto-interstitial pathway?}, series = {European Journal of Neurology}, volume = {29}, journal = {European Journal of Neurology}, number = {5}, doi = {10.1111/ene.15257}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318700}, pages = {1545 -- 1549}, year = {2022}, abstract = {Background and purpose The aim was to characterize a combined vestibular, ocular motor and postural syndrome induced by deep brain stimulation (DBS) of the subthalamic nucleus in a patient with Parkinson's disease. Methods In a systematic DBS programming session, eye, head and trunk position in roll and pitch plane were documented as a function of stimulation amplitude and field direction. Repeat ocular coherence tomography was used to estimate ocular torsion. The interstitial nucleus of Cajal (INC), zona incerta (ZI) and ascending vestibular fibre tracts were segmented on magnetic resonance imaging using both individual and normative structural connectomic data. Thresholded symptom-associated volumes of tissue activated (VTA) were calculated based on documented stimulation parameters. Results Ipsilateral ocular tilt reaction and body lateropulsion as well as contralateral torsional nystagmus were elicited by the right electrode in a current-dependent manner and subsided after DBS deactivation. With increasing currents, binocular tonic upgaze and body retropulsion were observed. Symptoms were consistent with an irritative effect on the INC. Symptom-associated VTA was found to overlap with the dorsal ZI and the ipsilateral vestibulothalamic tract, while lying rather distant to the INC proper. A ZI-to-INC 'incerto-interstitial' tract with contact to the medial-uppermost portion of the VTA could be traced. Conclusion Unilateral stimulation of INC-related circuitry induces an ipsilateral vestibular, ocular motor and postural roll-plane syndrome, which converts into a pitch-plane syndrome when functional activation expands bilaterally. In this case, tractography points to an incerto-interstitial pathway, a tract previously only characterized in non-human primates. Directional current steering proved useful in managing this rare side effect.}, language = {en} } @phdthesis{Palmisano2022, author = {Palmisano, Chiara}, title = {Supraspinal Locomotor Network Derangements: A Multimodal Approach}, doi = {10.25972/OPUS-26644}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266442}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Parkinson's Disease (PD) constitutes a major healthcare burden in Europe. Accounting for aging alone, ~700,000 PD cases are predicted by 2040. This represents an approximately 56\% increase in the PD population between 2005 and 2040, with a consequent rise in annual disease-related medical costs. Gait and balance disorders are a major problem for patients with PD and their caregivers, mainly because to their correlation with falls. Falls occur as a result of a complex interaction of risk factors. Among them, Freezing of Gait (FoG) is a peculiar gait derangement characterized by a sudden and episodic inability to produce effective stepping, causing falls, mobility restrictions, poor quality of life, and increased morbidity and mortality. Between 50-70\% of PD patients have FoG and/or falls after a disease duration of 10 years, only partially and inconsistently improved by dopaminergic treatment and Deep Brain Stimulation (DBS). Treatment-induced worsening has been also observed under certain conditions. Effective treatments for gait disturbances in PD are lacking, probably because of the still poor understanding of the supraspinal locomotor network. In my thesis, I wanted to expand our knowledge of the supraspinal locomotor network and in particular the contribution of the basal ganglia to the control of locomotion. I believe this is a key step towards new preventive and personalized therapies for postural and gait problems in patients with PD and related disorders. In addition to patients with PD, my studies also included people affected by Progressive Supranuclear Palsy (PSP). PSP is a rare primary progressive parkinsonism characterized at a very early disease stage by poor balance control and frequent backwards falls, thus providing an in vivo model of dysfunctional locomotor control. I focused my attention on one of the most common motor transitions in daily living, the initiation of gait (GI). GI is an interesting motor task and a relevant paradigm to address balance and gait impairments in patients with movement disorders, as it is associated with FoG and high risk of falls. It combines a preparatory (i.e., the Anticipatory Postural Adjustments [APA]) and execution phase (the stepping) and allows the study of movement scaling and timing as an expression of muscular synergies, which follow precise and online feedback information processing and integration into established feedforward patterns of motor control. By applying a multimodal approach that combines biomechanical assessments and neuroimaging investigations, my work unveiled the fundamental contribution of striatal dopamine to GI in patients with PD. Results in patients with PSP further supported the fundamental role of the striatum in GI execution, revealing correlations between the metabolic intake of the left caudate nucleus with diverse GI measurements. This study also unveiled the interplay of additional brain areas in the motor control of GI, namely the Thalamus, the Supplementary Motor Area (SMA), and the Cingulate cortex. Involvement of cortical areas was also suggested by the analysis of GI in patients with PD and FoG. Indeed, I found major alterations in the preparatory phase of GI in these patients, possibly resulting from FoG-related deficits of the SMA. Alterations of the weight shifting preceding the stepping phase were also particularly important in PD patients with FoG, thus suggesting specific difficulties in the integration of somatosensory information at a cortical level. Of note, all patients with PD showed preserved movement timing of GI, possibly suggesting preserved and compensatory activity of the cerebellum. Postural abnormalities (i.e., increased trunk and thigh flexion) showed no relationship with GI, ruling out an adaptation of the motor pattern to the altered postural condition. In a group of PD patients implanted with DBS, I further explored the pathophysiological functioning of the locomotor network by analysing the timely activity of the Subthalamic Nucleus (STN) during static and dynamic balance control (i.e., standing and walking). For this study, I used novel DBS devices capable of delivering stimulation and simultaneously recording Local Field Potentials (LFP) of the implanted nucleus months and years after surgery. I showed a gait-related frequency shift in the STN activity of PD patients, possibly conveying cortical (feedforward) and cerebellar (feedback) information to mesencephalic locomotor areas. Based on this result, I identified for each patient a Maximally Informative Frequency (MIF) whose power changes can reliably classify standing and walking conditions. The MIF is a promising input signal for new DBS devices that can monitor LFP power modulations to timely adjust the stimulation delivery based on the ongoing motor task (e.g., gait) performed by the patient (adaptive DBS). Altogether my achievements allowed to define the role of different cortical and subcortical brain areas in locomotor control, paving the way for a better understanding of the pathophysiological dynamics of the supraspinal locomotor network and the development of tailored therapies for gait disturbances and falls prevention in PD and related disorders.}, language = {en} } @article{SchuhmannPappStolletal.2021, author = {Schuhmann, Michael K. and Papp, Lena and Stoll, Guido and Blum, Robert and Volkmann, Jens and Fluri, Felix}, title = {Mesencephalic electrical stimulation reduces neuroinflammation after photothrombotic stroke in rats by targeting the cholinergic anti-inflammatory pathway}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms22031254}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259099}, year = {2021}, abstract = {Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)\(^+\) CD4\(^+\)-cells and α7nAchR\(^+\)-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT\(^+\) CD4\(^+\)-cells increased after MLR-HFS, whereas the amount of α7nAchR\(^+\)-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR.}, language = {en} } @article{KremerPauwelsPozzietal.2021, author = {Kremer, Naomi I. and Pauwels, Rik W. J. and Pozzi, Nicol{\`o} G. and Lange, Florian and Roothans, Jonas and Volkmann, Jens and Reich, Martin M.}, title = {Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {16}, issn = {2077-0383}, doi = {10.3390/jcm10163468}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244982}, year = {2021}, abstract = {Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus is one of the main advanced neurosurgical treatments for drug-resistant tremor. However, not every patient may be eligible for this procedure. Nowadays, various other functional neurosurgical procedures are available. In particular cases, radiofrequency thalamotomy, focused ultrasound and radiosurgery are proven alternatives to DBS. Besides, other DBS targets, such as the posterior subthalamic area (PSA) or the dentato-rubro-thalamic tract (DRT), may be appraised as well. In this review, the clinical characteristics and pathophysiology of tremor syndromes, as well as long-term outcomes of DBS in different targets, will be summarized. The effectiveness and safety of lesioning procedures will be discussed, and an evidence-based clinical treatment approach for patients with drug-resistant tremor will be presented. Lastly, the future directions in the treatment of severe tremor syndromes will be elaborated.}, language = {en} }