Plasma autoantibodies to glial fibrillary acidic protein (GFAP) react with brain areas according to Braak staging of Parkinson's disease.

Idiopathic Parkinson's disease (PD) is characterized by a progredient degeneration of the brain, starting at deep subcortical areas such as the dorsal motor nucleus of the glossopharyngeal and vagal nerves (DM) (stage 1), followed by the coeruleus-subcoeruleus complex; (stage 2), the substantia nigra (SN) (stage 3), the anteromedial temporal mesocortex (MC) (stage 4), high-order sensory association areas and prefrontal fields (HC) (stage 5) and finally first-order sensory association areas, premotor areas, as well as primary sensory and motor field (FC) (stage 6). Autoimmunity might play a role in PD pathogenesis. Here we analyzed whether anti-brain autoantibodies differentially recognize different human brain areas and identified autoantigens that correlate with the above-described dissemination of PD pathology in the brain. Brain tissue was obtained from deceased individuals with no history of neurological or psychiatric disease and no neuropathological abnormalities. Tissue homogenates from different brain regions (DM, SN, MC, HC, FC) were subjected to SDS-PAGE and Western blot. Blots were incubated with plasma samples from 30 PD patients and 30 control subjects and stained with anti-IgG antibodies to detect anti-brain autoantibodies. Signals were quantified. Prominent autoantigens were identified by 2D-gel-coupled mass spectrometry sequencing. Anti-brain autoantibodies are frequent and occur both in healthy controls and individuals with PD. Glial fibrillary acidic protein (GFAP) was identified as a prominent autoantigen recognized in all plasma samples. GFAP immunoreactivity was highest in DM areas and lowest in FC areas with no significant differences in anti-GFAP autoantibody titers between healthy controls and individuals with PD. The anti-GFAP autoimmunoreactivity of different brain areas correlates with the dissemination of histopathological neurodegeneration in PD. We hypothesize that GFAP autoantibodies are physiological but might be involved as a cofactor in PD pathogenesis secondary to a leakage of the blood-brain barrier.

Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming.

Objectives: Deep brain stimulation (DBS) programming is based on clinical response testing. Our clinical pilot trial assessed the feasibility of image-guided programing using software depicting the lead location in a patient-specific anatomical model. Methods: Parkinson's disease patients with subthalamic nucleus-DBS were randomly assigned to standard clinical-based programming (CBP) or anatomical-based (imaging-guided) programming (ABP) in an 8-week crossover trial. Programming characteristics and clinical outcomes were evaluated. Results: In 10 patients, both programs led to similar motor symptom control (MDS-UPDRS III) after 4 weeks (medicationOFF/stimulationON; CPB: 18.27 ± 9.23; ABP: 18.37 ± 6.66). Stimulation settings were not significantly different, apart from higher frequency in the baseline program than CBP (p = 0.01) or ABP (p = 0.003). Time spent in a program was not significantly different (CBP: 86.1 ± 29.82%, ABP: 88.6 ± 29.0%). Programing time was significantly shorter (p = 0.039) with ABP (19.78 ± 5.86 min) than CBP (45.22 ± 18.32). Conclusion: Image-guided DBS programming in PD patients drastically reduces programming time without compromising symptom control and patient satisfaction in this small feasibility trial.

Smell and taste in idiopathic blepharospasm.

The pathophysiology of blepharospasm is incompletely understood. Current concepts suggest that blepharospasm is a network disorder, involving basal ganglia, thalamus, cortex, and, possibly, the cerebellum. Tracing, imaging, and clinical studies revealed that these structures are also concerned with olfaction and taste. Because of this anatomical overlap, dysfunction of the chemical senses in blepharospasm is expected. Injections of botulinum toxin into the eyelid muscles are the first-line treatment of blepharospasm. Yet, the effects of botulinum toxin on the chemical senses have not been systematically assessed. To contribute to a better understanding of blepharospasm, olfactory and gustatory abilities were assessed in 17 subjects with blepharospasm and 17 age-/sex-matched healthy controls. Sniffin Sticks were used to assess odor threshold, odor discrimination, and odor identification. Results of these three Sniffin Sticks subtests were added to the composite olfactory score. The Taste Strips were applied to assess taste. In an adjacent study, we assessed the sense of smell and taste in eight subjects with blepharospasm before and 4 weeks after botulinum toxin treatment. Subjects with blepharospasm had significantly lower (= worse) scores for odor threshold and for the composite olfactory score than healthy controls, while odor discrimination, odor identification, and the composite taste score were not different between groups. The adjacent study revealed that botulinum toxin did not impact the chemical senses. In this study, subjects with blepharospasm had a lower (= worse) odor threshold than healthy controls. As olfaction is important in daily life, findings justify further research of olfaction in blepharospasm.

Directional Leads for Deep Brain Stimulation: Technical Notes and Experiences.

OBJECTIVE: Deep brain stimulation (DBS) is an approved treatment for movement disorders. Despite high precision in electrode placement, side effects do occur by current spread to adjacent fibers or nuclei. Directional leads (D-leads) are designed to adapt the volume of stimulation relative to the position within the target by horizontal and vertical current steering directions. The feasibility of implanting these new leads, possible difficulties, and complications were the focus of this study. MATERIAL AND METHODS: This analysis is based on 31 patients who underwent a DBS procedure with D-leads and an implantable pulse generator (IPG) capable of multiple independent current control and 31 patients who received non-D-leads with a similar IPG. While trajectory planning and most steps of the surgical procedure were identical to conventional DBS lead implantation, differences in indication, electrode handling, lead control, and complications were documented and analyzed in comparison to a control group with ring electrodes. RESULTS: During a consecutive series of 51 patients implanted with a DBS system, 31 patients (60.1%) were selected for implantation of D-leads and received 59 D-leads, 28 bilateral, and 3 unilateral implantations. The control group consisted of a consecutive series of a comparable time period, with 31 patients who received conventional ring electrodes. Indication of D-lead implantation was based on the anatomic conditions of the trajectory and target regions and the results of intraoperative test stimulations. In 1 patient, primary D-lead implantation on both sides was performed without any microelectrode implantation to minimize risk for hemorrhage. In the absence of an externally visible marker, the control of implant depth and of the orientation of the D-lead needs to be controlled by X-ray resulting in a longer fluoroscopy time and, therefore, higher X-ray dose compared to conventional lead implantations (415.53 vs. 328.96 Gy cm2; p = 0.09). Mean procedure duration for complete system implantation did not differ between either type of leads (ring electrodes vs. D-leads, 08:55 vs. 09:02 h:min). Surgical complications were unrelated to the type of electrode: surgical revision was necessary and successfully performed in 1 subcutaneous hematoma and 1 unilateral electrode dislocation. A rather rare complication, symptomatic idiopathic delayed-onset edema, was observed in 4 patients with D-leads. They recovered completely within 1-3 weeks, spontaneously or after short-term cortisone medication. In the control group, in a series of 31 patients (20 implanted with Medtronic 3389 lead and 11 with Boston Scientific Vercise lead), not a single problem of this kind was encountered at any time. CONCLUSION: Precise positioning of D-leads is more challenging than that of conventional DBS leads. By adding an external lead marker, control of optimal lead position and orientation is enhanced. In case of supposed increased risk for hemorrhage because of vessels crossing all possible trajectories in the pre-surgical navigated simulation program, primary D-lead implantation instead of the sharper microelectrodes may be a feasible alternative and it may offer more options than ring electrodes especially in these cases. Prospective studies comparing ring-mode stimulation to directional stimulation to examine the differences of the clinical effects have been started.

Longitudinal Assessment of Rotation Angles after Implantation of Directional Deep Brain Stimulation Leads.

PURPOSE: The risk/benefit-ratio of deep brain stimulation (DBS) depends on focusing the electrical field onto the target volume, excluding side-effect eliciting structures. Directional leads limiting radial current diffusion can target stimulation but add a spatial degree of freedom that requires control to align multimodal imaging datasets and for anatomical interpretation of stimulation. Unpredictable postoperative lead rotations have been reported. The extent and timing of rotation from the surgically intended alignment remain uncertain, as does the time point at which directional stimulation can be safely initiated without risking unexpected shifts in stimulation volume. We present a retrospective analysis of clinically indicated, repeated neuroimaging controls postimplantation in patients with directional DBS systems, which allow estimation of the amount and timing of postoperative lead rotation. METHODS: Data from 67 patients with directional leads and multiple cranial computer tomographies (CCT) and/or rotation fluoroscopies at different postoperative time points were included. Rotation angles were detected based on CCT artifacts (n = 56) or direct visualization of lead segments on rotation fluoroscopies (n = 52). Cross-validation of both methods was conducted in patients who received both imaging modalities (n = 51). RESULTS: Rotation angles deviated significantly (∼30°) from their intended 0° anterior/posterior orientation. Rotation was firmly established within the first postoperative day, with no additional torque in subsequent scans. The two methods highly correlated (right hemisphere: R2 = 0.94, left hemisphere: R2 = 0.91). CONCLUSION: Both methods for measuring rotation angles led to comparable results and can be used interchangeably. Directional stimulation settings can safely be initiated after the first postoperative day, without risking subsequent lead rotation-related anatomical shifts.

Combined subthalamic and nucleus basalis of Meynert deep brain stimulation for Parkinson's disease with dementia (DEMPARK-DBS): protocol of a randomized, sham-controlled trial.

INTRODUCTION: Dementia in Parkinson's disease (PDD) is a common non-motor symptom of advanced disease, associated with pronounced neocortical cholinergic deficits due to neurodegeneration of the nucleus basalis of Meynert (NBM) and its cholinergic terminals. In advanced PD, patients often require advanced therapies such as infusion therapy or deep brain stimulation (DBS) to improve motor control. However, patients with associated dementia are commonly excluded from DBS because of potential deterioration of cognitive functions. Yet marked reductions in dopaminergic medication and the subsequent risk of side effects (e.g., cognitive decline, psychosis, delirium) suggest that critical re-consideration of DBS of the subthalamic nucleus (STN-DBS) for advanced stages of PD and PDD is worthwhile. In this Phase 1b study, we will provide STN-DBS to a cohort of PDD patients with severe motor fluctuations and combine two additional electrodes for augmentative neurostimulation of the NBM. METHODS: We aim to include 12 patients with mild-to-moderately severe PDD who fulfill indication criteria regarding motor symptoms for STN-DBS. Eligible patients will undergo implantation of a neurostimulation system with bilateral electrodes in both the STN and NBM. After 12 weeks of STN-DBS (visit 1/V1), participants will be randomized to receive either effective neurostimulation of the NBM (group 1) or sham stimulation of the NBM (group 2). NBM-DBS will be activated in all participants after 24 weeks of blinded treatment (visit 2/V2). The primary outcome will be the safety of combined bilateral STN- and NBM-DBS, determined by spontaneously-reported adverse events. Other outcome measures will comprise changes on scales evaluating cognition, activities of daily living functioning and clinical global impression, as well as motor functions, mood, behavior, caregiver burden and health economic aspects, and several domain-specific cognitive tests. Changes in scores (V1 - V2) for both treatment arms will undergo analysis of covariances, with baseline scores as covariates. PERSPECTIVE: The feasibility and safety of combined STN-NBM-DBS in patients with PDD will be assessed to determine whether additional NBM-DBS improves or slows the progression of cognitive decline. Positive results would provide a basic concept for future studies evaluating the efficacy of NBM-DBS in larger PDD cohorts. Indirectly, proof-of-safety of STN-DBS in PDD might influence patient selection for this standard treatment option in advanced PD. TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT number): NCT02589925.

Freezing of gait in Parkinson's disease reflects a sudden derangement of locomotor network dynamics.

Freezing of gait is a disabling symptom of Parkinson's disease that causes a paroxysmal inability to generate effective stepping. The underlying pathophysiology has recently migrated towards a dysfunctional supraspinal locomotor network, but the actual network derangements during ongoing gait freezing are unknown. We investigated the communication between the cortex and the subthalamic nucleus, two main nodes of the locomotor network, in seven freely-moving subjects with Parkinson's disease with a novel deep brain stimulation device, which allows on-demand recording of subthalamic neural activity from the chronically-implanted electrodes months after the surgical procedure. Multisite neurophysiological recordings during (effective) walking and ongoing gait freezing were combined with kinematic measurements and individual molecular brain imaging studies. Patients walked in a supervised environment closely resembling everyday life challenges. We found that during (effective) walking, the cortex and subthalamic nucleus were synchronized in a low frequency band (4-13 Hz). In contrast, gait freezing was characterized in every patient by low frequency cortical-subthalamic decoupling in the hemisphere with less striatal dopaminergic innervation. Of relevance, this decoupling was already evident at the transition from normal (effective) walking into gait freezing, was maintained during the freezing episode, and resolved with recovery of the effective walking pattern. This is the first evidence for a decoding of the networked processing of locomotion in Parkinson's disease and suggests that freezing of gait is a 'circuitopathy' related to a dysfunctional cortical-subcortical communication. A successful therapeutic approach for gait freezing in Parkinson's disease should aim at directly targeting derangements of neural network dynamics.

Levodopa Modulates Functional Connectivity in the Upper Beta Band Between Subthalamic Nucleus and Muscle Activity in Tonic and Phasic Motor Activity Patterns in Parkinson's Disease.

Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson's disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons. Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI). Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50-150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300-500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF. Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus' functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy.

Comparing two randomized deep brain stimulation trials for Parkinson's disease.

OBJECTIVE: Several randomized studies have compared the effect of deep brain stimulation (DBS) of the subthalamic nucleus with the best medical treatment in large groups of patients. Important outcome measures differ between studies. Two such major studies, the life-quality study of the German Competence Network for Parkinson's disease (LQ study) and the US Veterans Affairs/National Institute of Neurological Disorders and Stroke trial (VA/NINDS trial), were compared here in order to understand their differences in outcomes. METHODS: Unless otherwise noted, analyses were based on those subjects in each study who received a DBS implant (LQ study 76 patients, VA/NINDS trial 140 patients) and who had data for the measurement under consideration (i.e., no imputations for missing data), referred to hereafter as the "as-treated completers" (LQ 69 patients, VA/NINDS 125 patients). Data were prepared and analyzed by biostatisticians at the US Department of Veterans Affairs Cooperative Studies Program Coordinating Center, the Coordinating Center for Clinical Trials Marburg, and Medtronic, under the direction of two authors (G.D. and K.A.F.). Data were extracted from the respective databases into SAS data sets and analyzed using SAS software. Analyses were based on the 6-month follow-up data from both studies because this was the endpoint for the LQ study. RESULTS: Pre-DBS baseline demographics differed significantly between the studies, including greater levodopa responsiveness (LDR) in the LQ study population than in the VA/NINDS group. After DBS, LQ subjects demonstrated greater improvement in motor function (Unified Parkinson's Disease Rating Scale, Motor Examination [UPDRS-III]), activities of daily living (ADLs), and complications of therapy. Medication reduction and improvements in life quality other than ADLs were not significantly different between LQ and VA/NINDS subjects. When the two populations were compared according to pre-DBS LDR, the "full responders" to levodopa (≥ 50% improvement on UPDRS-III with medication) in the two studies showed no significant difference in motor improvement with DBS (LQ 18.5 ± 12.0-point improvement on UPDRS-III vs VA/NINDS 17.7 ± 15.6-point improvement, p = 0.755). Among levodopa full responders, ADLs improved slightly more in the LQ group, but scores on other UPDRS subscales and the Parkinson's Disease Questionnaire-39 were not significantly different between the two studies. CONCLUSIONS: This comparison suggests that patient selection criteria, especially preoperative LDR, are the most important source of differences in motor outcomes and quality of life between the two studies.

Development of evidence-based quality indicators for deep brain stimulation in patients with Parkinson's disease and first year experience of implementation of a nation-wide registry.

INTRODUCTION: Deep Brain Stimulation (DBS) is a complex, invasive and cost-intensive therapy that requires a high level of expertise. To date, data on quality of DBS in clinical routine in the German health care system are lacking. METHODS: The development of evidence-based QIs for DBS in PD patients was performed following a standardized process by a multidisciplinary board between 2014 and 2016. The process was initiated by the German Parkinson Society and followed international recommendations for developing QIs including: a systematic literature search; an appraisal of the published evidence; a consensus-based selection of the QI set; and a pilot study to assess the feasibility in implementing the QIs in clinical routine. RESULTS: A set of 28 QIs for determining the quality of DBS in PD was established by the board covering different dimensions of health care quality (structure, process, and outcome) in different treatment phases of DBS care (pre-operative, peri-operative, and post-operative). Implementation in clinical practice was tested in a pilot study comprising three hospitals delivering DBS care. The feasibility of the QI set was evaluated positively by the participating physicians and hospitals. Mean time to document one patient was 25 min. The German-wide implementation of the defined indicator set within a dedicated quality registry (QualiPa) started in June 2016. CONCLUSION: QIs are a necessary requirement to monitor hospital performance in DBS care. The evidence-based approach to develop the proposed indicator set is expected to assure transparency, acceptance and long-term applicability of the QI set in Germany.

Evaluation of a programming algorithm for deep brain stimulation in dystonia used in a double-blind, sham-controlled multicenter study.

BACKGROUND: Programming deep brain stimulation in dystonia is difficult because of the delayed benefits and absence of evidence-based guidelines. Therefore, we evaluated the efficacy of a programming algorithm applied in a double-blind, sham-controlled multicenter study of pallidal deep brain stimulation in dystonia. METHODS: A standardized monopolar review to identify the contact with the best acute antidystonic effect was applied in 40 patients, who were then programmed 0.5 V below the adverse effect threshold and maintained on these settings for at least 3 months, if tolerated. If no acute effects were observed, contact selection was based on adverse effects or anatomical criteria. Three-year follow-up data was available for 31 patients, and five-year data for 32 patients. The efficacy of the algorithm was based on changes in motor scores, adverse events, and the need for reprogramming. RESULTS: The mean (±standard deviation) dystonia motor score decreased by 73 ± 24% at 3 years and 63 ± 38% at 5 years for contacts that exhibited acute improvement of dystonia (n = 17) during the monopolar review. Contacts without acute benefit improved by 58 ± 30% at 3 years (n = 63) and 53 ± 31% at 5 years (n = 59). Interestingly, acute worsening or induction of dystonia/dyskinesia (n = 9) correlated significantly with improvement after 3 years, but not 5 years. CONCLUSIONS: Monopolar review helped to detect the best therapeutic contact in approximately 30% of patients exhibiting acute modulation of dystonic symptoms. Acute improvement, as well as worsening of dystonia, predicted a good long-term outcome, while induction of phosphenes did not correlate with outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT00142259.

Directional Deep Brain Stimulation.

Over the last years, deep brain stimulation has seen many technological innovations. New electrode designs allowing to direct the current flow not only in the vertical but also in the horizontal plane are the most recent. We summarize the concept of "directional deep brain stimulation" with its opportunities and challenges and the available study data and discuss the use of imaging techniques to assist programming deep brain stimulation devices.

Retinal changes in Parkinson's disease and glaucoma.

BACKGROUND: The topic of retinal neurodegeneration in PD is controversial, therefore the objective was to compare macular ganglion cell complex (mGCC) and peripapillary retinal nerve fiber layer (pRNFL) thickness in PD using 2 Spectral-Domain (SD) Optical Coherence Tomography (OCT) devices. METHODS: In total, 146 eyes of 130 age-similar patients were included, of these 46 eyes of 30 PD patients, 60 eyes of 60 glaucoma patients and 40 eyes of 40 healthy controls. Peripapillary RNFL and mGCC were measured. Correlation analyses were performed for evaluation of association between pRNFL or mGCC and PD severity using the Movement Disorder Society (MDS)-Unified Parkinson Disease Rating Scale (UPDRS). Scatterplots were used to evaluate relationships between disease duration, dopamine dose, olfactory assessment and retinal thickness. RESULTS: No significant difference was found for both eyes of PD patients compared to healthy subjects neither for overall mGCC nor each sector. However, the ipsilateral eye to the most-affected body side with bradykinesia in PD patients had a statistically significant thinner superior pRNFL compared to healthy controls (P = 0.03). There was no significant correlation between pRNFL or mGCC and disease severity; also, the scatterplots did not indicate a correlation between disease duration, dopamine dose, olfactory testing and OCT results. CONCLUSIONS: Imaging of the retina revealed thinning of some retinal layers of the ipsilateral eye to the most-affected body side in PD patients compared to healthy controls. Peripapillary RNFL and mGCC did not correlate to disease severity; however, this was a fairly small and heterogeneous group of PD patients.

Anodic versus cathodic neurostimulation of the subthalamic nucleus: A randomized-controlled study of acute clinical effects.

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 ±â€¯1.58 mA vs. 1.99 ±â€¯1.37 mA; 6.05 ±â€¯1.52 mA vs. 4.15 ±â€¯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.

Pulse duration settings in subthalamic stimulation for Parkinson's disease.

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.

Movement-Related Activity of Human Subthalamic Neurons during a Reach-to-Grasp Task.

The aim of the study was to record movement-related single unit activity (SUA) in the human subthalamic nucleus (STN) during a standardized motor task of the upper limb. We performed microrecordings from the motor region of the human STN and registered kinematic data in 12 patients with Parkinson's disease (PD) undergoing deep brain stimulation surgery (seven women, mean age 62.0 ± 4.7 years) while they intraoperatively performed visually cued reach-to-grasp movements using a grip device. SUA was analyzed offline in relation to different aspects of the movement (attention, start of the movement, movement velocity, button press) in terms of firing frequency, firing pattern, and oscillation. During the reach-to-grasp movement, 75/114 isolated subthalamic neurons exhibited movement-related activity changes. The largest proportion of single units showed modulation of firing frequency during several phases of the reach and grasp (polymodal neurons, 45/114), particularly an increase of firing rate during the reaching phase of the movement, which often correlated with movement velocity. The firing pattern (bursting, irregular, or tonic) remained unchanged during movement compared to rest. Oscillatory single unit firing activity (predominantly in the theta and beta frequency) decreased with movement onset, irrespective of oscillation frequency. This study shows for the first time specific, task-related, SUA changes during the reach-to-grasp movement in humans.

Striatal Dopaminergic Innervation Regulates Subthalamic Beta-Oscillations and Cortical-Subcortical Coupling during Movements: Preliminary Evidence in Subjects with Parkinson's Disease.

Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the functional interaction of cortical and subcortical brain areas during movement and the relative contribution of dopaminergic striatal innervation remains unclear. We recorded local field potential (LFP) activity from the subthalamic nucleus (STN) and high-density electroencephalography (EEG) signals in four patients with Parkinson's disease (PD) off dopaminergic medication during a multi-joint motor task performed with their dominant and non-dominant hand. Recordings were performed by means of a fully-implantable deep brain stimulation (DBS) device at 4 months after surgery. Three patients also performed a single-photon computed tomography (SPECT) with [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane (FP-CIT) to assess striatal dopaminergic innervation. Unilateral movement execution led to event-related desynchronization (ERD) followed by a rebound after movement termination event-related synchronization (ERS) of oscillatory beta activity in the STN and primary sensorimotor cortex of both hemispheres. Dopamine deficiency directly influenced movement-related beta-modulation, with greater beta-suppression in the most dopamine-depleted hemisphere for both ipsi- and contralateral hand movements. Cortical-subcortical, but not interhemispheric subcortical coherencies were modulated by movement and influenced by striatal dopaminergic innervation, being stronger in the most dopamine-depleted hemisphere. The data are consistent with a role of dopamine in shielding subcortical structures from an excessive cortical entrapment and cross-hemispheric coupling, thus allowing fine-tuning of movement.

Distinctive neuronal firing patterns in subterritories of the subthalamic nucleus.

OBJECTIVE: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established treatment for Parkinson's disease (PD). Anatomical connectivity analyses and task-related physiological studies have divided the STN into different functional domains: sensorimotor, limbic, and associative - located in its dorsolateral (dSTN), anteroventral (vSTN) and medial territories, respectively. Targeting sensorimotor STN is essential for stimulation efficacy and is supported by intraoperative micro-electrode recordings. A different neuronal signature in microelectrode recordings across STN subterritories was explored in this study. METHODS: Stable recordings from 30 PD patients were assigned to dSTN or vSTN by means of an anatomical method (based on fused computed tomography/magnetic resonance images) and through a priori tri-segmented partition of the recording itself. We computed the inter-spike interval (ISI) and ISI-characteristics, mean firing rate (MFR), discharge patterns and mean burst rate (MBR) of each detected single unit activity. RESULTS: We showed a different MBR between dSTN and vSTN (1.51±0.18 vs. 1.76±0.22events/minute, Wilcoxon rank sum test, p<0.05) and a trend in the difference between their MFR (12.78 vs. 15.05Hz, Wilcoxon rank sum test, p=0.053) only with the anatomically based method. CONCLUSION: Burst firing differs across STN subterritories. SIGNIFICANCE: Different functions of subthalamic domains might be reflected by distinctive burst signalling of its subterritories.