Subthalamic Nucleus Deep Brain Stimulation Research Articles

Changes in Anticholinergic Burden in Parkinson’s Disease After Deep Brain Stimulation

ObjectiveThis study aimed to evaluate the effect of deep brain stimulation (DBS) on anticholinergic burden in Parkinson’s disease (PD) and the association of anticholinergic burden with cognition. Materials and MethodsA retrospective chart review in patients with PD who underwent bilateral subthalamic nucleus (STN) or globus pallidus internus (GPi) DBS from 2010 to 2020 reviewed medications with anticholinergic burden at baseline, six months, and one year (N = 216) after surgery. The cumulative anticholinergic burden at each visit was calculated using the Anticholinergic Risk Scale (ARS). ResultsARS scores were significantly lower for patients six months and one year after surgery than at baseline (z = 6.58, p < 0.0001; z = 6.99, p < 0.0001). Change in ARS scores at both six months and one year were driven by down-titration of PD medications (z = 9.35, p < 0.0001; z = 8.61, p < 0.0001), rather than changes in pain, psychiatric, or urinary medications with anticholinergic effects. There was no significant difference in change in ARS scores at one year between targets (t = 0.41, p = 0.68). In addition, there was no significant association between anticholinergic burden and cognitive performance. ConclusionGPi and STN DBS are associated with decreased anticholinergic burden due to PD medications in the first year after surgery.

Sjogren's syndrome meets Meige's syndrome

This report details a rare case where a patient simultaneously suffered from Sjogren's syndrome (SS) and Meige's syndrome (MS). SS, an autoimmune disorder, and MS, a rare neurological condition characterized by involuntary eyelid closure, presented in a 73-year-old male. The patient had been experiencing dry eye symptoms for the past 5 years, with the onset of eyelid spasms and tetanic eye closure occurring 3 years ago. Traditional treatments, including subthalamic nucleus deep brain stimulation, provided only temporary relief. Diagnostic evaluations, including blood tests and imaging, confirmed SS and MS coexistence. Treatment involved a combination of steroids, immunosuppressants, and immunoglobulin, leading to significant symptom relief. This case suggests a potential association between SS and the development of MS, highlighting the importance of immunomodulatory therapy in managing neurological symptoms. Further research is needed to explore the relationship between these two conditions and to develop more effective treatment strategies.

The Related Factors and Effect of Electrode Displacement on Motor Outcome of Subthalamic Nuclei Deep Brain Stimulation in Parkinson's Disease.

Previous studies have revealed the existence of electrode displacement during subthalamic nucleus deep brain stimulation (STN-DBS). However, the effect of electrode displacement on treatment outcomes is still unclear. In this study, we aimed to analyze the related factors of electrode displacement and assess postoperative electrode displacement in relation to the motor outcomes of STN-DBS. A total of 88 patients aged 62.73 ± 6.35 years (55 males and 33 females) with Parkinson's disease undergoing STN-DBS, with comprehensive clinical characterization before and 1 month after surgery, were involved retrospectively and divided into a cross-incision group and cannula puncture group according to different dura opening methods. The electrode displacement, unilateral pneumocephalus volume percent (uPVP), and brain volume percent were estimated. A significant anterior and lateral electrode displacement was observed among all implanted electrodes after pneumocephalus absorption (p < 0.0001). The degree of electrode displacement was positively correlated with the uPVP (p = 0.005) and smaller in females than males (p = 0.0384). Electrode displacement was negatively correlated with motor improvement following STN-DBS in both on-medication and off-medication conditions (p < 0.05). Dural puncture reduced the uPVP (p < 0.0001) and postoperative electrode displacement (p = 0.0086) compared with dural incision. Electrode displacement had a negative impact on the therapeutic efficacy of STN-DBS. Opening the dura via cannula puncture is recommended to increase the accuracy of the lead implantation.

Does Impaired Plantar Cutaneous Vibration Perception Contribute to Axial Motor Symptoms in Parkinson's Disease? Effects of Medication and Subthalamic Nucleus Deep Brain Stimulation.

To investigate whether impaired plantar cutaneous vibration perception contributes to axial motor symptoms in Parkinson's disease (PD) and whether anti-parkinsonian medication and subthalamic nucleus deep brain stimulation (STN-DBS) show different effects. Three groups were evaluated: PD patients in the medication "on" state (PD-MED), PD patients in the medication "on" state and additionally "on" STN-DBS (PD-MED-DBS), as well as healthy subjects (HS) as reference. Motor performance was analyzed using a pressure distribution platform. Plantar cutaneous vibration perception thresholds (VPT) were investigated using a customized vibration exciter at 30 Hz. Motor performance of PD-MED and PD-MED-DBS was characterized by greater postural sway, smaller limits of stability ranges, and slower gait due to shorter strides, fewer steps per minute, and broader stride widths compared to HS. Comparing patient groups, PD-MED-DBS showed better overall motor performance than PD-MED, particularly for the functional limits of stability and gait. VPTs were significantly higher for PD-MED compared to those of HS, which suggests impaired plantar cutaneous vibration perception in PD. However, PD-MED-DBS showed less impaired cutaneous vibration perception than PD-MED. PD patients suffer from poor motor performance compared to healthy subjects. Anti-parkinsonian medication in tandem with STN-DBS seems to be superior for normalizing axial motor symptoms compared to medication alone. Plantar cutaneous vibration perception is impaired in PD patients, whereas anti-parkinsonian medication together with STN-DBS is superior for normalizing tactile cutaneous perception compared to medication alone. Consequently, based on our results and the findings of the literature, impaired plantar cutaneous vibration perception might contribute to axial motor symptoms in PD.

The advantages of general anesthesia subthalamic deep brain stimulation for Parkinson's disease in the enhanced recovery after surgery: A randomized clinical trial.

With advancements in imaging and microelectrode recording techniques, general anesthesia (GA) has emerged as an alternative option for Parkinson's disease (PD) patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS). In this study, we compared the advantages and disadvantages of using GA and local anesthesia for STN-DBS in enhanced recovery after surgery (ERAS). Surgical outcomes of STN-DBS were evaluated using the unified PD rating scales (UPDRS). CT and magnetic resonance imaging scans are used to evaluate intracranial conditions. State-trait anxiety inventory and hospital anxiety and depression scale are used to evaluate patients' perioperative psychology. Anesthesia method does not significantly impact the accuracy of microelectrode placement or the improvement of postoperative symptoms. However, the local anesthesia group had a higher incidence of intracranial air, as well as higher rates of postoperative complications such as headache, dizziness, vomiting, and delirium. GA effectively alleviated preoperative anxiety and resulted in lower levels of perioperative anxiety and psychological stress compared to local anesthesia. Additionally, the GA group had shorter surgery duration, earlier ambulation, and a shorter average hospital stay. DBS under GA is safe and effective. Due to shorter surgical duration, reduced occurrence of perioperative complications, effective reduction of preoperative anxiety, and faster postoperative recovery, DBS under GA is better aligned with the concept of ERAS.

Long-term follow-up of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease: An analysis of survival and disability milestones

BackgroundData on the long-term survival and incidence of disability milestones after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) is limited. ObjectivesTo estimate mortality and assess the frequency/time-to-development of disability milestones (falls, freezing, hallucinations, dementia, and institutionalization) among PD patients post STN-DBS. MethodsA longitudinal retrospective study of patients undergoing STN-DBS. For mortality, Cox proportional hazards regression analysis was performed. For disease milestones, competing risk analyses were performed and cumulative incidence functions reported. The strength of association between baselines features and event occurrence was calculated based on adjusted hazard ratios. ResultsThe overall mortality for the 109 patients was 16 % (62.1 ± 21.3 months after surgery). Falls (73 %) and freezing (47 %) were both the earliest (40.4 ± 25.4 and 39.6 ± 28.4 months, respectively) and most frequent milestones. Dementia (34 %) and hallucinations (32 %) soon followed (56.2 ± 21.2 and mean 60.0 ± 20.7 months after surgery, respectively). Higher ADL scores in the OFF state and higher age at surgery were associated with falls, freezing, dementia and institutionalization. ConclusionsLong-term mortality rate is low after STN-DBS. Disease milestones occur later during the disease course, with motor milestones appearing first and at a higher frequency than cognitive ones.

Subthalamic nucleus deep brain stimulation in primary Meige syndrome: motor and non-motor outcomes.

Deep brain stimulation (DBS) has emerged as a promising treatment for movement disorders. This prospective study aims to evaluate the effects of bilateral subthalamic nucleus DBS (STN-DBS) on motor and non-motor symptoms in patients with primary Meige syndrome. Thirty patients who underwent bilateral STN-DBS between April 2017 and June 2020 were included. Standardized and validated scales were utilized to assess the severity of dystonia, health-related quality of life, sleep, cognitive function and mental status at baseline and at 1 year and 3 years after neurostimulation. The Burke-Fahn-Marsden Dystonia Rating Scale movement scores showed a mean improvement of 63.0% and 66.8% at 1 year and 3 years, respectively, after neurostimulation. Similarly, the Burke-Fahn-Marsden Dystonia Rating Scale disability scores improved by 60.8% and 63.3% at the same time points. Postoperative quality of life demonstrated a significant and sustained improvement throughout the follow-up period. However, cognitive function, mental status, sleep quality and other neuropsychological functions did not change after 3 years of neurostimulation. Eight adverse events occurred in six patients, but no deaths or permanent sequelae were reported. Bilateral STN-DBS is a safe and effective alternative treatment for primary Meige syndrome, leading to improvements in motor function and quality of life. Nevertheless, it did not yield significant amelioration in cognitive, mental, sleep status and other neuropsychological functions after 3 years of neurostimulation.

Cognitive Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease with GBA1 Pathogenic Variants.

Genetic subtyping of patients with Parkinson's disease (PD) may assist in predicting the cognitive and motor outcomes of subthalamic deep brain stimulation (STN-DBS). Practical questions were recently raised with the emergence of new data regarding suboptimal cognitive outcomes after STN-DBS in individuals with PD associated with pathogenic variants in glucocerebrosidase gene (GBA1-PD). However, a variety of gaps and controversies remain. (1) Does STN-DBS truly accelerate cognitive deterioration in GBA1-PD? If so, what is the clinical significance of this acceleration? (2) How should the overall risk-to-benefit ratio of STN-DBS in GBA1-PD be established? (3) If STN-DBS has a negative effect on cognition in GBA1-PD, how can this effect be minimized? (4) Should PD patients be genetically tested before STN-DBS? (5) How should GBA1-PD patients considering STN-DBS be counseled? We aim to summarize the currently available relevant data and detail the gaps and controversies that exist pertaining to these questions. In the absence of evidence-based data, all authors strongly agree that clinicians should not categorically deny DBS to PD patients based solely on genotype (GBA1 status). We suggest that PD patients considering DBS may be offered genetic testing for GBA1, where available and feasible, so the potential risks and benefits of STN-DBS can be properly weighed by both the patient and clinician. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

White matter connectivity of subthalamic nucleus and globus pallidus interna targets for deep brain stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) have differential therapeutic effects for Parkinson's disease (PD) that drive patient selection. For example, GPi DBS is preferred for dystonic features and dyskinesia, whereas STN DBS has shown faster tremor control and medication reduction. Connectivity studies comparing these two targets, using patient-specific data, are still lacking. The objective was to find STN and GPi structural connectivity patterns in order to better understand differences in DBS-activated brain circuits between these two stimulation targets and to guide optimal contact selection. The authors simulated DBS activation along the main axis of both the STN and GPi by using volume of activated tissue (VAT) modeling with known average stimulation parameters (2.8 V and 60 μsec for STN; 3.3 V and 90 μsec for GPi). The authors modeled VATs in the anterior, middle, and posterior STN and the anterior, midanterior, midposterior, and posterior GPi. The authors generated maps of the connections shared by the patients for each VAT by using probabilistic tractography of diffusion-weighted imaging data obtained in 46 PD patients who underwent DBS (26 with STN and 20 with GPi targeting), and differences between VATs for whole-brain and distal regions of interest (prefrontal cortex, supplementary motor area, primary motor cortex, primary sensory cortex, caudate, motor thalamus, and cerebellum) were generated from structural atlases. Differences between maps were quantified and compared. VATs across the STN and GPi had different structural connectivity patterns. The authors found significant connectivity differences between VATs for all regions of interest. Posterior and middle STN showed stronger connectivity to the primary motor cortex and supplementary motor area (SMA) (p < 0.001). Posterior STN had the strongest connectivity to the primary sensory cortex and motor thalamus (p < 0.001). Posterior GPi showed stronger connectivity to the primary motor cortex (p < 0.001). Connectivity to the SMA was similar for the posterior and midposterior GPi (p > 0.05), which was greater than that for the anterior GPi (p < 0.001). When both nuclei were compared, posterior and middle STN had stronger connectivity to the SMA, cerebellum, and motor thalamus than GPi (all p < 0.001). Posterior GPi and STN had similar connectivity to the primary sensory cortex. On patient-specific imaging, structural connectivity differences existed between GPi and STN DBS, as measured with standardized electrical field modeling of the DBS targets. These connectivity differences may correlate with the differential clinical benefits obtained by targeting each of the two nuclei with DBS for PD. Prospective work is needed to relate these differences to clinical outcomes and to inform targeting and programming.

6 Improved verbal fluency following unilateral right hemisphere subthalamic nucleus deep brain stimulation for Parkinson’s disease: Is implant hemisphere a modifiable risk factor for cognitive decline?

Objective:Non-motor symptoms, such as mild cognitive impairment and dementia, are an overwhelming cause of disability in Parkinson’s disease (PD). While subthalamic nucleus deep brain stimulation (STN DBS) is safe and effective for motor symptoms, declines in verbal fluency after bilateral DBS surgery have been widely replicated. However, little is known about cognitive outcomes following unilateral surgeries.Participants and Methods:We enrolled 31 PD patients who underwent unilateral STN-DBS in a randomized, cross-over, double-blind study (SUNDIAL Trial). Targets were chosen based on treatment of the most symptomatic side (n = 17 left hemisphere and 14 right hemisphere). All participants completed a neuropsychological battery (FAS/CFL, AVLT, DKEFS Color-Word Test) at baseline, then 2, 4, and 6 months post-surgery. Outcomes include raw scores for verbal fluency, immediate and delayed recall, and DKEFS Color-Word Inhibition trial (Trial 3) completion time. At 2, 4, and 6 months, the neurostimulation type (directional versus ring mode) was randomized for each participant. We compared baseline scores for all cognitive outcome measures using Welch’s two-sample t-tests and used linear mixed effects models to examine longitudinal effects of hemisphere and stimulation on cognition. This test battery was converted to a teleneuropsychology administration because of COVID-19 mid-study, and this was included as a covariate in all statistical models, along with years of education, baseline cognitive scores, and levodopa equivalent medication dose at each time point.Results:At baseline, patients who underwent left hemisphere implants scored lower on verbal fluency than right implants (t(20.66) = -2.49, p = 0.02). There were not significant differences between hemispheres in immediate recall (p = 0.57), delayed recall (p = 0.22), or response inhibition (p = 0.51). Post-operatively, left STN DBS patients experienced significant declines in verbal fluency over the study period (p = 0.02), while patients with right-sided stimulation demonstrated improvements (p &lt; .001). There was no main effect of stimulation parameters (directional versus ring) on verbal fluency, memory, or inhibition, but there was a three-way interaction between time, stimulation parameters, and hemisphere on inhibition, such that left STN DBS patients receiving ring stimulation completed the inhibition trial faster (p = 0.035). After surgery, right STN DBS patients displayed faster inhibition times than patients with left implants (p = 0.015).Conclusions:Declines in verbal fluency after bilateral stimulation are the most commonly reported cognitive sequalae of DBS for movement disorders. Here we found group level declines in verbal fluency after unilateral left STN implants, but not right STN DBS up to 6 months after surgery. Patients with right hemisphere implants displayed improvements in verbal fluency. Compared to bilateral DBS, unilateral DBS surgery, particularly in the right hemisphere, is likely a modifiable risk factor for verbal fluency declines in patients with Parkinson’s disease.

Anatomical substrates and connectivity for bradykinesia motor features in Parkinson's disease after subthalamic nucleus deep brain stimulation.

Parkinsonian bradykinesia is rated using a composite scale incorporating the slowed frequency of repetitive movements, decrement amplitude and arrhythmicity. Differential localization of these movement components within the basal ganglia will drive the development of more personalized network-targeted symptomatic therapies. In this study, using an optical motion sensor, we evaluated the amplitude and frequency of hand movements during a grasping task with subthalamic nucleus deep brain stimulation 'on' or 'off' in 15 patients with Parkinson's disease. The severity of bradykinesia was assessed blindly using the Unified Parkinson's Disease Rating Part III scale. The volumes of activated tissue of each subject were estimated where changes in amplitude and frequency were mapped to identify distinct anatomical substrates of each component in the subthalamic nucleus. The volumes of activated tissue were used to seed a normative functional connectome to generate connectivity maps associated with amplitude and frequency changes. Deep brain stimulation-induced change in amplitude was negatively correlated with a change in Unified Parkinson's Disease Rating Part III scale for right (r = -0.65, P < 0.05) and left hand grasping scores (r = -0.63, P < 0.05). The change in frequency was negatively correlated with amplitude for both right (r = -0.63, P < 0.05) and left hands (r = -0.57, P < 0.05). The amplitude and frequency changes were represented as a spatial gradient with overlapping and non-overlapping regions spanning the anteromedial-posterolateral axis of the subthalamic nucleus. Whole-brain correlation maps between functional connectivity and motor changes were also inverted between amplitude and frequency changes. Deep brain stimulation-associated changes in frequency and amplitude were topographically and distinctly represented both locally in the subthalamic nucleus and in whole-brain functional connectivity.

Premature drug reduction after subthalamic nucleus deep brain stimulation leading to worse depression in patients with Parkinson's disease

BackgroundReduction of medication in Parkinson's disease (PD) following subthalamic nucleus deep brain stimulation (STN-DBS) has been recognized, but the optimal timing for medication adjustments remains unclear, posing challenges in postoperative patient management.ObjectiveThis study aimed to provide evidence for the timing of medication reduction post-DBS using propensity score matching (PSM).MethodsIn this study, initial programming and observation sessions were conducted over 1 week for patients 4–6 weeks postoperatively. Patients were subsequently categorized into medication reduction or non-reduction groups based on their dyskinesia evaluation using the 4.2-item score from the MDS-UPDRS-IV. PSM was employed to maintain baseline comparability. Short-term motor and neuropsychiatric symptom assessments for both groups were conducted 3–6 months postoperatively.ResultsA total of 123 PD patients were included. Baseline balance in motor and non-motor scores was achieved between the two groups based on PSM. Short-term efficacy revealed a significant reduction in depression scores within the non-reduction group compared to baseline (P &amp;lt; 0.001) and a significant reduction compared to the reduction group (P = 0.037). No significant differences were observed in UPDRS-III and HAMA scores between the two groups. Within-group analysis showed improvements in motor symptoms, depression, anxiety, and subdomains in the non-reduction group, while the reduction group exhibited improvements only in motor symptoms.ConclusionThis study provides evidence for the timing of medication reduction following DBS. Our findings suggest that early maintenance of medication stability is more favorable for improving neuropsychiatric symptoms.

Temporally non-regular patterns of deep brain stimulation (DBS) enhance assessment of evoked potentials while maintaining motor symptom management in Parkinson's disease (PD)

BackgroundTraditional deep brain stimulation (DBS) at fixed regular frequencies (>100 Hz) is effective in treating motor symptoms of Parkinson's disease (PD). Temporally non-regular patterns of DBS are a new parameter space that may help increase efficacy and efficiency. ObjectiveTo compare the effects of temporally non-regular patterns of DBS to traditional regularly-spaced pulses. MethodsWe simultaneously recorded local field potentials (LFP) and monitored motor symptoms (tremor and bradykinesia) in persons with PD during DBS in subthalamic nucleus (STN). We quantified both oscillatory activity and DBS local evoked potentials (DLEPs) from the LFP. ResultsTemporally non-regular patterns were as effective as traditional pulse patterns in modulating motor symptoms, oscillatory activity, and DLEPs. Moreover, one of our novel patterns enabled recording of longer duration DLEPs during clinically effective stimulation. ConclusionsStimulation gaps of 50 ms can be used to increase efficiency and to enable regular assessment of long-duration DLEPs while maintaining effective symptom management. This may be a promising paradigm for closed-loop DBS with biomarker assessment during the gaps.

Subthalamic nucleus physiology is correlated with deep brain stimulation motor and non-motor outcomes.

Subthalamic nucleus deep brain stimulation is commonly indicated for symptomatic relief of idiopathic Parkinson's disease. Despite the known improvement in motor scores, affective, cognitive, voice and speech functions might deteriorate following this procedure. Recent studies have correlated motor outcomes with intraoperative microelectrode recordings. However, there are no microelectrode recording-based tools with predictive values relating to long-term outcomes of integrative motor and non-motor symptoms. We conducted a retrospective analysis of the outcomes of patients with idiopathic Parkinson's disease who had subthalamic nucleus deep brain stimulation at Tel Aviv Sourasky Medical Centre (Tel Aviv, Israel) during 2015-2016. Forty-eight patients (19 women, 29 men; mean age, 58 ± 8 years) who were implanted with a subthalamic nucleus deep brain stimulation device underwent pre- and postsurgical assessments of motor, neuropsychological, voice and speech symptoms. Significant improvements in all motor symptoms (except axial signs) and levodopa equivalent daily dose were noted in all patients. Mild improvements were observed in more posterior-related neuropsychological functions (verbal memory, visual memory and organization) while mild deterioration was observed in frontal functions (personality changes, executive functioning and verbal fluency). The concomitant decline in speech intelligibility was mild and only partial, probably in accordance with the neuropsychological verbal fluency results. Acoustic characteristics were the least affected and remained within normal values. Dimensionality reduction of motor, neuropsychological and voice scores rendered six principal components that reflect the main clinical aspects: the tremor-dominant versus the rigidity-bradykinesia-dominant motor symptoms, frontal versus posterior neuropsychological deficits and acoustic characteristics versus speech intelligibility abnormalities. Microelectrode recordings of subthalamic nucleus spiking activity were analysed off-line and correlated with the original scores and with the principal component results. Based on 198 microelectrode recording trajectories, we suggest an intraoperative subthalamic nucleus deep brain stimulation score, which is a simple sum of three microelectrode recording properties: normalized neuronal activity, the subthalamic nucleus width and the relative proportion of the subthalamic nucleus dorsolateral oscillatory region. A threshold subthalamic nucleus deep brain stimulation score >2.5 (preferentially composed of normalized root mean square >1.5, subthalamic nucleus width >3 mm and a dorsolateral oscillatory region/subthalamic nucleus width ratio >1/3) predicts better motor and non-motor long-term outcomes. The algorithm presented here optimizes intraoperative decision-making of deep brain stimulation contact localization based on microelectrode recording with the aim of improving long-term (>1 year) motor, neuropsychological and voice symptoms.

Directional versus ring-mode deep brain stimulation for Parkinson’s disease: protocol of a multi-centre double-blind randomised crossover trial

BackgroundThe effectiveness of Deep Brain Stimulation (DBS) therapy for Parkinson’s disease can be limited by side-effects caused by electrical current spillover into structures adjacent to the target area. The objective of the STEEred versus RING-mode DBS for Parkinson’s disease (STEERING) study is to investigate if directional DBS for Parkinson’s disease results in a better clinical outcome when compared to ring-mode DBS.MethodsThe STEERING study is a prospective multi-centre double-blind randomised crossover trial. Inclusion criteria are Parkinson’s disease, subthalamic nucleus DBS in a ‘classic’ ring-mode setting for a minimum of six months, and optimal ring-mode settings have been established. Participants are categorised into one of two subgroups according to their clinical response to the ring-mode settings as ‘responders’ (i.e., patient with a satisfactory effect of ring-mode DBS) or ‘non-responder’ (i.e., patient with a non-satisfactory effect of ring-mode DBS). A total of 64 responders and 38 non-responders will be included (total 102 patients). After an optimisation period in which an optimal directional setting is found, participants are randomised to first receive ring-mode DBS for 56 days (range 28–66) followed by directional DBS for 56 days (28–66) or vice-versa. The primary outcome is the difference between ring-mode DBS and directional DBS settings on the Movement Disorders Society Unified Parkinson’s Disease Rating Scale – Motor Evaluation (MDS-UPDRS-ME) in the off-medication state. Secondary outcome measures consist of MDS-UPDRS-ME in the on-medication state, MDS-UPDRS Activities of Daily Living, MDS-UPDRS Motor Complications–Dyskinesia, disease related quality of life measured with the Parkinson’s Disease Questionnaire 39, stimulation-induced side-effects, antiparkinsonian medication use, and DBS-parameters. Participants’ therapy preference is measured at the end of the study. Outcomes will be analysed for both responder and non-responder groups, as well as for both groups pooled together.DiscussionThe STEERING trial will provide insights into whether or not directional DBS should be standardly used in all Parkinson’s disease DBS patients or if directional DBS should only be used in a case-based approach.Trial registrationThis trial was registered on the Netherlands Trial Register, as trial NL6508 (NTR6696) on June 23, 2017.

Decreased bladder contraction interval induced by periaqueductal grey stimulation is reversed by subthalamic stimulation in a Parkinson’s disease model rat

The medial prefrontal cortex (mPFC) regulates bladder contractions via the periaqueductal grey (PAG). Subthalamic nucleus deep brain stimulation (STN-DBS) modulates urinary afferent information from PAG in Parkinson’s disease (PD). We do not know how STN-DBS modulates the activities of mPFC induced by PAG stimulation. We aim to clarify how STN-DBS modulates the neuronal activity of mPFC induced by PAG stimulation and its effects on bladder contraction Experiments were conducted under urethane anesthesia in normal (n = 9) and 6-hydroxydopamine hemi-lesioned PD rats (n = 7). Left-sided PAG stimulation and STN-DBS were applied with simultaneous bladder contraction monitoring. Local field potential (LFP) recording and collection of extracellular fluid in the mPFC were performed before stimulation, during PAG stimulation, during PAG+STN stimulation, and after stimulation. The bladder inter-contraction intervals significantly decreased with PAG stimulation with a concomitant decrease in mPFC LFP power in PD rats. Adding STN stimulation to PAG stimulation significantly increased the bladder inter-contraction intervals with a concomitant increase in mPFC LFP power in PD rats. Several mPFC catecholamine levels were modulated by PAG or PAG+STN stimulation in PD rats. The present study revealed that STN-DBS modulate the activities of mPFC induced by PAG, thereby leading to normalization of bladder contraction.

Spinal cord stimulation for gait impairment in Parkinson Disease: scoping review and mechanistic considerations.

Advanced Parkinson's Disease (PD) is associated with Parkinson's Disease gait impairment (PDg), which increases the risk for falls and is often treatment-refractory. Subthalamic nucleus (STN) and globus pallidus pars interna (GPi) deep brain stimulation (DBS) often fails to improve axial symptoms like PDg. Spinal cord stimulation (SCS) has been suggested to improve PDg. SCS may benefit PDg by disrupting pathologic beta-oscillations and hypersynchrony in cortico-striatal-thalamic circuits to override excessive inhibition of brainstem locomotor regions. SCS may potentially improve locomotion by acting at any of these levels, either alone or in combination. We conducted a comprehensive literature search and scoping review, identifying 106 patients in whom SCS was evaluated for PDg. Among the identified patients, 63% carried a pain diagnosis. Overall, the most common stimulation location was thoracic (78%), most commonly T9-T10. Burst (sub-perception) was the most common stimulation modality (59%). Prior treatment with DBS was used in 25%. Motor outcomes were assessed by the Unified Parkinson Disease Rating Scale (UPDRS) III-motor, UPDRS, the Timed Up and Go (TUG), and/or 10-/20-meter walking tests.Among these patients, 95 (90%) had PDg amelioration and improved motor outcomes. Despite small sample sizes, patient heterogeneity, and unblinded evaluations complicating interpretations of efficacy and safety, SCS may be beneficial for at least a subset of PDg. Further research is required to clarify the role of SCS for PDg and the patients most suitable to benefit from this intervention.

Selective Activation of Subthalamic Nucleus Output Quantitatively Scales Movements.

The subthalamic nucleus (STN) is a common target for deep brain stimulation (DBS) treatments of Parkinsonian motor symptoms. According to the dominant model, the STN output can suppress movement by enhancing inhibitory basal ganglia (BG) output via the indirect pathway, and disrupting STN output using DBS can restore movement in Parkinson's patients. But the mechanisms underlying STN DBS remain poorly understood, as previous studies usually relied on electrical stimulation, which cannot selectively target STN output neurons. Here, we selectively stimulated STN projection neurons using optogenetics and quantified behavior in male and female mice using 3D motion capture. STN stimulation resulted in movements with short latencies (10-15 ms). A single pulse of light was sufficient to generate movement, and there was a highly linear relationship between stimulation frequency and kinematic measures. Unilateral stimulation caused movement in the ipsiversive direction (toward the side of stimulation) and quantitatively determined head yaw and head roll, while stimulation of either STN raises the head (pitch). Bilateral stimulation does not cause turning but raised the head twice as high as unilateral stimulation of either STN. Optogenetic stimulation increased the firing rate of STN neurons in a frequency-dependent manner, and the increased firing is responsible for stimulation-induced movements. Finally, stimulation of the STN's projection to the brainstem mesencephalic locomotor region was sufficient to reproduce the behavioral effects of STN stimulation. These results question the common assumption that the STN suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem.SIGNIFICANCE STATEMENT Our results question the common assumption that the subthalamic nucleus (STN) suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem.

H - 57 Case Study: Chinese Older Adult with Parkinson Disease and Visual Impairment Presenting for Pre-Deep Brain Stimulation Evaluation.

We present a case in which intersecting linguistic and disability factors necessitated a flexible, qualitative approach to clinical decision making in the context of pre-deep brain stimulation (DBS) evaluation. LZ is a 70-year-old, right-handed, cisgender, Chinese male with history of Parkinson disease (PD) presenting for DBS evaluation. Symptoms included right extremity tremor with decreased effectiveness from dopamine therapy. Cognitive, behavioral, personality, or functional changes were denied. He had severe visual impairment due to macular degeneration and cataracts. LZ immigrated to the U.S. 30years prior and obtained a Ph.D. in Law. His English was not at the level of native speaker, but he declined use of an interpreter. Nevertheless, English proficiency was adequate to conduct testing. LZ's premorbid functioning was estimated as average. Scores on attention/working memory and verbal fluency were intact. Processing speed and auditory naming were below average. Memory performance was characterized by inefficient learning and intact recall. Executive functions were variable in verbal set switching and motor sequencing was intact. Typically, such a case with language/cultural differences would rely on more visuospatial than verbal tests; however, visual impairment necessitated reliance on verbal tests only. It was determined that variability of performances and low scores on naming were more likely attributable to language/cultural factors, and LZ was therefore deemed a good candidate for DBS surgery based on multiple intact cognitive abilities and strong social support. LZ received left subthalamic nucleus DBS. There was initial hemorrhagic complication during electrode placement resulting in language loss, which he recovered after five weeks.

Medication only improves limb movements while deep brain stimulation improves eye and limb movements during visually-guided reaching in Parkinson's disease.

Antiparkinson medication and subthalamic nucleus deep brain stimulation (STN-DBS), two common treatments of Parkinson's disease (PD), effectively improve skeletomotor movements. However, evidence suggests that these treatments may have differential effects on eye and limb movements, although both movement types are controlled through the parallel basal ganglia loops. Using a task that requires both eye and upper limb movements, we aimed to determine the effects of medication and STN-DBS on eye and upper limb movement performance. Participants performed a visually-guided reaching task. We collected eye and upper limb movement data from participants with PD who were tested both OFF and ON medication (n = 34) or both OFF and ON bilateral STN-DBS while OFF medication (n = 11). We also collected data from older adult healthy controls (n = 14). We found that medication increased saccade latency, while having no effect on reach reaction time (RT). Medication significantly decreased saccade peak velocity, while increasing reach peak velocity. We also found that bilateral STN-DBS significantly decreased saccade latency while having no effect on reach RT, and increased saccade and reach peak velocity. Finally, we found that there was a positive relationship between saccade latency and reach RT, which was unaffected by either treatment. These findings show that medication worsens saccade performance and benefits reaching performance, while STN-DBS benefits both saccade and reaching performance. We explore what the differential beneficial and detrimental effects on eye and limb movements suggest about the potential physiological changes occurring due to treatment.