At home adaptive dual target deep brain stimulation in Parkinson's disease with proportional control.

Continuous deep brain stimulation (cDBS) of the subthalamic nucleus (STN) or globus pallidus is an effective treatment for the motor symptoms of Parkinson's disease. The relative benefit of one region over the other is of great interest but cannot usually be compared in the same patient. Simultaneous DBS of both regions may synergistically increase the therapeutic benefit. Continuous DBS is limited by a lack of responsiveness to dynamic, fluctuating symptoms intrinsic to the disease. Adaptive DBS (aDBS) adjusts stimulation in response to biomarkers to improve efficacy, side effects, and efficiency. We combined bilateral DBS of both STN and globus pallidus (dual target DBS) in a prospective within-participant, clinical trial in six patients with Parkinson's disease (n = 6, 55-65 years, n = 2 females). Dual target cDBS was tested for Parkinson's disease symptom control annually over 2 years, measured by motor rating scales, on time without dyskinesia, and medication reduction. Random amplitude experiments probed system dynamics to estimate parameters for aDBS. We then implemented proportional-plus-integral aDBS using a novel distributed (off-implant) architecture. In the home setting, we collected tremor and dyskinesia scores as well as individualized ß and DBS amplitudes. Dual target cDBS reduced motor symptoms as measured by Unified Parkinson's Disease Rating Scale (UPDRS) to a greater degree than either region alone (P < 0.05, linear mixed model) in the cohort. The amplitude of ß-oscillations in the STN correlated to the speed of hand grasp movements for five of six participants (P < 0.05, Pearson correlation). Random amplitude experiments provided insight into temporal windowing to avoid stimulation artefacts and demonstrated a correlation between STN ß amplitude and DBS amplitude. Proportional plus integral control of aDBS reduced average power, while preserving UPDRS III scores in the clinic (P = 0.28, Wilcoxon signed rank), and tremor and dyskinesia scores during blinded testing at home (n = 3, P > 0.05, Wilcoxon ranked sum). In the home setting, DBS power reductions were slight but significant. Dual target cDBS may offer an improvement in treatment of motor symptoms of Parkinson's disease over DBS of either the STN or globus pallidus alone. When combined with proportional plus integral aDBS, stimulation power may be reduced, while preserving the increased benefit of dual target DBS.

Patient Experience with Rechargeable Implantable Pulse Generator Deep Brain Stimulation for Movement Disorders.

BACKGROUND/AIMS: Nonrechargeable deep brain stimulation implantable pulse generators (IPGs) for movement disorders require surgical replacement every few years due to battery depletion. Rechargeable IPGs reduce frequency of replacement surgeries and inherent risks of complications but require frequent recharging. Here, we evaluate patient experience with rechargeable IPGs and define predictive characteristics for higher satisfaction. METHODS: We contacted all patients implanted with rechargeable IPGs at a single center in a survey-based study. We analyzed patient satisfaction with respect to age, diagnosis, target, charging duration, and body mass index. We tabulated hardware-related adverse events. RESULTS: Dystonia patients had significantly higher satisfaction than Parkinson's disease patients in recharging, display, programmer, and training domains. Common positive responses were "fewer surgeries" and "small size." Common negative responses were "difficulty finding the right position to recharge" and "need to recharge every day." Hardware-related adverse events occurred in 21 of 59 participants. CONCLUSION: Patient experience with rechargeable IPGs was largely positive; however, frustrations with recharging and adverse events were common. Dystonia diagnosis was most predictive of high satisfaction across multiple categories, potentially related to expected long disease duration with need for numerous IPG replacements.

Comparative efficacy of surgical approaches to disease modification in Parkinson disease.

Parkinson's disease (PD) may optimally be treated with a disease-modifying therapy to slow progression. We compare data underlying surgical approaches proposed to impart disease modification in PD: (1) cell transplantation therapy with stem cell-derived dopaminergic neurons to replace damaged cells; (2) clinical trials of growth factors to promote survival of existing dopaminergic neurons; (3) subthalamic nucleus deep brain stimulation early in the course of PD; and (4) abdominal vagotomy to lower risk of potential disease spread from gut to brain. Though targeted to engage potential mechanisms of PD these surgical approaches remain experimental, indicating the difficulty in translating therapeutic concepts into clinical practice. The choice of outcome measures to assess disease modification separate from the symptomatic benefit will be critical to evaluate the effect of the disease-modifying intervention on long-term disease burden, including imaging studies and clinical rating scales, i.e., Unified Parkinson Disease Rating Scale. Therapeutic interventions will require long follow-up times (i.e., 5-10 years) to analyze disease modification compared to symptomatic treatments. The promise of invasive, surgical treatments to achieve disease modification through mechanistic approaches has been constrained by the reality of translating these concepts into effective clinical trials.

Benefits and Risks of a Staged-Bilateral VIM Versus Unilateral VIM DBS for Essential Tremor.

Background: Despite over 30 years of clinical experience, high-quality studies on the efficacy of bilateral versus unilateral deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus for medically refractory essential tremor (ET) remain limited. Objectives: To compare benefits and risks of bilateral versus unilateral VIM DBS using the largest ET DBS clinical trial dataset available to date. Methods: Participants from the US St. Jude/Abbott pivotal ET DBS trial who underwent staged-bilateral VIM implantation constituted the primary cohort in this sub-analysis. Their assessments "on" DBS at six months after second-side VIM DBS implantation were compared to the assessments six months after unilateral implantation. Two control cohorts of participants with unilateral implantation only were also used for between-group comparisons. Results: The primary cohort consisted of n = 38 ET patients (22M/16F; age of 65.3 ± 9.5 years). The second side VIM-DBS resulted in a 29.6% additional improvement in the total motor CRST score (P < 0.001), with a 64.1% CRST improvement in the contralateral side (P < 0.001). An added improvement was observed in the axial tremor score (21.4%, P = 0.005), and CRST part B (24.8%, P < 0.001) score. Rate of adverse events was slightly higher after bilateral stimulation. Conclusions: In the largest ET DBS study to date, staged-bilateral VIM DBS was a highly effective treatment for ET with bilateral implantation resulting in greater reduction in total motor tremor scores when compared to unilateral stimulation alone.

Initial Clinical Outcome With Bilateral, Dual-Target Deep Brain Stimulation Trial in Parkinson Disease Using Summit RC + S.

BACKGROUND: Deep brain stimulation (DBS) is an effective therapy in advanced Parkinson disease (PD). Although both subthalamic nucleus (STN) and globus pallidus (GP) DBS show equivalent efficacy in PD, combined stimulation may demonstrate synergism. OBJECTIVE: To evaluate the clinical benefit of stimulating a combination of STN and GP DBS leads and to demonstrate biomarker discovery for adaptive DBS therapy in an observational study. METHODS: We performed a pilot trial (n = 3) of implanting bilateral STN and GP DBS leads, connected to a bidirectional implantable pulse generator (Medtronic Summit RC + S; NCT03815656, IDE No. G180280). Initial 1-year outcome in 3 patients included Unified PD Rating Scale on and off medications, medication dosage, Hauser diary, and recorded beta frequency spectral power. RESULTS: Combined DBS improved PD symptom control, allowing >80% levodopa medication reduction. There was a greater decrease in off-medication motor Unified PD Rating Scale with multiple electrodes activated (mean difference from off stimulation off medications -18.2, range -25.5 to -12.5) than either STN (-12.8, range -20.5 to 0) or GP alone (-9, range -11.5 to -4.5). Combined DBS resulted in a greater reduction of beta oscillations in STN in 5/6 hemispheres than either site alone. Adverse events occurred in 2 patients, including a small cortical hemorrhage and seizure at 24 hours postoperatively, which resolved spontaneously, and extension wire scarring requiring revision at 2 months postoperatively. CONCLUSION: Patients with PD preferred combined DBS stimulation in this preliminary cohort. Future studies will address efficacy of adaptive DBS as we further define biomarkers and control policy.

Falling down the digital divide: A cautionary tale.

The disruptions of the coronavirus pandemic have enabled new opportunities for telehealth expansion within movement disorders. However, inadequate internet infrastructure has, unfortunately, led to fragmented implementation and may worsen disparities in some areas. In this Correspondence, we report on geographic and racial/ethnic disparities in access to our center's comprehensive care clinic for people with Parkinson's disease. While both in-person and virtual versions of the clinic enjoyed high patient satisfaction, we discovered that participation by Black/African-American individuals was cut in half when we shifted to a virtual delivery format in April 2020. We outline potential barriers in access using a socio-ecological model.

Treatment of diaphragmatic dystonia with pallidal deep brain stimulation.

We present the case of a 70-year-old woman with treatment-refractory diaphragmatic dystonia. Patient initially presented with blepharospasms followed by development of involuntary inspiratory spasms during speech. Her symptoms were drug-refractory, and she therefore underwent awake bilateral pallidal deep brain stimulation with microelectrode recording. No intraoperative or postoperative complications or adverse events occurred, and there were no undesired effects of stimulation. Using contacts in bilateral dorsal globus pallidus interna and ventral globus pallidus externa, symptoms alleviated after a latency period of 2-4 weeks. At 5-month follow-up, the patient maintained a 16.5-point reduction in Burke-Fahn-Marsden movement scale (from 20/120 to 3.5/120) with resolution of blepharospasm, irregular inspirations and broken and irregular speech.

The TOPAZ study: a home-based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism.

The Trial of Parkinson's And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414 ) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants' homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.

Surgical Treatment of Parkinson Disease.

Surgery in Parkinson disease is effective for a select group of patients when optimal medical management is not sufficient. Functional neurosurgery can be used as either a salvage therapy in patients with disabling symptoms or to maintain quality of life and independence before progression to severe disability in high-functioning patients. With recent technological advancements in imaging and targeting as well as novel neuromodulation paradigms, there are numerous options for targeted brain lesions and deep brain stimulation. Surgical decision making and postoperative management in Parkinson disease therefore often requires a multidisciplinary team effort with neurology, neurosurgery, neuropsychology, and psychiatry.

Smart neuromodulation in movement disorders.

Deep brain stimulation (DBS) is a technique for invasive subcortical neuromodulation using a totally implantable permanent device. DBS is an effective therapy for movement disorders and is under investigation for the treatment of many other conditions including Tourette syndrome, epilepsy, and depression. Traditional DBS is limited by labor-intensive manual programming, high current requirements, and lack of responsiveness to fluctuations in the patient's signs and symptoms. The field is moving toward adaptive closed loop systems with stimulation modulated by peripheral or intracranial sensors, a technique often described as "smart neuromodulation." Advances in the understanding of brain rhythms associated with specific neurologic symptoms and the introduction of novel bidirectional neural interfaces are facilitating investigative studies of closed loop stimulation in movement disorders. These studies suggest the potential for greater efficacy with fewer adverse effects. It may be possible to generalize the hardware platforms and control strategies developed to other brain disorders.

Bilateral Subthalamic Nucleus Deep Brain Stimulation in Elderly Patients With Parkinson Disease: A Case-Control Study.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an effective adjunctive therapy for Parkinson disease. Studies have shown improvement of motor function but often exclude patients older than 75 yr. OBJECTIVE: To determine the safety and effectiveness of STN DBS in patients 75 yr and older. METHODS: A total of 104 patients (52 patients >75 yr old, 52 patients <75 yr old) with STN DBS were paired and retrospectively analyzed. The primary outcome was change in Unified Parkinson Disease Rating Scale (UPDRS) subscale III at 1 yr postoperatively, OFF medication. Secondary outcomes were changes in UPDRS I, II, and IV subscales and levodopa equivalents. Complications and all-cause mortality were assessed at 30 d and 1 yr. RESULTS: Both cohorts had significant improvements in UPDRS III at 6 mo and 1 yr with no difference between cohorts. Change in UPDRS III was noninferior to the younger cohort. The cohorts had similar worsening in UPDRS I at 1 yr, no change in UPDRS II, similar improvement in UPDRS IV, and similar levodopa equivalent reduction. There were similar numbers of postoperative intracerebral hemorrhages (2/52 in each cohort, more severe in the older cohort) and surgical complications (4/52 in each cohort), and mortality in the older cohort was similar to an additional matched cohort not receiving DBS. CONCLUSION: STN DBS provides substantial motor benefit and reduction in levodopa equivalents with a low rate of complications in older patients, which is also noninferior to the benefit in younger patients. STN DBS remains an effective therapy for those over 75 yr.

Benefits and risks of unilateral and bilateral ventral intermediate nucleus deep brain stimulation for axial essential tremor symptoms.

INTRODUCTION: Many experts assume bilateral deep brain stimulation (DBS) is necessary to improve axial tremor in essential tremor (ET). In the largest clinical trial of DBS for ET to date evaluating a non-directional, constant current device, we studied the effects of unilateral and staged bilateral DBS on axial tremor. METHODS: We included all participants from the original trial with unilateral ventral intermediate nucleus (VIM) DBS and 90-day follow up at minimum. Primary outcomes were changes in pooled axial subscores in the Clinical Rating Scale for Tremor (CRST) at 90 and 180 days after activation of unilateral VIM DBS compared to pre-operative baseline (n=119). Additionally, we performed within-subject analyses for unilateral versus bilateral DBS at 180 days in the cohort who underwent staged surgery to bilateral DBS (n=39). RESULTS: Unilateral VIM DBS improved midline tremor by 58% at 90 days (median[IQR]) (3[3] to 1[2], p<0.001) and 65% at 180 days (3[3] to 1[2], p<0.001) versus pre-op baseline. In the staged to bilateral DBS cohort, midline tremor scores further improved after bilateral DBS at 180 days by 63% versus unilateral DBS (3[3] to 1[3], p=0.007). There were, however, 35 additional DBS and surgery-related adverse events, 14 related to incoordination, gait impairment, or speech impairment, versus 6 after unilateral DBS. CONCLUSION: Unilateral VIM DBS for ET significantly improved associated axial tremor. Staged bilateral DBS was associated with additional axial tremor improvement but also additional adverse events. Unilateral VIM DBS may be sufficient to achieve a goal of contralateral limb and axial tremor attenuation.

Automated Deep Brain Stimulation Programming for Tremor.

Deep brain stimulation (DBS) programming, the systematic selection of fixed electrical stimulation parameters that deliver maximal therapeutic benefit while limiting side effects, poses several challenges in the treatment of movement disorders. DBS programming requires the expertise of trained neurologists or nurses who assess patient symptoms according to standardized clinical rating scales and use patient reports of DBS-related side effects to adjust stimulation parameters and optimize therapy. In this paper, we describe and validate an automated software platform for DBS programming for tremor associated with Parkinson's disease and essential tremor. DBS parameters are changed automatically through a direct computer interface with implanted neurostimulators. Each tested DBS setting is ranked according to its effect on tremor, which is assessed using smartwatch inertial measurement unit data, and side effects, which are reported through a user interface. Blinded neurologist assessments showed the automated programming method performed at least as well as clinician mediated programming in selecting the optimal settings for tremor therapy. This proof of concept study describes a novel DBS programming paradigm that may improve programming efficiency and outcomes, increase access to programming outside specialty clinics, and aid in the development of adaptive and closed-loop DBS strategies.

Intractable Blepharospasm Treated with Bilateral Pallidal Deep Brain Stimulation.

BACKGROUND: Blepharospasm can be present as an isolated dystonia or in conjunction with other forms of cranial dystonia, causing significant disability. CASE REPORT: We report a case of a 69-year-old male with craniocervical dystonia, manifesting primarily as incapacitating blepharospasm refractory to medical treatments. He underwent bilateral globus pallidus (GP) deep brain stimulation (DBS) with complete resolution of his blepharospasm and sustained benefit at 12 months postoperatively. DISCUSSION: This case illustrates successful treatment of blepharospasm with pallidal stimulation. GP-DBS should be considered a reasonable therapeutic option for intractable blepharospasm.