Thalamic deep brain stimulation for acquired dystonia in children and young adults: a phase 1 clinical trial.

OBJECTIVE: The aim of this study was to evaluate the feasibility and preliminary efficacy and safety of combined bilateral ventralis oralis posterior/ventralis intermedius (Vop/Vim) deep brain stimulation (DBS) for the treatment of acquired dystonia in children and young adults. Pallidal DBS is efficacious for severe, medication-refractory isolated dystonia, providing 50%-60% long-term improvement. Unfortunately, pallidal stimulation response rates in acquired dystonia are modest and unpredictable, with frequent nonresponders. Acquired dystonia, most commonly caused by cerebral palsy, is more common than isolated dystonia in pediatric populations and is more recalcitrant to standard treatments. Given the limitations of pallidal DBS in acquired dystonia, there is a need to explore alternative brain targets. Preliminary evidence has suggested that thalamic stimulation may be efficacious for acquired dystonia. METHODS: Four participants, 3 with perinatal brain injuries and 1 with postencephalitic symptomatic dystonia, underwent bilateral Vop/Vim DBS and bimonthly evaluations for 12 months. The primary efficacy outcome was the change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS) scores between the baseline and 12-month assessments. Video documentation was used for blinded ratings. Secondary outcomes included evaluation of spasticity (Modified Ashworth Scale score), quality of life (Pediatric Quality of Life Inventory [PedsQL] and modified Unified Parkinson's Disease Rating Scale Part II [UPDRS-II] scores), and neuropsychological assessments. Adverse events were monitored for safety. RESULTS: All participants tolerated the procedure well, and there were no safety concerns or serious adverse events. There was an average improvement of 21.5% in the BFMDRS motor subscale score, but the improvement was only 1.6% according to the BADS score. Following blinded video review, dystonia severity ratings were even more modest. Secondary outcomes, however, were more encouraging, with the BFMDRS disability subscale score improving by 15.7%, the PedsQL total score by 27%, and the modified UPDRS-II score by 19.3%. Neuropsychological assessment findings were unchanged 1 year after surgery. CONCLUSIONS: Bilateral thalamic neuromodulation by DBS for severe, medication-refractory acquired dystonia was well tolerated. Primary and secondary outcomes showed highly variable treatment effect sizes comparable to those of pallidal stimulation in this population. As previously described, improvements in quality of life and disability were not reflected in dystonia severity scales, suggesting a need for the development of scales specifically for acquired dystonia.Clinical trial registration no.: NCT03078816 (clinicaltrials.gov).

Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study.

BACKGROUND: Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting. METHODS: We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases. RESULTS: Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi. CONCLUSION: The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities.

An Acute Randomized Controlled Trial of Noninvasive Peripheral Nerve Stimulation in Essential Tremor.

OBJECTIVE: To evaluate the safety and effectiveness of a wrist-worn peripheral nerve stimulation device in patients with essential tremor (ET) in a single in-office session. METHODS: This was a randomized controlled study of 77 ET patients who received either treatment stimulation (N = 40) or sham stimulation (N = 37) on the wrist of the hand with more severe tremor. Tremor was evaluated before and immediately after the end of a single 40-minute stimulation session. The primary endpoint compared spiral drawing in the stimulated hand using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) Archimedes spiral scores in treatment and sham groups. Additional endpoints included TETRAS upper limb tremor scores, subject-rated tasks from the Bain and Findley activities of daily living (ADL) scale before and after stimulation as well as clinical global impression-improvement (CGI-I) rating after stimulation. RESULTS: Subjects who received peripheral nerve stimulation did not show significantly larger improvement in the Archimedes spiral task compared to sham but did show significantly greater improvement in upper limb TETRAS tremor scores (p = 0.017) compared to sham. Subject-rated improvements in ADLs were significantly greater with treatment (49% reduction) than with sham (27% reduction; p = 0.001). A greater percentage of ET patients (88%) reported improvement in the stimulation group as compared to the sham group (62%) according to CGI-I ratings (p = 0.019). No significant adverse events were reported; 3% of subjects experienced mild adverse events. CONCLUSIONS: Peripheral nerve stimulation in ET may provide a safe, well-tolerated, and effective treatment for transient relief of hand tremor symptoms.

Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry.

Importance: Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome. Objective: To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome. Design, Setting, and Participants: The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide. Exposures: Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]). Main Outcomes and Measures: Scores on the Yale Global Tic Severity Scale and adverse events. Results: The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P < .001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P < .001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P < .001). The overall adverse event rate was 35.4% (56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Conclusions and Relevance: Deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.

Chronic multisite brain recordings from a totally implantable bidirectional neural interface: experience in 5 patients with Parkinson's disease.

OBJECTIVE Dysfunction of distributed neural networks underlies many brain disorders. The development of neuromodulation therapies depends on a better understanding of these networks. Invasive human brain recordings have a favorable temporal and spatial resolution for the analysis of network phenomena but have generally been limited to acute intraoperative recording or short-term recording through temporarily externalized leads. Here, the authors describe their initial experience with an investigational, first-generation, totally implantable, bidirectional neural interface that allows both continuous therapeutic stimulation and recording of field potentials at multiple sites in a neural network. METHODS Under a physician-sponsored US Food and Drug Administration investigational device exemption, 5 patients with Parkinson's disease were implanted with the Activa PC+S system (Medtronic Inc.). The device was attached to a quadripolar lead placed in the subdural space over motor cortex, for electrocorticography potential recordings, and to a quadripolar lead in the subthalamic nucleus (STN), for both therapeutic stimulation and recording of local field potentials. Recordings from the brain of each patient were performed at multiple time points over a 1-year period. RESULTS There were no serious surgical complications or interruptions in deep brain stimulation therapy. Signals in both the cortex and the STN were relatively stable over time, despite a gradual increase in electrode impedance. Canonical movement-related changes in specific frequency bands in the motor cortex were identified in most but not all recordings. CONCLUSIONS The acquisition of chronic multisite field potentials in humans is feasible. The device performance characteristics described here may inform the design of the next generation of totally implantable neural interfaces. This research tool provides a platform for translating discoveries in brain network dynamics to improved neurostimulation paradigms. Clinical trial registration no.: NCT01934296 (clinicaltrials.gov).

Thalamic DBS with a constant-current device in essential tremor: A controlled clinical trial.

INTRODUCTION: This study of thalamic deep brain stimulation (DBS) investigated whether a novel constant-current device improves tremor and activities of daily living (ADL) in patients with essential tremor (ET). METHODS: A prospective, controlled, multicenter study was conducted at 12 academic centers. We investigated the safety and efficacy of unilateral and bilateral constant-current DBS of the ventralis intermedius (VIM) nucleus of the thalamus in patients with essential tremor whose tremor was inadequately controlled by medications. The primary outcome measure was a rater-blinded assessment of the change in the target limb tremor score in the stimulation-on versus stimulation-off state six months following surgery. Multiple secondary outcomes were assessed at one-year follow-up, including motor, mood, and quality-of-life measures. RESULTS: 127 patients were implanted with VIM DBS. The blinded, primary outcome variable (n = 76) revealed a mean improvement of 1.25 ± 1.26 points in the target limb tremor rating scale (TRS) score in the arm contralateral to DBS (p < 0.001). Secondary outcome variables at one year revealed significant improvements (p ≤ 0.001) in quality of life, depression symptoms, and ADL scores. Forty-seven patients had a second contralateral VIM-DBS, and this group demonstrated reduction in second-sided tremor at 180 days (p < 0.001). Serious adverse events related to the surgery included infection (n = 3), intracranial hemorrhage (n = 3), and device explantation (n = 3). CONCLUSION: Unilateral and bilateral constant-current VIM DBS significantly improves upper extremity tremor, ADL, quality of life, and depression in patients with severe ET.

Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease.

Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinson's disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation-or to a control group that receives the DBS treatment alone-has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by "piggybacking" onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain.

Acute effects of thalamic deep brain stimulation and thalamotomy on sensorimotor cortex local field potentials in essential tremor.

OBJECTIVE: Essential tremor (ET) is characterized by an action tremor believed to be due to excessive theta-alpha activity in the cerebello-thalamo-cortical system. This study aimed to test the hypothesis that therapeutic thalamic stimulation in patients with ET decreases theta-alpha oscillatory activity in primary motor (M1) and sensory (S1) cortices. METHODS: During surgical treatment of ET in 10 patients, an electrocorticography (ECoG) strip electrode was placed temporarily over the arm region of M1 and S1. Local field potentials (LFP) were recorded at rest, during a tremor-inducing posture, during acute therapeutic thalamic stimulation, and following therapeutic thalamotomy (three patients). Power spectral density (PSD) was calculated using the Fast Fourier Transform. RESULTS: At rest, alpha activity (8-13Hz) in M1 was significantly decreased during high-frequency stimulation, while theta activity (4-8Hz) decreased in S1. Following thalamotomy, theta and beta (13-30Hz) was increased in M1. Induction of postural tremor reduced M1 theta, alpha and beta activity compared to the resting state. CONCLUSIONS: High-frequency thalamic deep brain stimulation (DBS) significantly reduces alpha oscillatory activity in the primary motor cortex of patients with ET, though this change is probably not critical for therapeutic efficacy. SIGNIFICANCE: We demonstrate that ECoG can be effectively used to study the effect of subcortical stimulation on cortical oscillations.

Multiple target deep brain stimulation for multiple sclerosis related and poststroke Holmes' tremor.

BACKGROUND: The results from thalamic deep brain stimulation (DBS) for atypical tremor syndromes including tremor from multiple sclerosis (MS) and stroke are often disappointing. Three recent case reports have suggested that simultaneous stimulation of multiple thalamic targets can result in sustained improvement in such cases. METHODS: We analyzed the effectiveness of multiple target DBS in one patient with MS-related tremor and another with poststroke Holmes' tremor. RESULTS: In the patient with MS tremor, we implanted bilateral ventralis intermedius (V.im.) and ventralis oralis anterior (V.o.a.) thalamic electrodes; this patient had significant tremor improvement with stimulation of either V.im. or V.o.a. targets; however, we did not observe additive effects with simultaneous stimulation. In our patient with a poststroke Holmes' tremor, we implanted DBS electrodes in unilateral V.im., V.o.a., and the globus pallidus internus (Gpi); this patient had moderate tremor reduction with Gpi stimulation alone; neither V.im. nor V.o.a. stimulation provided additional benefit. CONCLUSION: In one patient with MS tremor, simultaneous V.im. and V.o.a. stimulation was not superior to V.im. or V.o.a. stimulation alone. In one case of Holmes' tremor, Gpi stimulation was a useful alternative to thalamic stimulation.

Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes.

Object. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a promising new procedure for the treatment of dystonia. The authors present their technical approach for placement of electrodes into the GPi in awake patients with dystonia, including the methodology used for electrophysiological mapping of the GPi in the dystonic state, clinical outcomes and complications, and the location of electrodes associated with optimal benefit. Methods. Twenty-three adult and pediatric patients who had various forms of dystonia were included in this study. Baseline neurological status and improvement in motor function resulting from DBS were measured using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Implantation of the DBS lead was performed using magnetic resonance (MR) imaging-based stereotaxy, single-cell microelectrode recording, and intraoperative test stimulation to determine thresholds for stimulation-induced adverse effects. Electrode locations were measured on computationally reformatted postoperative MR images according to a prospective protocol. Conclusions. Physiologically guided implantation of DBS electrodes in patients with dystonia is technically feasible in the awake state in most cases, with low morbidity rates. Spontaneous discharge rates of GPi neurons in dystonia are similar to those of globus pallidus externus neurons, such that the two nuclei must be distinguished by neuronal discharge patterns rather than by rates. Active electrode locations associated with robust improvement (> 50% decrease in BFMDRS score) were located near the intercommissural plane, at a mean distance of 3.7 mm from the pallidocapsular border. Patients with juvenile-onset primary dystonia and those with the tardive form benefited greatly from this procedure, whereas benefits for most secondary dystonias and the adult-onset craniocervical form of this disorder were more modest.