Embedding digital chronotherapy into bioelectronic medicines.

Biological rhythms pervade physiology and pathophysiology across multiple timescales. Because of the limited sensing and algorithm capabilities of neuromodulation device technology to-date, insight into the influence of these rhythms on the efficacy of bioelectronic medicine has been infeasible. As the development of new devices begins to mitigate previous technology limitations, we propose that future devices should integrate chronobiological considerations in their control structures to maximize the benefits of neuromodulation therapy. We motivate this proposition with preliminary longitudinal data recorded from patients with Parkinson's disease and epilepsy during deep brain stimulation therapy, where periodic symptom biomarkers are synchronized to sub-daily, daily, and longer timescale rhythms. We suggest a physiological control structure for future bioelectronic devices that incorporates time-based adaptation of stimulation control, locked to patient-specific biological rhythms, as an adjunct to classical control methods and illustrate the concept with initial results from three of our recent case studies using chronotherapy-enabled prototypes.

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).

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).

Neurofeedback Control in Parkinsonian Patients Using Electrocorticography Signals Accessed Wirelessly With a Chronic, Fully Implanted Device.

Parkinson's disease (PD) is characterized by motor symptoms such as rigidity and bradykinesia that prevent normal movement. Beta band oscillations (13-30 Hz) in neural local field potentials (LFPs) have been associated with these motor symptoms. Here, three PD patients implanted with a therapeutic deep brain neural stimulator that can also record and wirelessly stream neural data played a neurofeedback game where they modulated their beta band power from sensorimotor cortical areas. Patients' beta band power was streamed in real-time to update the position of a cursor that they tried to drive into a cued target. After playing the game for 1-2 hours each, all three patients exhibited above chance-level performance regardless of subcortical stimulation levels. This study, for the first time, demonstrates using an invasive neural recording system for at-home neurofeedback training. Future work will investigate chronic neurofeedback training as a potentially therapeutic tool for patients with neurological disorders.

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.

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease.

BACKGROUND: Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinson's disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS: At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinson's disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS: Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS: Patients with Parkinson's disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

First case of X-linked dystonia-parkinsonism ("Lubag") to demonstrate a response to bilateral pallidal stimulation.

"Lubag" or X-linked dystonia-parkinsonism (XDP) is a genetic syndrome afflicting Filipino men. Intracranial surgical procedures for Lubag have been unsuccessful. We report a 45-year-old Filipino male with genetically confirmed XDP who underwent bilateral pallidal deep brain stimulation (DBS) surgery. The patient started to exhibit improvement on initial programming, most notably of his severe jaw-opening dystonia. At 1-year follow-up, his Burke-Fahn-Marsden dystonia score and motor Unified Parkinson's Disease Rating Scale score were improved by 71% and 62%, respectively, with the stimulators on compared to stimulators off state. Bilateral pallidal DBS may be a viable option for Lubag patients with medically refractory symptoms.

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.

Thalamic deep brain stimulation for essential tremor: relation of lead location to outcome.

OBJECTIVE: Thalamic deep brain stimulation (DBS) is commonly used to treat essential tremor, but the optimal lead location within the thalamus has not been systematically evaluated. We examined the relation of lead location to clinical outcome in a series of essential tremor patients treated by thalamic DBS. METHODS: Fifty-seven leads in 37 patients were studied. Lead locations were measured by postoperative magnetic resonance imaging. Contralateral arm tremor was assessed in the DBS-on and DBS-off states using the Fahn-Tolosa-Marin tremor rating scale, with a mean follow-up of 26 months. Lead locations were statistically correlated, using analysis of variance, with percent improvement in tremor resulting from DBS activation. RESULTS: Improvement in tremor score was significantly correlated with lead location in both the anteroposterior and lateral dimensions. In the plane of the commissures, the optimal electrode location was determined statistically to be 6.3 mm anterior to the posterior commissure and 12.3 mm lateral to the midline, or 10.0 mm lateral to the third ventricle. CONCLUSION: Optimal electrode location for thalamic DBS in essential tremor corresponds to the anterior margin of the ventralis intermedius nucleus. Leads located greater than 2 mm (in the plane of the commissures) from the optimal coordinates are more likely to be associated with poor tremor control than leads within 2 mm of the optimal location. The incidence of true physiological tolerance to the antitremor effect of thalamic DBS (defined as poor tremor control in spite of lead location within 2 mm of the optimal site) was found to be 9%.

Locations of movement-related cells in the human subthalamic nucleus in Parkinson's disease.

The subthalamic nucleus (STN) is an emerging target for deep brain stimulator (DBS) implantation for the treatment of advanced Parkinson's disease (PD). Understanding the somatotopic organization of the STN is important for surgical navigation within the nucleus. We analyzed intraoperative data obtained during 54 procedures for the implantation of STN stimulators to assess the locations of movement-related cells. Cells were considered movement-related if they exhibited modulation of the cell discharge during passive movement of the contralateral upper or lower extremity. Microelectrode track reconstructions were plotted on a human brain atlas, using the location of the DBS electrode from postoperative magnetic resonance images as a registration mark in reconstructing microelectrode track locations. Movement-related cells were predominantly located in the dorsal part of the nucleus. The majority of the cells were related to proximal joint manipulation. Arm-related cells were located laterally and at the rostral and caudal poles, whereas leg-related cells were located medially and centrally. The finding of three or more leg-related cells on a given microelectrode track was predictive of a medial localization within the motor area. Our findings are consistent with the small number of published studies on STN somatopy in the human and the nonhuman primate.

Hemorrhagic complications of microelectrode-guided deep brain stimulation.

BACKGROUND: The incidence of intracranial hemorrhage occurring during microelectrode-guided implantation of deep brain stimulators (DBS) for movement disorders has not been well defined. We report the incidence of hemorrhage in a large series of DBS implants into the subthalamic nucleus (STN), thalamus (VIM) and internal globus pallidus (GPi). METHODS: All DBS procedures performed by a single surgeon (P.A.S.) between June 1998 and April 2003 were included in this study. Patients had postoperative imaging (MRI or CT) 4-24 h following surgery, and all hematomas >0.2 cm(3) in volume were noted and scored as symptomatic (associated with any new neurologic deficit lasting >24 h) or asymptomatic. RESULTS: The total number of lead implants was 357. There were 5 symptomatic hematomas and 6 asymptomatic hematomas. The relative risk of hematoma (any type) per lead implant was 3.1%. The incidence of hematoma by target site was 2.5% per lead for STN-DBS, 6.7% for GPi-DBS and 0% for VIM-DBS. CONCLUSION: The overall risk of intraoperative or early postoperative symptomatic hemorrhage with microelectrode-guided DBS, over all targets, was 1.4% per lead implant. The brain target had a significant effect on the risk of hemorrhage.

Implantation of deep brain stimulators into the subthalamic nucleus: technical approach and magnetic resonance imaging-verified lead locations.

OBJECT: Chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a procedure that is rapidly gaining acceptance for the treatment of symptoms in patients with Parkinson disease (PD), but there are few detailed descriptions of the surgical procedure itself. The authors present the technical approach used to implant 76 stimulators into the STNs of patients with PD and the lead locations, which were verified on postoperative magnetic resonance (MR) images. METHODS: Implantation procedures were performed with the aid of stereotactic MR imaging, microelectrode recording (MER) in the region of the stereotactic target to define the motor area of the STN, and intraoperative test stimulation to assess the thresholds for stimulation-induced adverse effects. All patients underwent postoperative MR imaging, which was performed using volumetric gradient-echo and T2-weighted fast-spin echo techniques, computational reformatting of the MR image into standard anatomical planes, and quantitative measurements of lead location with respect to the midcommissural point and the red nucleus. Lead locations were statistically correlated with physiological data obtained during MER and intraoperative test stimulation. CONCLUSIONS: The authors' approach to implantation of DBS leads into the STN was associated with consistent lead placement in the dorsolateral STN, a low rate of morbidity, efficient use of operating room time, and robust improvement in motor function. The mean coordinates of the middle of the electrode array, measured on postoperative MR images, were 11.6 mm lateral, 2.9 mm posterior, and 4.7 mm inferior to the midcommissural point, and 6.5 mm lateral and 3.5 mm anterior to the center of the red nucleus. Voltage thresholds for several types of stimulation-induced adverse effects were predictive of lead location. Technical nuances of the surgery are described in detail.

Placement of deep brain stimulators into the subthalamic nucleus or Globus pallidus internus: technical approach.

Deep brain stimulation (DBS) represents a major advance in the treatment of Parkinson's disease (PD). As more neurosurgeons enter this field, technical descriptions of implantation techniques are needed. Here we present our technical approach to subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS implantation, based on 180 STN implants and 75 GPi implants. The essential steps in DBS implantation are magnetic resonance imaging (MRI)-guided stereotactic localization, confirmation of the motor territory of the target nucleus with microelectrode mapping, and intra-operative test stimulation to determine voltage thresholds for stimulation-induced adverse effects. Lead locations are documented by postoperative MRI in all cases.