Benjamin L. Walter

How does deep brain stimulation work? Present understanding and future questions.

Abstract: High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson’s disease, essential tremor, and dystonia). In addition, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been vaulted forward. Although DBS has been effective in the treatment of movement disorders and is rapidly being explored for the treatment of other neurologic disorders, the scientific understanding of its mechanisms of action remains unclear and continues to be debated in the scientific community. Optimization of DBS technology for present and future therapeutic applications will depend on identification of the therapeutic mechanism(s) of action. The goal of this review is to address the present knowledge of the effects of high frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathologic network activity. Using the results from microdialysis, neural recording, functional imaging, and neural modeling experiments, the authors address the main hypotheses and attempt to reconcile what have been considered conflicting results from different research modalities.

Tourette syndrome deep brain stimulation: A review and updated recommendations

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25‐year‐old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post‐DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients.

Restoration of reaching and grasping movements through brain-controlled muscle stimulation in a person with tetraplegia: a proof-of-concept demonstration

SUMMARY Background People with chronic tetraplegia due to high cervical spinal cord injury (SCI) can regain limb movements through coordinated electrical stimulation of peripheral muscles and nerves, known as Functional Electrical Stimulation (FES). Users typically command FES systems through other preserved, but limited and unrelated, volitional movements (e.g. facial muscle activity, head movements). We demonstrate an individual with traumatic high cervical SCI performing coordinated reaching and grasping movements using his own paralyzed arm and hand, reanimated through FES, and commanded using his own cortical signals through an intracortical brain-computer-interface (iBCI). Methods The study participant (53 years old, C4, ASIA A) received two intracortical microelectrode arrays in the hand area of motor cortex, and 36 percutaneous electrodes for electrically stimulating hand, elbow, and shoulder muscles. The participant used a motorized mobile arm support for gravitational assistance and to provide humeral ab/adduction under cortical control. We assessed the participant’s ability to cortically command his paralyzed arm to perform simple single-joint arm/hand movements and functionally meaningful multi-joint movements. We compared iBCI control of his paralyzed arm to that of a virtual 3D arm. This study is registered with ClinicalTrials.gov, NCT00912041. Findings The participant successfully cortically commanded single-joint and coordinated multi-joint arm movements for point-to-point target acquisitions (80% – 100% accuracy) using first a virtual arm, and second his own arm animated by FES. Using his paralyzed arm, the participant volitionally performed self-paced reaches to drink a mug of coffee (successfully completing 11 of 12 attempts within a single session) and feed himself. Interpretation This is the first demonstration of a combined FES+iBCI neuroprosthesis for both reaching and grasping for people with SCI resulting in chronic tetraplegia, and represents a major advance, with a clear translational path, for clinically viable neuroprostheses for restoring reaching and grasping post-paralysis.BACKGROUND People with chronic tetraplegia, due to high-cervical spinal cord injury, can regain limb movements through coordinated electrical stimulation of peripheral muscles and nerves, known as functional electrical stimulation (FES). Users typically command FES systems through other preserved, but unrelated and limited in number, volitional movements (eg, facial muscle activity, head movements, shoulder shrugs). We report the findings of an individual with traumatic high-cervical spinal cord injury who coordinated reaching and grasping movements using his own paralysed arm and hand, reanimated through implanted FES, and commanded using his own cortical signals through an intracortical brain-computer interface (iBCI). METHODS We recruited a participant into the BrainGate2 clinical trial, an ongoing study that obtains safety information regarding an intracortical neural interface device, and investigates the feasibility of people with tetraplegia controlling assistive devices using their cortical signals. Surgical procedures were performed at University Hospitals Cleveland Medical Center (Cleveland, OH, USA). Study procedures and data analyses were performed at Case Western Reserve University (Cleveland, OH, USA) and the US Department of Veterans Affairs, Louis Stokes Cleveland Veterans Affairs Medical Center (Cleveland, OH, USA). The study participant was a 53-year-old man with a spinal cord injury (cervical level 4, American Spinal Injury Association Impairment Scale category A). He received two intracortical microelectrode arrays in the hand area of his motor cortex, and 4 months and 9 months later received a total of 36 implanted percutaneous electrodes in his right upper and lower arm to electrically stimulate his hand, elbow, and shoulder muscles. The participant used a motorised mobile arm support for gravitational assistance and to provide humeral abduction and adduction under cortical control. We assessed the participants ability to cortically command his paralysed arm to perform simple single-joint arm and hand movements and functionally meaningful multi-joint movements. We compared iBCI control of his paralysed arm with that of a virtual three-dimensional arm. This study is registered with ClinicalTrials.gov, number NCT00912041. FINDINGS The intracortical implant occurred on Dec 1, 2014, and we are continuing to study the participant. The last session included in this report was Nov 7, 2016. The point-to-point target acquisition sessions began on Oct 8, 2015 (311 days after implant). The participant successfully cortically commanded single-joint and coordinated multi-joint arm movements for point-to-point target acquisitions (80-100% accuracy), using first a virtual arm and second his own arm animated by FES. Using his paralysed arm, the participant volitionally performed self-paced reaches to drink a mug of coffee (successfully completing 11 of 12 attempts within a single session 463 days after implant) and feed himself (717 days after implant). INTERPRETATION To our knowledge, this is the first report of a combined implanted FES+iBCI neuroprosthesis for restoring both reaching and grasping movements to people with chronic tetraplegia due to spinal cord injury, and represents a major advance, with a clear translational path, for clinically viable neuroprostheses for restoration of reaching and grasping after paralysis. FUNDING National Institutes of Health, Department of Veterans Affairs.

Pseudobulbar crying induced by stimulation in the region of the subthalamic nucleus

We describe a case of pseudobulbar crying associated with deep brain stimulation (DBS) in the region of the subthalamic nucleus (STN). Patients with pseudobulbar crying show no other evidence of subjective feelings of depression such as dysphoria, anhedonia, or vegetative signs. This may be accompanied by other symptoms of pseudobulbar palsy and has been reported to occur with ischaemic or structural lesions in both cortical and subcortical regions of the brain. Although depression has been observed to result from DBS in the region of the STN, pseudobulbar crying has not been reported. A single patient who reported the symptoms of pseudobulbar crying after placement of an STN DBS was tested in the off DBS and on DBS conditions. The patient was tested using all four DBS lead contacts and the observations and results of the examiners were recorded. The Geriatric Depression Scale was used to evaluate for depression in all of the conditions. The patient exhibited pseudobulbar crying when on monopolar stimulation at all four lead contacts. The pseudobulbar crying resolved off stimulation. This case describes another type of affective change that may be associated with stimulation in the region of or within the STN. Clinicians should be aware of this potential complication, the importance of differentiating it from stimulation induced depression, and its response to a serotonin reuptake inhibitor, such as sertraline.

Fiber tractography of the axonal pathways linking the basal ganglia and cerebellum in Parkinson disease: implications for targeting in deep brain stimulation

OBJECT Stimulation of white matter pathways near targeted structures may contribute to therapeutic effects of deep brain stimulation (DBS) for patients with Parkinson disease (PD). Two tracts linking the basal ganglia and cerebellum have been described in primates: the subthalamopontocerebellar tract (SPCT) and the dentatothalamic tract (DTT). The authors used fiber tractography to evaluate white matter tracts that connect the cerebellum to the region of the basal ganglia in patients with PD who were candidates for DBS. METHODS Fourteen patients with advanced PD underwent 3-T MRI, including 30-directional diffusion-weighted imaging sequences. Diffusion tensor tractography was performed using 2 regions of interest: ipsilateral subthalamic and red nuclei, and contralateral cerebellar hemisphere. Nine patients underwent subthalamic DBS, and the course of each tract was observed relative to the location of the most effective stimulation contact and the volume of tissue activated. RESULTS In all patients 2 distinct tracts were identified that corresponded closely to the described anatomical features of the SPCT and DTT, respectively. The mean overall distance from the active contact to the DTT was 2.18 ± 0.35 mm, and the mean proportional distance relative to the volume of tissue activated was 1.35 ± 0.48. There was a nonsignificant trend toward better postoperative tremor control in patients with electrodes closer to the DTT. CONCLUSIONS The SPCT and the DTT may be related to the expression of symptoms in PD, and this may have implications for DBS targeting. The use of tractography to identify the DTT might assist with DBS targeting in the future.

Psychosocial interventions for depression and anxiety in Parkinson's disease.

Background: Depression has been estimated to affect 1 in 3 individuals with Parkinsons disease (PD) and can lead to worse health outcomes and decreased quality of life. Anxiety further complicates PD outcomes. Pharmacologic treatments of depression and anxiety can have negative side effects in patients with PD, including exacerbation of PD symptoms. There is a critical need for alternative treatment approaches that address depression and anxiety among patients with PD. Psychosocial or behavioral approaches are known to be effective for depression generally, but only a handful of studies have examined the role of psychosocial treatments of patients with depression in PD. Objective: The aim of this article was to review published psychosocial treatment studies of depression and anxiety in patients with PD. Methods: The PubMed database was searched for articles published in English before April 2011 using the terms Parkinson’s disease, depression, anxiety, psychotherapy, cognitive therapy, behavioral treatment, behavioral therapy, nonpharmacologic treatment, psychoeducation, education, psychosocial treatment, and stress management. Articles included were prospective clinical trials utilizing specific depression or anxiety assessments as primary or secondary outcomes in patients with PD. Results: Nine reports derived from 8 separate studies fit the inclusion criteria and were included in this review. All studies were published between 1997 and 2011, and all but 3 had small sample sizes (<40 patients). Interventions included cognitive behavioral therapy (CBT), psychodrama, education, and behavior therapy as well as multidisciplinary rehabilitation. Cognitive behavioral therapy was the most studied and was shown to decrease depressive and anxiety symptoms in patients with PD. Other individual and group therapies may improve depression and anxiety in patients with PD, but the general paucity of studies and study methods limit the interpretation of these results. Conclusions: There have been few studies on psychosocial treatments that specifically assess change in depression and anxiety among patients with PD. While results for CBT and other modes of therapy are promising for acute management of depression and anxiety, longer term effects after treatment have been variable. There is a need for additional studies on psychosocial interventions in people with PD.

Automated 3-dimensional brain atlas fitting to microelectrode recordings from deep brain stimulation surgeries.

Objective: Deep brain stimulation (DBS) surgeries commonly rely on brain atlases and microelectrode recordings (MER) to help identify the target location for electrode implantation. We present an automated method for optimally fitting a 3-dimensional brain atlas to intraoperative MER and predicting a target DBS electrode location in stereotactic coordinates for the patient. Methods: We retrospectively fit a 3-dimensional brain atlas to MER points from 10 DBS surgeries targeting the subthalamic nucleus (STN). We used a constrained optimization algorithm to maximize the MER points correctly fitted (i.e., contained) within the appropriate atlas nuclei. We compared our optimization approach to conventional anterior commissure-posterior commissure (AC/PC) scaling, and to manual fits performed by four experts. A theoretical DBS electrode target location in the dorsal STN was customized to each patient as part of the fitting process and compared to the location of the clinically defined therapeutic stimulation contact. Results: The human expert and computer optimization fits achieved significantly better fits than the AC/PC scaling (80, 81, and 41% of correctly fitted MER, respectively). However, the optimization fits were performed in less time than the expert fits and converged to a single solution for each patient, eliminating interexpert variance. Conclusions and Significance: DBS therapeutic outcomes are directly related to electrode implantation accuracy. Our automated fitting techniques may aid in the surgical decision-making process by optimally integrating brain atlas and intraoperative neurophysiological data to provide a visual guide for target identification.

Automated motion sensor quantification of gait and lower extremity bradykinesia

The objective was to develop and evaluate algorithms for quantifying gait and lower extremity bradykinesia in patients with Parkinsons disease using kinematic data recorded on a heel-worn motion sensor unit. Subjects were evaluated by three movement disorder neurologists on four domains taken from the Movement Disorders Society Unified Parkinsons Disease Rating Scale while wearing the motion sensor unit. Multiple linear regression models were developed based on the recorded kinematic data and clinician scores and produced outputs highly correlated to clinician scores with an average correlation coefficient of 0.86. The newly developed models have been integrated into a home-based system for monitoring Parkinsons disease motor symptoms.

Somatotopic organization in the internal segment of the globus pallidus in Parkinson's disease

Ablation or deep brain stimulation in the internal segment of the globus pallidus (GPi) is an effective therapy for the treatment of Parkinsons disease (PD). Yet many patients receive only partial benefit, including varying levels of improvement across different body regions, which may relate to a differential effect of GPi surgery on the different body regions. Unfortunately, our understanding of the somatotopic organization of human GPi is based on a small number of studies with limited sample sizes, including several based upon only a single recording track or plane. To fully address the three-dimensional somatotopic organization of GPi, we examined the receptive field properties of pallidal neurons in a large cohort of patients undergoing stereotactic surgery. The response of neurons to active and passive movements of the limbs and orofacial structures was determined, using a minimum of three tracks across at least two medial-lateral planes. Neurons (3183) were evaluated from 299 patients, of which 1972 (62%) were modulated by sensorimotor manipulation. Of these, 1767 responded to a single, contralateral body region, with the remaining 205 responding to multiple and/or ipsilateral body regions. Leg-related neurons were found dorsal, medial and anterior to arm-related neurons, while arm-related neurons were dorsal and lateral to orofacial-related neurons. This study provides a more detailed map of individual body regions as well as specific joints within each region and provides a potential explanation for the differential effect of lesions or DBS of the GPi on different body parts in patients undergoing surgical treatment of movement disorders.

Standard Guidelines for Publication of Deep Brain Stimulation Studies in Parkinson's Disease (Guide4DBS-PD)

While the use of deep brain stimulation (DBS) for the treatment of neurological disorders has risen substantially over the last decade, it is often difficult to compare the results from different studies due to the lack of consistent reporting of key study parameters. We present guidelines to standardize the reporting of clinical studies of DBS for Parkinsons disease (PD). These guidelines provide a minimal set of required data elements to facilitate the interpretation and comparison of results across published clinical studies. The guidelines, summarized in the format of a checklist, may also have utility in the planning of clinical studies of DBS for PD as well as other neurological and psychiatric disorders.