Jennifer A. Sweet

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.

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.

Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases

Memory loss after brain injury can be a source of considerable morbidity, but there are presently few therapeutic options for restoring memory function. We have previously demonstrated that burst stimulation of the fornix is able to significantly improve memory in a rodent model of traumatic brain injury. The present study is a preliminary investigation with a small group of cases to explore whether theta burst stimulation of the fornix might improve memory in humans. Four individuals undergoing stereo-electroencephalography evaluation for drug-resistant epilepsy were enrolled. All participants were implanted with an electrode into the proximal fornix and dorsal hippocampal commissure on the language dominant (n = 3) or language non-dominant (n = 1) side, and stimulation of this electrode reliably produced a diffuse evoked potential in the head and body of the ipsilateral hippocampus. Each participant underwent testing of verbal memory (Rey Auditory-Verbal Learning Test), visual-spatial memory (Medical College of Georgia Complex Figure Test), and visual confrontational naming (Boston Naming Test Short Form) once per day over at least two consecutive days using novel test forms each day. For 50% of the trials, the fornix electrode was continuously stimulated using a burst pattern (200 Hz in 100 ms trains, five trains per second, 100 µs, 7 mA) and was compared with sham stimulation. Participants and examiners were blinded to whether stimulation was active or not, and the order of stimulation was randomized. The small sample size precluded use of inferential statistics; therefore, data were analysed using descriptive statistics and graphic analysis. Burst stimulation of the fornix was not perceived by any of the participants but was associated with a robust reversible improvement in immediate and delayed performance on the Medical College of Georgia Complex Figure Test. There were no apparent differences on either Rey Auditory-Verbal Learning Test or Boston Naming Test. There was no apparent relationship between performance and side of stimulation (language dominant or non-dominant). There were no complications. Preliminary evidence in this small sample of patients with drug-resistant epilepsy suggests that theta burst stimulation of the fornix may be associated with improvement in visual-spatial memory.

Improved learning and memory with theta-burst stimulation of the fornix in rat model of traumatic brain injury

Objective: Learning and memory deficits are a source of considerable morbidity after traumatic brain injury (TBI). We investigated the effect of different patterns of hippocampal stimulation via a fornix electrode on cognitively demanding tasks after TBI. Methods: Male Sprague‐Dawley rats underwent fluid‐percussion injury and were compared with sham‐operated rats. Electrodes were implanted into the fornix and hippocampus, and stimulation of the fornix produced robust evoked potentials in the hippocampus. A 60‐s delayed non‐match‐to‐sample (DNMS) swim T‐maze was serially performed using four stimulation patterns: no stimulation (No Stim), low‐frequency stimulation (LFS, 5 Hz), high‐frequency stimulation (HFS, 130 Hz), and theta‐burst stimulation (TBS, 200 Hz in 50 ms trains, five trains per second; 60 µA biphasic pulses). In a separate cohort of sham and injured animals, Morris water maze (MWM) was performed with or without TBS. Results: In the DNMS swim T‐maze, LFS and HFS did not significantly improve performance after TBI. However, there was a significant difference in performance between TBI + No Stim and TBI + TBS groups (P < 0.05) with no significant difference between Sham + No Stim and TBI + TBS. In the MWM, latency in the TBI + TBS group was significantly different from TBI + No Stim starting on day 2 (P < 0.05) and was not different from Sham + No Stim. The TBI + TBS group performed significantly more platform crossings in the probe trial (P < 0.01) and exhibited improved search strategy starting on day 3 (P < 0.05) compared with TBI + No Stim. Conclusions: Deficits in learning and memory after TBI are improved with TBS of the hippocampus. HFS and LFS do not appear to produce as great an effect as TBS.

Proposal: Different types of alteration and loss of consciousness in epilepsy

There are at least five types of alterations of consciousness that occur during epileptic seizures: auras with illusions or hallucinations, dyscognitive seizures, epileptic delirium, dialeptic seizures, and epileptic coma. Each of these types of alterations of consciousness has a specific semiology and a distinct pathophysiologic mechanism. In this proposal we emphasize the need to clearly define each of these alterations/loss of consciousness and to apply this terminology in semiologic descriptions and classifications of epileptic seizures. The proposal is a consensus opinion of experienced epileptologists, and it is hoped that it will lead to systematic studies that will allow a scientific characterization of the different types of alterations/loss of consciousness described in this article.

Hippocampal Neurophysiologic Changes after Mild Traumatic Brain Injury and Potential Neuromodulation Treatment Approaches

Traumatic brain injury (TBI) is the leading cause of death and disability in individuals below age 45, and five million Americans live with chronic disability as a result. Mild TBI (mTBI), defined as TBI in the absence of major imaging or histopathological defects, is responsible for a majority of cases. Despite the lack of overt morphological defects, victims of mTBI frequently suffer lasting cognitive deficits, memory difficulties, and behavioral disturbances. There is increasing evidence that cognitive and memory dysfunction is related to subtle physiological changes that occur in the hippocampus, and these impact both the phenotype of deficits observed and subsequent recovery. Therapeutic modulation of physiological activity by means of medications commonly used for other indications or brain stimulation may represent novel treatment approaches. This review summarizes the present body of knowledge regarding neurophysiologic changes that occur in the hippocampus after mTBI, as well as potential targets for therapeutic modulation of neurologic activity.

Occipital Nerve Stimulation for the Treatment of Patients With Medically Refractory Occipital Neuralgia: Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline.

BACKGROUND Occipital neuralgia (ON) is a disorder characterized by sharp, electrical, paroxysmal pain, originating from the occiput and extending along the posterior scalp, in the distribution of the greater, lesser, and/or third occipital nerve. Occipital nerve stimulation (ONS) constitutes a promising therapy for medically refractory ON because it is reversible with minimal side effects and has shown continued efficacy with long-term follow-up. OBJECTIVE To conduct a systematic literature review and provide treatment recommendations for the use of ONS for the treatment of patients with medically refractory ON. METHODS A systematic literature search was conducted using the PubMed database and the Cochrane Library to locate articles published between 1966 and April 2014 using MeSH headings and keywords relevant to ONS as a means to treat ON. A second literature search was conducted using the PubMed database and the Cochrane Library to locate articles published between 1966 and June 2014 using MeSH headings and keywords relevant to interventions that predict response to ONS in ON. The strength of evidence of each article that underwent full text review and the resulting strength of recommendation were graded according to the guidelines development methodology of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Guidelines Committee. RESULTS Nine studies met the criteria for inclusion in this guideline. All articles provided Class III Level evidence. CONCLUSION Based on the data derived from this systematic literature review, the following Level III recommendation can be made: the use of ONS is a treatment option for patients with medically refractory ON.

Paresthesia-Free High-Density Spinal Cord Stimulation for Postlaminectomy Syndrome in a Prescreened Population: A Prospective Case Series

Spinal cord stimulation (SCS) traditionally is thought to require paresthesia, but there is evidence that paresthesia‐free stimulation using high‐density (HD) parameters might also be effective. The purpose of this study is to evaluate relative effectiveness of conventional, subthreshold HD, and sham stimulation on pain intensity and quality of life.

Temporal lobe epilepsy in patients with nonlesional MRI and normal memory: an SEEG study

OBJECT Temporal lobe epilepsy (TLE) in the absence of MRI abnormalities and memory deficits is often presumed to have an extramesial or even extratemporal source. In this paper the authors report the results of a comprehensive stereoelectroencephalography (SEEG) analysis in patients with TLE with normal MRI images and memory scores. METHODS Eighteen patients with medically refractory epilepsy who also had unremarkable MR images and normal verbal and visual memory scores on neuropsychological testing were included in the study. All patients had seizure semiology and video electroencephalography (EEG) findings suggestive of TLE. A standardized SEEG investigation was performed for each patient with electrodes implanted into the mesial and lateral temporal lobe, temporal tip, posterior temporal neocortex, orbitomesiobasal frontal lobe, posterior cingulate gyrus, and insula. This information was used to plan subsequent surgical management. RESULTS Interictal SEEG abnormalities were observed in the mesial temporal structures in 17 patients (94%) and in the temporal tip in 6 (33%). Seizure onset was exclusively from mesial structures in 13 (72%), exclusively from lateral temporal cortex and/or temporal tip structures in 2 (11%), and independently from mesial and neocortical foci in 3 (17%). No seizure activity was observed arising from any extratemporal location. All patients underwent surgical intervention targeting the temporal lobe and tailored to the SEEG findings, and all experienced significant improvement in seizure frequency with a postoperative follow-up observation period of at least 1 year. CONCLUSIONS This study demonstrates 3 important findings: 1) normal memory does not preclude mesial temporal seizure onset; 2) onset of seizures exclusively from mesial temporal structures without early neocortical involvement is common, even in the absence of memory deficits; and 3) extratemporal seizure onset is rare when video EEG and semiology are consistent with focal TLE.

Depths and grids in brain tumors: Implantation strategies, techniques, and complications

Patients with intracranial mass lesions are at increased risk of intractable epilepsy even after tumor resection due to the potential epileptogenicity of lesional and perilesional tissue. Risk factors for tumoral epilepsy include tumor location, histology, and extent of tumor resection. In epilepsy that occurs after tumor resection, the epileptogenic zone often does not correspond precisely with the area of abnormality on imaging, and seizures often arise from a relatively restricted area despite widespread changes on imaging. Invasive monitoring via subdural grids and/or depth electrodes can therefore be helpful to delineate areas of eloquence and localize the epileptogenic zone for subsequent resection. Subdural grids offer excellent contiguous coverage of superficial cortex and allow resection using the same craniotomy, facilitating understanding of anatomic relationships. Depth electrodes offer superior coverage of deep structures, are easier to use in cases where a previous craniotomy is present, are not associated with anatomic distortion due to brain shift, and may be associated with a lower complication rate. We review the biology of focal postoperative epilepsy and invasive diagnostic strategies for the surgical evaluation of medically refractory epilepsy in patients who have undergone resection of intracranial mass lesions.