Search

Long-term recovery of limb function is a significant unmet need in people with paralysis. Neuromodulation of the spinal cord through epidural stimulation, when paired with intense activity-based training, has shown promising results toward restoring volitional limb control in people with spinal cord injury. Non-invasive neuromodulation of the cervical spinal cord using transcutaneous spinal cord stimulation (tSCS) has shown similar improvements in upper-limb motor control rehabilitation. However, the motor and sensory rehabilitative effects of activating specific cervical spinal segments using tSCS have largely remained unexplored. We show in two individuals with motor-complete SCI that targeted stimulation of the cervical spinal cord resulted in up to a 1,136% increase in exerted force, with weekly activity-based training. Furthermore, this is the first study to document up to a 2-point improvement in clinical assessment of tactile sensation in SCI after receiving tSCS. Lastly, participant gains persisted after a one-month period void of stimulation, suggesting that targeted tSCS may lead to persistent recovery of motor and sensory function.

Peripheral nerve injury can lead to chronic pain, paralysis, and loss of sensation, severely affecting quality of life. Spinal cord stimulation has been used in the clinic to provide pain relief arising from peripheral nerve injuries, however, its ability to restore function after peripheral nerve injury have not been explored. Neuromodulation of the spinal cord through transcutaneous spinal cord stimulation (tSCS), when paired with activity-based training, has shown promising results towards restoring volitional limb control in people with spinal cord injury. We show, for the first time, the effectiveness of targeted tSCS in restoring strength (407% increase from 1.79 ± 1.24 N to up to 7.3 ± 0.93 N) and significantly increasing hand dexterity in an individual with paralysis due to a peripheral nerve injury (PNI). Furthermore, this is the first study to document a persisting 3-point improvement during clinical assessment of tactile sensation in peripheral injury after receiving 6 weeks of tSCS. Lastly, the motor and sensory gains persisted for several months after stimulation was received, suggesting tSCS may lead to long-lasting benefits, even in PNI. Non-invasive spinal cord stimulation shows tremendous promise as a safe and effective therapeutic approach with broad applications in functional recovery after debilitating injuries.

Abstract Almost 100 years ago experiments involving electrically stimulating and recording from the brain and the body launched new discoveries and debates on how electricity, movement, and thoughts are related. Decades later the development of brain-computer interface technology began, which now targets a wide range of applications. Potential uses include augmentative communication for locked-in patients and restoring sensorimotor function in those who are battling disease or have suffered traumatic injury. Technical and surgical challenges still surround the development of brain-computer technology, however, before it can be widely deployed. In this review we explore these challenges, historical perspectives, and the remarkable achievements of clinical study participants who have bravely forged new paths for future beneficiaries.

Background: Paralysis and neuropathy, affecting millions of people worldwide, can be accompanied by significant loss of somatosensation. With tactile sensation being central to achieving dexterous movement, brain-computer interface (BCI) researchers have used intracortical and cortical surface electrical stimulation to restore somatotopically-relevant sensation to the hand. However, these approaches are restricted to stimulating the gyral areas of the brain. Since representation of distal regions of the hand extends into the sulcal regions of human primary somatosensory cortex (S1), it has been challenging to evoke sensory percepts localized to the fingertips. Objective/hypothesis: Targeted stimulation of sulcal regions of S1, using stereoelectroencephalography (SEEG) depth electrodes, can evoke focal sensory percepts in the fingertips. Methods: Two participants with intractable epilepsy received cortical stimulation both at the gyri via high-density electrocorticography (HD-ECoG) grids and in the sulci via SEEG depth electrode leads. We characterized the evoked sensory percepts localized to the hand. Results: We show that highly focal percepts can be evoked in the fingertips of the hand through sulcal stimulation. fMRI, myelin content, and cortical thickness maps from the Human Connectome Project elucidated specific cortical areas and sub-regions within S1 that evoked these focal percepts. Within-participant comparisons showed that percepts evoked by sulcal stimulation via SEEG electrodes were significantly more focal (80% less area; p = 0.02) and localized to the fingertips more often, than by gyral stimulation via HD-ECoG electrodes. Finally, sulcal locations with consistent modulation of high-frequency neural activity during mechanical tactile stimulation of the fingertips showed the same somatotopic correspondence as cortical stimulation. Conclusions: Our findings indicate minimally invasive sulcal stimulation via SEEG electrodes could be a clinically viable approach to restoring sensation.

Devices interfacing with the brain through implantation in cortical or subcortical structures have great potential for restoration and rehabilitation in patients with sensory or motor dysfunction. Typical implantation surgeries are planned based on maps of brain activity generated from intact function. However, mapping brain activity for planning implantation surgeries is challenging in the target population due to abnormal residual function and, increasingly often, existing MRI-incompatible implanted hardware. Here, we present methods and results for mapping impaired somatosensory and motor function in an individual with paralysis and an existing brain–computer interface (BCI) device. Magnetoencephalography (MEG) was used to directly map the neural activity evoked during transcutaneous electrical stimulation and attempted movement of the impaired hand. Evoked fields were found to align with the expected anatomy and somatotopic organization. This approach may be valuable for guiding implants in other applications, such as cortical stimulation for pain and to improve implant targeting to help reduce the craniotomy size.

Abstract Background Glucose is a crucial energy source. In humans, it is the primary sugar for high energy demanding cells in brain, muscle and peripheral neurons. Deviations of blood glucose levels from normal levels for an extended period of time is dangerous or even fatal, so regulation of blood glucose levels is a biological imperative. The vagus nerve, comprised of sensory and motor fibres, provides a major anatomical substrate for regulating metabolism. While prior studies have implicated the vagus nerve in the neurometabolic interface, its specific role in either the afferent or efferent arc of this reflex remains elusive. Methods Here we use recently developed methods to isolate and decode specific neural signals acquired from the surface of the vagus nerve in BALB/c wild type mice to identify those that respond robustly to hypoglycemia. We also attempted to decode neural signals related to hyperglycemia. In addition to wild type mice, we analyzed the responses to acute hypo- and hyperglycemia in transient receptor potential cation channel subfamily V member 1 (TRPV1) cell depleted mice. The decoding algorithm uses neural signals as input and reconstructs blood glucose levels. Results Our algorithm was able to reconstruct the blood glucose levels with high accuracy (median error 18.6 mg/dl). Hyperglycemia did not induce robust vagus nerve responses, and deletion of TRPV1 nociceptors attenuated the hypoglycemia-dependent vagus nerve signals. Conclusion These results provide insight to the sensory vagal signaling that encodes hypoglycemic states and suggest a method to measure blood glucose levels by decoding nerve signals. Trial registration Not applicable.

Abstract Background Understanding the long-term behavior of intracortically-recorded signals is essential for improving the performance of Brain Computer Interfaces. However, few studies have systematically investigated chronic neural recordings from an implanted microelectrode array in the human brain. Methods In this study, we show the applicability of wavelet decomposition method to extract and demonstrate the utility of long-term stable features in neural signals obtained from a microelectrode array implanted in the motor cortex of a human with tetraplegia. Wavelet decomposition was applied to the raw voltage data to generate mean wavelet power (MWP) features, which were further divided into three sub-frequency bands, low-frequency MWP (lf-MWP, 0–234 Hz), mid-frequency MWP (mf-MWP, 234 Hz–3.75 kHz) and high-frequency MWP (hf-MWP, >3.75 kHz). We analyzed these features using data collected from two experiments that were repeated over the course of about 3 years and compared their signal stability and decoding performance with the more standard threshold crossings, local field potentials (LFP), multi-unit activity (MUA) features obtained from the raw voltage recordings. Results All neural features could stably track neural information for over 3 years post-implantation and were less prone to signal degradation compared to threshold crossings. Furthermore, when used as an input to support vector machine based decoding algorithms, the mf-MWP and MUA demonstrated significantly better performance, respectively, in classifying imagined motor tasks than using the lf-MWP, hf-MWP, LFP, or threshold crossings. Conclusions Our results suggest that using MWP features in the appropriate frequency bands can provide an effective neural feature for brain computer interface intended for chronic applications. Trial registration This study was approved by the U.S. Food and Drug Administration (Investigational Device Exemption) and the Ohio State University Medical Center Institutional Review Board (Columbus, Ohio). The study conformed to institutional requirements for the conduct of human subjects and was filed on ClinicalTrials.gov (Identifier NCT01997125).

Abstract Neuroprosthetics that combine a brain computer interface (BCI) with functional electrical stimulation (FES) can restore voluntary control of a patients’ own paralyzed limbs. To date, human studies have demonstrated an “all-or-none” type of control for a fixed number of pre-determined states, like hand-open and hand-closed. To be practical for everyday use, a BCI-FES system should enable smooth control of limb movements through a continuum of states and generate situationally appropriate, graded muscle contractions. Crucially, this functionality will allow users of BCI-FES neuroprosthetics to manipulate objects of different sizes and weights without dropping or crushing them. In this study, we present the first evidence that using a BCI-FES system, a human with tetraplegia can regain volitional, graded control of muscle contraction in his paralyzed limb. In addition, we show the critical ability of the system to generalize beyond training states and accurately generate wrist flexion states that are intermediate to training levels. These innovations provide the groundwork for enabling enhanced and more natural fine motor control of paralyzed limbs by BCI-FES neuroprosthetics.

Abstract Following traumatic brain injury (TBI), ischemia and hypoxia play a major role in further worsening of the damage, a process referred to as ‘secondary injury’. Protecting neurons from causative factors of secondary injury has been the guiding principle of modern TBI management. Stimulation of trigeminal nerve induces pressor response and improves cerebral blood flow (CBF) by activating the rostral ventrolateral medulla. Moreover, it causes cerebrovasodilation through the trigemino-cerebrovascular system and trigemino-parasympathetic reflex. These effects are capable of increasing cerebral perfusion, making trigeminal nerve stimulation (TNS) a promising strategy for TBI management. Here, we investigated the use of electrical TNS for improving CBF and brain oxygen tension (PbrO2), with the goal of decreasing secondary injury. Severe TBI was produced using controlled cortical impact (CCI) in a rat model, and TNS treatment was delivered for the first hour after CCI. In comparison to TBI group, TBI animals with TNS treatment demonstrated significantly increased systemic blood pressure, CBF and PbrO2 at the hyperacute phase of TBI. Furthermore, rats in TNS-treatment group showed significantly reduced brain edema, blood-brain barrier disruption, lesion volume, and brain cortical levels of TNF-α and IL-6. These data provide strong early evidence that TNS could be an effective neuroprotective strategy.

Abstract The axons of the sensory, or afferent, vagus nerve transmit action potentials to the central nervous system in response to changes in the body’s metabolic and physiological status. Recent advances in identifying neural circuits that regulate immune responses to infection, inflammation and injury have revealed that vagus nerve signals regulate the release of cytokines and other factors produced by macrophages. Here we record compound action potentials in the cervical vagus nerve of adult mice and reveal the specific activity that occurs following administration of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 1β (IL-1β). Importantly, the afferent vagus neurograms generated by TNF exposure are abolished in double knockout mice lacking TNF receptors 1 and 2 (TNF-R1/2KO), whereas IL-1 β-specific neurograms are eliminated in knockout mice lacking IL-1 β receptor (IL-1RKO). Conversely, TNF neurograms are preserved in IL-1RKO mice, and IL-1 β neurograms are unchanged in TNF-R1/2KO mice. Analysis of the temporal dynamics and power spectral characteristics of afferent vagus neurograms for TNF and IL-1β reveals cytokine-selective signals. The nodose ganglion contains the cell bodies of the sensory neurons whose axons run through the vagus nerve. The nodose neurons express receptors for TNF and IL-1β, and we show that exposing them to TNF and IL-1β significantly stimulates their calcium uptake. Together these results indicate that afferent vagus signals in response to cytokines provide a basic model of nervous system sensing of immune responses.