Reconnecting the Hand and Arm to the Brain: Efficacy of Neural Interfaces for Sensorimotor Restoration After Tetraplegia.

BACKGROUND AND OBJECTIVES: Paralysis after spinal cord injury involves damage to pathways that connect neurons in the brain to peripheral nerves in the limbs. Re-establishing this communication using neural interfaces has the potential to bridge the gap and restore upper extremity function to people with high tetraplegia. We report a novel approach for restoring upper extremity function using selective peripheral nerve stimulation controlled by intracortical microelectrode recordings from sensorimotor networks, along with restoration of tactile sensation of the hand using intracortical microstimulation. METHODS: A 27-year-old right-handed man with AIS-B (motor-complete, sensory-incomplete) C3-C4 tetraplegia was enrolled into the clinical trial. Six 64-channel intracortical microelectrode arrays were implanted into left hemisphere regions involved in upper extremity function, including primary motor and sensory cortices, inferior frontal gyrus, and anterior intraparietal area. Nine 16-channel extraneural peripheral nerve electrodes were implanted to allow targeted stimulation of right median, ulnar (2), radial, axillary, musculocutaneous, suprascapular, lateral pectoral, and long thoracic nerves, to produce selective muscle contractions on demand. Proof-of-concept studies were performed to demonstrate feasibility of using a brain-machine interface to read from and write to the brain for restoring motor and sensory functions of the participant's own arm and hand. RESULTS: Multiunit neural activity that correlated with intended motor action was successfully recorded from intracortical arrays. Microstimulation of electrodes in somatosensory cortex produced repeatable sensory percepts of individual fingers for restoration of touch sensation. Selective electrical activation of peripheral nerves produced antigravity muscle contractions, resulting in functional movements that the participant was able to command under brain control to perform virtual and actual arm and hand movements. The system was well tolerated with no operative complications. CONCLUSION: The combination of implanted cortical electrodes and nerve cuff electrodes has the potential to create bidirectional restoration of motor and sensory functions of the arm and hand after neurological injury.

Reconnecting the Hand and Arm to the Brain: Efficacy of Neural Interfaces for Sensorimotor Restoration after Tetraplegia.

Background: Paralysis after spinal cord injury involves damage to pathways that connect neurons in the brain to peripheral nerves in the limbs. Re-establishing this communication using neural interfaces has the potential to bridge the gap and restore upper extremity function to people with high tetraplegia. Objective: We report a novel approach for restoring upper extremity function using selective peripheral nerve stimulation controlled by intracortical microelectrode recordings from sensorimotor networks, along with restoration of tactile sensation of the hand using intracortical microstimulation. Methods: A right-handed man with motor-complete C3-C4 tetraplegia was enrolled into the clinical trial. Six 64-channel intracortical microelectrode arrays were implanted into left hemisphere regions involved in upper extremity function, including primary motor and sensory cortices, inferior frontal gyrus, and anterior intraparietal area. Nine 16-channel extraneural peripheral nerve electrodes were implanted to allow targeted stimulation of right median, ulnar (2), radial, axillary, musculocutaneous, suprascapular, lateral pectoral, and long thoracic nerves, to produce selective muscle contractions on demand. Proof-of-concept studies were performed to demonstrate feasibility of a bidirectional brain-machine interface to restore function of the participant's own arm and hand. Results: Multi-unit neural activity that correlated with intended motor action was successfully recorded from intracortical arrays. Microstimulation of electrodes in somatosensory cortex produced repeatable sensory percepts of individual fingers for restoration of touch sensation. Selective electrical activation of peripheral nerves produced antigravity muscle contractions. The system was well tolerated with no operative complications. Conclusion: The combination of implanted cortical electrodes and nerve cuff electrodes has the potential to allow restoration of motor and sensory functions of the arm and hand after neurological injury.

Investigation of the Feasibility of Ventricular Delivery of Resveratrol to the Microelectrode Tissue Interface.

(1) Background: Intracortical microelectrodes (IMEs) are essential to basic brain research and clinical brain-machine interfacing applications. However, the foreign body response to IMEs results in chronic inflammation and an increase in levels of reactive oxygen and nitrogen species (ROS/RNS). The current study builds on our previous work, by testing a new delivery method of a promising antioxidant as a means of extending intracortical microelectrodes performance. While resveratrol has shown efficacy in improving tissue response, chronic delivery has proven difficult because of its low solubility in water and low bioavailability due to extensive first pass metabolism. (2) Methods: Investigation of an intraventricular delivery of resveratrol in rats was performed herein to circumvent bioavailability hurdles of resveratrol delivery to the brain. (3) Results: Intraventricular delivery of resveratrol in rats delivered resveratrol to the electrode interface. However, intraventricular delivery did not have a significant impact on electrophysiological recordings over the six-week study. Histological findings indicated that rats receiving intraventricular delivery of resveratrol had a decrease of oxidative stress, yet other biomarkers of inflammation were found to be not significantly different from control groups. However, investigation of the bioavailability of resveratrol indicated a decrease in resveratrol accumulation in the brain with time coupled with inconsistent drug elution from the cannulas. Further inspection showed that there may be tissue or cellular debris clogging the cannulas, resulting in variable elution, which may have impacted the results of the study. (4) Conclusions: These results indicate that the intraventricular delivery approach described herein needs further optimization, or may not be well suited for this application.

Both high fat and high carbohydrate diets impair vagus nerve signaling of satiety.

Obesity remains prevalent in the US. One potential treatment is vagus nerve stimulation (VNS), which activates the sensory afferents innervating the stomach that convey stomach volume and establish satiety. However, current VNS approaches and stimulus optimization could benefit from additional understanding of the underlying neural response to stomach distension. In this study, obesity-prone Sprague Dawley rats consumed a standard, high-carbohydrate, or high-fat diet for several months, leading to diet-induced obesity in the latter two groups. Under anesthesia, the neural activity in the vagus nerve was recorded with a penetrating microelectrode array while the stomach was distended with an implanted balloon. Vagal tone during distension was compared to baseline tone prior to distension. Responses were strongly correlated with stomach distension, but the sensitivity to distension was significantly lower in animals that had been fed the nonstandard diets. The results indicate that both high fat and high carbohydrate diets impair vagus activity.

Toward Standardization of Electrophysiology and Computational Tissue Strain in Rodent Intracortical Microelectrode Models.

Progress has been made in the field of neural interfacing using both mouse and rat models, yet standardization of these models' interchangeability has yet to be established. The mouse model allows for transgenic, optogenetic, and advanced imaging modalities which can be used to examine the biological impact and failure mechanisms associated with the neural implant itself. The ability to directly compare electrophysiological data between mouse and rat models is crucial for the development and assessment of neural interfaces. The most obvious difference in the two rodent models is size, which raises concern for the role of device-induced tissue strain. Strain exerted on brain tissue by implanted microelectrode arrays is hypothesized to affect long-term recording performance. Therefore, understanding any potential differences in tissue strain caused by differences in the implant to tissue size ratio is crucial for validating the interchangeability of rat and mouse models. Hence, this study is aimed at investigating the electrophysiological variances and predictive device-induced tissue strain. Rat and mouse electrophysiological recordings were collected from implanted animals for eight weeks. A finite element model was utilized to assess the tissue strain from implanted intracortical microelectrodes, taking into account the differences in the depth within the cortex, implantation depth, and electrode geometry between the two models. The rat model demonstrated a larger percentage of channels recording single unit activity and number of units recorded per channel at acute but not chronic time points, relative to the mouse model Additionally, the finite element models also revealed no predictive differences in tissue strain between the two rodent models. Collectively our results show that these two models are comparable after taking into consideration some recommendations to maintain uniform conditions for future studies where direct comparisons of electrophysiological and tissue strain data between the two animal models will be required.

Targeting CD14 on blood derived cells improves intracortical microelectrode performance.

Intracortical microelectrodes afford researchers an effective tool to precisely monitor neural spiking activity. Additionally, intracortical microelectrodes have the ability to return function to individuals with paralysis as part of a brain computer interface. Unfortunately, the neural signals recorded by these electrodes degrade over time. Many strategies which target the biological and/or materials mediating failure modes of this decline of function are currently under investigation. The goal of this study is to identify a precise cellular target for future intervention to sustain chronic intracortical microelectrode performance. Previous work from our lab has indicated that the Cluster of Differentiation 14/Toll-like receptor pathway (CD14/TLR) is a viable target to improve chronic laminar, silicon intracortical microelectrode recordings. Here, we use a mouse bone marrow chimera model to selectively knockout CD14, an innate immune receptor, from either brain resident microglia or blood-derived macrophages, in order to understand the most effective targets for future therapeutic options. Using single-unit recordings we demonstrate that inhibiting CD14 from the blood-derived macrophages improves recording quality over the 16 week long study. We conclude that targeting CD14 in blood-derived cells should be part of the strategy to improve the performance of intracortical microelectrodes, and that the daunting task of delivering therapeutics across the blood-brain barrier may not be needed to increase intracortical microelectrode performance.

Inhibition of the cluster of differentiation 14 innate immunity pathway with IAXO-101 improves chronic microelectrode performance.

OBJECTIVE: Neuroinflammatory mechanisms are hypothesized to contribute to intracortical microelectrode failures. The cluster of differentiation 14 (CD14) molecule is an innate immunity receptor involved in the recognition of pathogens and tissue damage to promote inflammation. The goal of the study was to investigate the effect of CD14 inhibition on intracortical microelectrode recording performance and tissue integration. APPROACH: Mice implanted with intracortical microelectrodes in the motor cortex underwent electrophysiological characterization for 16 weeks, followed by endpoint histology. Three conditions were examined: (1) wildtype control mice, (2) knockout mice lacking CD14, and (3) wildtype control mice administered a small molecule inhibitor to CD14 called IAXO-101. MAIN RESULTS: The CD14 knockout mice exhibited acute but not chronic improvements in intracortical microelectrode performance without significant differences in endpoint histology. Mice receiving IAXO-101 exhibited significant improvements in recording performance over the entire 16 week duration without significant differences in endpoint histology. SIGNIFICANCE: Full removal of CD14 is beneficial at acute time ranges, but limited CD14 signaling is beneficial at chronic time ranges. Innate immunity receptor inhibition strategies have the potential to improve long-term intracortical microelectrode performance.

A testbed for optimizing electrodes embedded in the skull or in artificial skull replacement pieces used after injury.

BACKGROUND: Custom-fitted skull replacement pieces are often used after a head injury or surgery to replace damaged bone. Chronic brain recordings are beneficial after injury/surgery for monitoring brain health and seizure development. Embedding electrodes directly in these artificial skull replacement pieces would be a novel, low-risk way to perform chronic brain monitoring in these patients. Similarly, embedding electrodes directly in healthy skull would be a viable minimally-invasive option for many other neuroscience and neurotechnology applications requiring chronic brain recordings. NEW METHOD: We demonstrate a preclinical testbed that can be used for refining electrode designs embedded in artificial skull replacement pieces or for embedding directly into the skull itself. Options are explored to increase the surface area of the contacts without increasing recording contact diameter to maximize recording resolution. RESULTS: Embedding electrodes in real or artificial skull allows one to lower electrode impedance without increasing the recording contact diameter by making use of conductive channels that extend into the skull. The higher density of small contacts embedded in the artificial skull in this testbed enables one to optimize electrode spacing for use in real bone. COMPARISON WITH EXISTING METHODS: For brain monitoring applications, skull-embedded electrodes fill a gap between electroencephalograms recorded on the scalp surface and the more invasive epidural or subdural electrode sheets. CONCLUSIONS: Embedding electrodes into the skull or in skull replacement pieces may provide a safe, convenient, minimally-invasive alternative for chronic brain monitoring. The manufacturing methods described here will facilitate further testing of skull-embedded electrodes in animal models.

Relationship between microelectrode array impedance and chronic recording quality of single units and local field potentials.

Practical application of intracortical microelectrode technology is currently hindered by the inability to reliably record neuronal signals chronically. The precise mechanism of device failure is still under debate, but most likely includes some combination of tissue reaction, mechanical failure, and chronic material degradation. Impedance is a measure of the ease with which current flows through a working electrode under a driving voltage. Impedance has been hypothesized to provide information about an electrode's surrounding tissue reaction as well as chronic insulation degradation. In this study, we investigated the relationship between an electrode's impedance and its chronic recording performance as measured by the number of isolatable single units and the quality of local field potential recordings. Two 64-channel electrode arrays implanted in separate monkeys were assessed. We found no simple relationship between impedance and recording quality that held for both animals across all time periods. This suggests that future investigations on the topic should adopt a more fine-grained within-day and within-animal analysis. We also found new evidence from local field potential spatial correlation supporting the theory that insulation degradation is an important contributor to electrode failure.

Speaking and cognitive distractions during EEG-based brain control of a virtual neuroprosthesis-arm.

BACKGROUND: Brain-computer interface (BCI) systems have been developed to provide paralyzed individuals the ability to command the movements of an assistive device using only their brain activity. BCI systems are typically tested in a controlled laboratory environment were the user is focused solely on the brain-control task. However, for practical use in everyday life people must be able to use their brain-controlled device while mentally engaged with the cognitive responsibilities of daily activities and while compensating for any inherent dynamics of the device itself. BCIs that use electroencephalography (EEG) for movement control are often assumed to require significant mental effort, thus preventing users from thinking about anything else while using their BCI. This study tested the impact of cognitive load as well as speaking on the ability to use an EEG-based BCI. FINDINGS: Six participants controlled the two-dimensional (2D) movements of a simulated neuroprosthesis-arm under three different levels of cognitive distraction. The two higher cognitive load conditions also required simultaneously speaking during BCI use. On average, movement performance declined during higher levels of cognitive distraction, but only by a limited amount. Movement completion time increased by 7.2%, the percentage of targets successfully acquired declined by 11%, and path efficiency declined by 8.6%. Only the decline in percentage of targets acquired and path efficiency were statistically significant (p < 0.05). CONCLUSION: People who have relatively good movement control of an EEG-based BCI may be able to speak and perform other cognitively engaging activities with only a minor drop in BCI-control performance.

Stereoelectroencephalography for continuous two-dimensional cursor control in a brain-machine interface.

Stereoelectroencephalography (SEEG) is becoming more prevalent as a planning tool for surgical treatment of intractable epilepsy. Stereoelectroencephalography uses long, thin, cylindrical "depth" electrodes containing multiple recording contacts along each electrode's length. Each lead is inserted into the brain percutaneously. The advantage of SEEG is that the electrodes can easily target deeper brain structures that are inaccessible with subdural grid electrodes, and SEEG does not require a craniotomy. Brain-machine interface (BMI) research is also becoming more common in the Epilepsy Monitoring Unit. A brain-machine interface decodes a person's desired movement or action from the recorded brain activity and then uses the decoded brain activity to control an assistive device in real time. Although BMIs are primarily being developed for use by severely paralyzed individuals, epilepsy patients undergoing invasive brain monitoring provide an opportunity to test the effectiveness of different invasive recording electrodes for use in BMI systems. This study investigated the ability to use SEEG electrodes for control of 2D cursor velocity in a BMI. Two patients who were undergoing SEEG for intractable epilepsy participated in this study. Participants were instructed to wiggle or rest the hand contralateral to their SEEG electrodes to control the horizontal velocity of a cursor on a screen. Simultaneously they were instructed to wiggle or rest their feet to control the vertical component of cursor velocity. The BMI system was designed to detect power spectral changes associated with hand and foot activity and translate those spectral changes into horizontal and vertical cursor movements in real time. During testing, participants used their decoded SEEG signals to move the brain-controlled cursor to radial targets that appeared on the screen. Although power spectral information from 28 to 32 electrode contacts were used for cursor control during the experiment, post hoc analysis indicated that better control may have been possible using only a single SEEG depth electrode containing multiple recording contacts in both hand and foot cortical areas. These results suggest that the advantages of using SEEG for epilepsy monitoring may also apply to using SEEG electrodes in BMI systems. Specifically, SEEG electrodes can target deeper brain structures, such as foot motor cortex, and both hand and foot areas can be targeted with a single SEEG electrode implanted percutaneously. Therefore, SEEG electrodes may be an attractive option for simple BMI systems that use power spectral modulation in hand and foot cortex for independent control of 2 degrees of freedom.

Engineering therapies in the CNS: what works and what can be translated.

Engineering is the art of taking what we know and using it to solve problems. As engineers, we build tool chests of approaches; we attempt to learn as much as possible about the problem at hand, and then we design, build, and test our approaches to see how they impact the system. The challenge of applying this approach to the central nervous system (CNS) is that we often do not know the details of what is needed from the biological side. New therapeutic options for treating the CNS range from new biomaterials to make scaffolds, to novel drug-delivery techniques, to functional electrical stimulation. However, the reality is that translating these new therapies and making them widely available to patients requires collaborations between scientists, engineers, clinicians, and patients to have the greatest chance of success. Here we discuss a variety of new treatment strategies and explore the pragmatic challenges involved with engineering therapies in the CNS.

Extracting Attempted Hand Movements from EEGs in People with Complete Hand Paralysis Following Stroke.

This study examines the feasibility of using electroencephalograms (EEGs) to rapidly detect the intent to open one's hand in individuals with complete hand paralysis following a subcortical ischemic stroke. If detectable, this motor-planning activity could be used in real time to trigger a motorized hand exoskeleton or an electrical stimulation device that opens/closes the hand. While EEG-triggered movement-assist devices could restore function, they may also promote recovery by reinforcing the use of remaining cortical circuits. EEGs were recorded while participants were cued to either relax or attempt to extend their fingers. Linear-discriminant analysis was used to detect onset of finger-extension from the EEGs in a leave-one-trial-out cross-validation process. In each testing trial, the classifier was applied in pseudo-real-time starting from an initial hand-relaxed phase, through movement planning, and into the initial attempted-finger-extension phase (finger-extension phase estimated from typical time-to-movement-onset measured in the unaffected hand). The classifiers detected attempted-finger-extension at a significantly higher rate during both motor-planning and early attempted execution compared to rest. To reduce inappropriate triggering of a movement-assist device during rest, the classification threshold could be adjusted to require more certainty about one's intent to move before triggering a device. Additionally, a device could be set to activate only after multiple time samples in a row were classified as finger-extension events. These options resulted in some sessions with no false triggers while the person was resting, but moderate-to-high true trigger rates during attempted-movements.

Discreet discrete commands for assistive and neuroprosthetic devices.

Many new assistive devices are available for individuals paralyzed below the neck due to spinal cord injury. Severely paralyzed individuals must be able to command their complex assistive devices using remaining activity from the neck up. Electromyographic (EMG) sensors enable people to use contractions of head and neck muscles to generate multiple proportional command signals. Electroencephalographic (EEG) signals can also be used to generate commands for assistive device control by conveying information about imagined or attempted movements. Fully-implanted wireless biopotential detection systems are now being developed to reliably detect EMGs, EEGs, or a mixture of the two from recording electrodes implanted just under the skin or scalp thus eliminating the need for externally worn hardware on the head or face. This present study shows how novel patterns of jaw muscle contractions, detected via biopotential sensors on the scalp surface or implanted just under the scalp, can be used to generate reliable discrete EMG commands, which can be differentiated from patterns generated during normal activities, such as chewing. These jaw contractions can be detected with sensors already in place to detect other muscle- or brain-based command signals thus adding to the functionality of current device control systems.

Virtual reality hardware and graphic display options for brain-machine interfaces.

Virtual reality hardware and graphic displays are reviewed here as a development environment for brain-machine interfaces (BMIs). Two desktop stereoscopic monitors and one 2D monitor were compared in a visual depth discrimination task and in a 3D target-matching task where able-bodied individuals used actual hand movements to match a virtual hand to different target hands. Three graphic representations of the hand were compared: a plain sphere, a sphere attached to the fingertip of a realistic hand and arm, and a stylized pacman-like hand. Several subjects had great difficulty using either stereo monitor for depth perception when perspective size cues were removed. A mismatch in stereo and size cues generated inappropriate depth illusions. This phenomenon has implications for choosing target and virtual hand sizes in BMI experiments. Target-matching accuracy was about as good with the 2D monitor as with either 3D monitor. However, users achieved this accuracy by exploring the boundaries of the hand in the target with carefully controlled movements. This method of determining relative depth may not be possible in BMI experiments if movement control is more limited. Intuitive depth cues, such as including a virtual arm, can significantly improve depth perception accuracy with or without stereo viewing.

Signal acquisition and analysis for cortical control of neuroprosthetics.

Work in cortically controlled neuroprosthetic systems has concentrated on decoding natural behaviors from neural activity, with the idea that if the behavior could be fully decoded it could be duplicated using an artificial system. Initial estimates from this approach suggested that a high-fidelity signal comprised of many hundreds of neurons would be required to control a neuroprosthetic system successfully. However, recent studies are showing hints that these systems can be controlled effectively using only a few tens of neurons. Attempting to decode the pre-existing relationship between neural activity and natural behavior is not nearly as important as choosing a decoding scheme that can be more readily deployed and trained to generate the desired actions of the artificial system. These artificial systems need not resemble or behave similarly to any natural biological system. Effective matching of discrete and continuous neural command signals to appropriately configured device functions will enable effective control of both natural and abstract artificial systems using compatible thought processes.

Information conveyed through brain-control: cursor versus robot.

Microwire electrode arrays were implanted in the motor and premotor cortical areas of rhesus macaques. The recorded activity was used to control the three-dimensional movements of a virtual cursor and of a robotic arm in real time. The goal was to move the cursor or robot to one of eight targets. Average information conveyed about the intended target was calculated from the observed trajectories at 30-ms intervals throughout the movements. Most of the information about intended target was conveyed within the first second of the movement. For the brain-controlled cursor, the instantaneous information transmission rate was at its maximum at the beginning of each movement (averaged 4.8 to 5.5 bits/s depending on the calculation method used). However, this instantaneous rate quickly slowed down as the movement progressed and additional information became redundant. Information was conveyed more slowly through the brain-controlled robot due to the dynamics and noise of the robot system. The brain-controlled cursor data was also used to demonstrate a method for optimizing information transmission rate in the case where repeated cursor movements are used to make long strings of sequential choices such as in a typing task.

Direct cortical control of 3D neuroprosthetic devices.

Three-dimensional (3D) movement of neuroprosthetic devices can be controlled by the activity of cortical neurons when appropriate algorithms are used to decode intended movement in real time. Previous studies assumed that neurons maintain fixed tuning properties, and the studies used subjects who were unaware of the movements predicted by their recorded units. In this study, subjects had real-time visual feedback of their brain-controlled trajectories. Cell tuning properties changed when used for brain-controlled movements. By using control algorithms that track these changes, subjects made long sequences of 3D movements using far fewer cortical units than expected. Daily practice improved movement accuracy and the directional tuning of these units.