Douglas J. Weber, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): The NIH neuroprosthesis program has fostered so much success in the area of cortically controlled neuroprostheses that the FDA has approved multiple human trials to test the safety and efficacy of cortical implants for brain machine interfaces (BMI). An important application of BMI technologies is the direct cortical control of prosthetic limbs. However, a critical gap in this effort is the lack of somatosensory feedback which is needed to support proprioception and tactile sensations for the artificial limb. We propose that multichannel microstimulation of primary afferent neurons in the dorsal root ganglia (DRG) would provide a viable and preferred route for restoring natural sensation of limb posture, movement, force, and tactile sensation. This approach is similar, in principle, to that of the cochlear implant, which uses multichannel electrical stimulation of auditory nerves to restore hearing to people with profound deafness. The primary objective of the proposed research is to create a new animal (cat) model for developing a neural interface with somatosensory afferent neurons in the cervical DRG. Our approach builds on our previous success with obtaining acute and chronic single unit recordings from large numbers of primary afferents in the lumbar DRG of cats (Stein et al. 2004; Weber et al. 2006). The proposed model will serve two important goals: 1) the development of a somatosensory neural interface for the neuroprosthetic applications described above and 2) basic investigations into the sensory feedback control of arm movement. It is useful to pursue these goals in parallel, because a comprehensive understanding of the role and nature of sensory feedback related to limb-state will guide the design and implementation of neuroprostheses that interface directly with the nervous system for feedback and control. The goal of this proposal is to develop a technique for providing proprioceptive sensations to users of prosthetic limbs using multichannel electrical microstimulation of primary afferent neurons in the dorsal root ganglia (DRG). This approach is similar, in principle, to that of the cochlear implant which uses patterned electrical stimulation of auditory nerves to restore hearing to people with profound deafness. These experiments will quantify the extent to which artificial electrical stimulation of peripheral afferents can drive natural patterns of neuronal activity in somatosensory regions of the brain. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The proposed research program will serve complementary objectives in neuroscience and neural engineering. The neuroscience objective is to further knowledge of the role and nature of somatosensory feedback in multi-joint limb control. The engineering objective is to design a system for extracting limb-state information (e.g. limb position and velocity) from the firing rate modulations of primary afferent neurons. State feedback is required for closed-loop control of functional electrical stimulation systems, which are used to restore action to muscles paralyzed by spinal cord or other central nervous system injuries. To achieve these goals, we are using state-of-the-art technologies that enable large numbers of afferent neurons to be recorded simultaneously and chronically during natural motor behaviors such as standing, walking, and reaching. Multichannel recordings are essential for this work, because there are multiple degrees-of-freedom for joint movement and several different kinematic and kinetic state variables that are of interest for closed- loop control applications. These data also permit the direct examination of the role and nature of primary afferent neurons in the perception of body state known as proprioception which is formed through the integration of multiple primary afferent neuronal inputs. This proposal will achieve 4 Specific Aims, with each Aim being an incremental progression toward fulfilling the broader goals stated above. Specific Aim 1 is to quantify, using Information Theory, the limb-state information conveyed by single neurons under the following conditions: 1) intact spinal cord, 2) acutely transected spinal cord, and 3) chronically transected spinal cord. These results will be used to evaluate changes in the quality and reliability of information transmitted by primary afferent neurons before and after spinal cord injury, a condition known to cause plastic changes in spinal neuronal circuitry potentially altering the response properties of muscle spindles. Using a decerebate cat preparation, the following state variables for the hindlimb will be studied: position, velocity, acceleration, endpoint force (e.g. ground reaction force during stance), and stance phase joint-torque. Neural recordings will be made during limb movements imposed by a robot arm attached to the foot. The state variables will be measured in reference frames based in intrinsic, joint-space coordinates (i.e. intersegmental angles) or extrinsic, end point-space coordinates (i.e. Cartesian or polar coordinates for the toe relative to the hip) to compare the extent to which state-information carried by afferent neurons depends on the chosen frame of reference. Specific Aim 2 is to use the data collected in SA-1, to develop mathematical models to decode position, velocity, force, and torque information from the ensembles of simultaneously recorded afferent neurons. Specific Aim 3 is to decode in near real-time, limb-state from ensemble firing rates of afferent neurons recorded during hindlimb stepping movements evoked by passive movement and fixed-pattern electrical stimulation in intact spinal cord and chronically spinalized decerebrate cats. Specific Aim 4 is to implement online state-feedback decoding (SA-3) in a finite state control system for FES-evoked hindlimb stepping in intact spinal cord and chronically spinalized decerebrate cats.

DESCRIPTION (provided by applicant): The NIH neuroprosthesis program has fostered so much success in the area of cortically controlled neuroprostheses that the FDA has approved multiple human trials to test the safety and efficacy of cortical implants for brain machine interfaces (BMI). One important application of BMI technologies is the direct cortical control of prosthetic limbs. Recent advances in this field have led to the creation of the most capable prosthetic arms yet developed, including the DEKA 'Luke arm' and Johns Hopkins APL 'Modular Prosthetic Limb'. However, a critical gap in this effort is the lack of somatosensory feedback which is needed to support propriception and tactile sensations for the artificial limb. Without these sensations, users will never achieve maximum benefit from these advanced limbs, because without sensory feedback, these devices will remain as numb, extracorporeal 'tools', rather than integrated fully functional limbs. Our goals are twofold: to better understand the nature of sensory feedback and the way in which peripheral sensory activity is conveyed to primary somatosensory cortex (S1), and to develop a somatosensory neural interface (SSNI) that will provide the user with proprioceptive feedback for their neuroprosthesics limb. We have previously proposed that primary afferent microstimulation (PAMS) in the dorsal root ganglia (DRG) can be used to deliver surrogate somatosensory feedback to the central nervous system. We have demonstrated that in cats, PAMS can recruit small populations of afferents from a variety of sensory modalities (Gaunt et al. 2009) and that this stimulation can transmit meaningful activity to S1 (Weber et al. 2011). The success achieved during the development of this animal model generated a number of new questions and hypothesis upon which a series of new experiments are proposed. Specifically, these experiments focus on characterizing the ability of PAMS to 1) transmit sensory information to S1 in anesthetized cats when the PAMS patterns are based on neural activity recorded in the DRG during movement, 2) transmit discriminable sensory information to S1 in anesthetized cats when the PAMS patterns are based on fabricated static and dynamic inputs, and 3) transmit discriminable sensory information to S1 in awake standing cats, useful for modifying postural responses to ground support perturbations. These experiments range from further investigations of the capabilities of PAMS to testing the ability of PAMS to predictably modify motor behaviors. This work will further the development of a SSNI, critical for the future of BMI based prosthetic limbs, as well as address fundamental questions regarding the role of sensory feedback in the control of normal motor behaviors. PUBLIC HEALTH RELEVANCE: Trauma, vascular disease, and diabetes are leading causes of limb amputation and sensory deficits in both civilian and military populations. The number of people living with the loss of a limb is expected to more than double to 3.6 million by 2050. Thus, there is an urgent and rapidly growing need for advanced prosthetic limbs that can restore the motor and sensory functions that are lost after amputation. The goal of this proposal is to develop a technique for providing proprioceptive sensations to users of prosthetic limbs using patterned electrical stimulation of sensory neurons in the dorsal root ganglia (DRG). This approach is similar, in principle, to that of the cochlear implant which uses patterned electrical stimulation of auditory nerves to restore hearing to people with profound deafness. The proposed study will determine if DRG stimulation is effective in: 1) delivering proprioceptive information to the brain and 2) providing feedback that is useful for maintaining balance during postural perturbations.

Spatial presence, in Virtual Reality (VR) terminology, refers to the perception (or illusion) of being physically present in a simulated environment. VR strives to create interactive environments that provide experiences of spatial presence through accurate delivery and perception of multimodal sensory stimuli. Research in VR spans fields ranging from neuroscience and medicine to gaming. While the computing and gaming industries have generated tremendous advances in hardware and software for graphics processing and 3D display technologies, VR systems still lack capabilities for providing users with haptic feedback (a sense of touch), which is crucial for generating truly immersive, real-world experiences. It is known that an increase in the feeling of spatial presence manifests itself in the form of increased brain activity. This research aims to achieve the control of haptic sensory stimulation adaptively, based on the changes in brain activity associated with perceptual responses elicited by sensory stimulation in VR environments. Project outcomes will include novel scientific discoveries and engineering enhancements that will make significant contributions to other areas of interest, such as prosthetic limbs, augmented reality, and telepresence applications. The project will help train a new generation of engineers skilled in addressing multidisciplinary challenges, while through outreach activities STEM careers will be promoted at the K-12 level.

The research objective is to identify and analyze brain activity associated with the increased feeling of haptic spatial presence elicited by electro-tactile stimulation and measured through EEG, and to investigate closed-loop techniques to control electro-tactile stimulation for enhanced haptic presence in VR environments. Specifically, the project will: (1) develop an electrical haptic stimulation framework; (2) design analysis techniques to identify markers of haptic inputs in EEG; (3) establish control policies for adaptive electrical stimulation; and (4) evaluate and refine EEG-guided adaptive stimuli control framework in VR environments. In particular, the proposition to actuate haptic feedback through electrical stimulation is novel, while formulating design principles for model-based optimal EEG-guided closed-loop haptic feedback for immersive spatial presence is transformative. Additional innovative propositions to advance adaptive control under uncertainty and psychophysical investigations are unique; these present a potentially game-changing opportunity for VR system development and perhaps for general human-computer interaction.

PROJECT SUMMARY / ABSTRACT Recent advances in design and actuation have led to important improvements in prosthetic limbs. However, these devices lack a means for providing direct sensory feedback, requiring users to infer information about limb state from pressure on the residual limb. Lack of sensation limits their ability to control the prosthesis and leads to slow gait and increased risk of falling. There is also evidence that lack of sensory feedback contributes to phantom limb pain (PLP), and that electrical stimulation at the dorsal root ganglia (DRG) can reduce PLP. The primary objective of this study is to use commercially available, FDA-cleared spinal cord stimulator (SCS) leads to test the effects of electrical stimulation of the DRG and dorsal rootlets (DR) as a means of restoring naturalistic sensation (e.g. pressure, movement), reducing PLP, and improving gait function in transtibial amputees. We will use stimulation to (1) produce sensations of pressure and joint movement, (2) reduce PLP, (3) evoke patterns of muscle activity that mimic automatic responses that occur normally during standing and walking, and (4) improve postural stability when standing and walking with a sensorized prosthesis. Aim 1: Use stimulation of the DRG/DR to generate naturalistic sensations of pressure and joint movement, localized to the amputated limb, and achieve a clinically relevant reduction in phantom limb pain To provide intuitive feedback, evoked sensations should be perceived as originating in the amputated limb and should feel naturalistic. A concomitant reduction in PLP may also have important effects on quality of life. We will perform detailed psychophysical testing in which stimulation parameters are varied while study participants are asked to report information about the evoked sensation (e.g. location, modality, naturalness) and the effects on PLP. Aim 2: Characterize the motor responses in the intact and amputated limbs evoked by DRG/DR stimulation and their relationship to stimulation parameters Bilaterally coordinated reflexes play an important role when responding to unexpected perturbations like slips and trips. Additionally, the transitions between phases of gait are largely mediated by reflexive responses to sensory input from the legs. For a prosthesis to restore the full capabilities of the amputated limb during standing and walking, the ability to evoke and precisely control these patterns of reflexive activity will be critical. We will record electromyogram (EMG) signals from the limbs during standing and walking while varying stimulus patterns and quantify the relationships between stimulation parameters and evoked reflexive responses. Understanding these relationships will aide in the programming of stimulation patterns for functional prosthesis use. Aim 3: Decrease postural sway and increase gait stability by providing sensory feedback via DRG/DR stimulation To quantify the functional impact of sensory restoration on prosthetic limb usage, we will instrument each participant's prosthetic limb with a pressure sensitive insole and joint angle sensors, and use signals from these devices to modulate stimulation. We will perform a battery of posture and balance measures, and we will track changes in functional prosthesis usage after a 7-day take-home trial of the device.

7. Project Summary Multiple early feasibility trials in humans have demonstrated that implantable Brain-Computer Interfaces (BCIs) can enable people with severe paralysis to use neural signals to control remote and digital communication technologies, including messaging and email. Such studies have demonstrated clearly that BCIs have the potential to improve the quality of life of patients who have physical disability due to paralysis of speech and upper limbs. However, until these technologies are commercialized, access to BCIs will remain limited to people involved in research studies, and only for the duration of their enrolment in the study. To address this unmet need, Synchron, Inc. has developed the StentrodeTM system, a fully implantable BCI that communicates wirelessly to an external interface on a mobile computing platform. The StentrodeTM BCI is a 16-channel array of sensors integrated into a self-expanding, stent-like substrate. The StentrodeTM is delivered endovascularly via a catheter to the Superior Sagittal Sinus, where it measures volitionally-modulated neural signals from the leg area of motor cortex in both hemispheres. A fully implantable, wireless telemetry unit digitizes and transmits the neural signals from the StentrodeTM to an external mobile processor that converts the neural signals into commands for operating a computer or other assistive device, such as a speller for communication. The Synchron team has already initiated a first-in-human trial of the StentrodeTM BCI system in Melbourne, Australia, under approvals granted by the Therapeutic Goods Administration (TGA) of Australia and the IRB of the Royal Melbourne Hospital. The first human implant was performed in a person with amyotrophic lateral sclerosis (ALS) in August, 2019. The participant has experienced no adverse events and is using the system to operate a computer and type messages to friends, family, and caregivers. The objective of the proposed research is to demonstrate in an Early Feasibility Study (EFS) that the StentrodeTM BCI communication system is safe and effective in providing a quantifiable improvement in independence and quality of life in n=6 people with severe paralysis due to ALS. Two Specific Aims are proposed: 1) Preclinical assessment of the StentrodeTM for safety and functionality to complete an FDA submission, and 2) Testing of StentrodeTM?s safety and efficacy in an EFS clinical trial in two centers of excellence in the USA. Under Aim 1 (UG3 phase), preclinical safety studies and software validation in large animal studies will be completed to test robustness of StentrodeTM, compliance to safety standards for Class III electromechanical implants, safety and baseline functionality in a large animal model, efficacy of custom-built software, and a functional neuroimaging study to support presurgical planning. Under Aim 2 (UH3 phase), an EFS study will test safety of StentrodeTM placement, monitoring adverse events, target patency, and device migration. When combined with eye-tracking technology, users will be trained to perform computer-based tasks using eye-gaze to control cursor position and BCI outputs to control discrete actions, such as letter or menu-item selection and zoom. Clinical efficacy outcomes will assess the restoration of independent function by use of personal devices, including technical capability (click and typing speed and accuracy, smart home, IoT, haptic feedback), independent domestic functionality (I-ADLs) and QOL and mental wellbeing (WHOQOL, MacGill QOL, HADS).

Project Summary/Abstract: Clinical trials targeting the reduction of amyloid-? and hyperphosphorylated tau load have been largely unsuccessful against neurodegenerative diseases including Alzheimer?s (AD) and AD-related dementias (ADRD). This may be due to the relatively late stage at which they are deployed, wherein cognitive symptoms are already manifest and the underlying inflammatory and degenerative processes are well underway. Conversely, prophylactic intervention aims to prevent or mitigate initiation of harmful, self-propagating disease processes before they become uncontrollable. For a treatment to be used prophylactically, ie before the presence of significant symptoms, it must be ?trivially invasive?, simple to use, and inexpensive. This is critical for the expected benefits when deployed before symptoms to outweigh the potential risks. In this supplement, we propose a novel application of the minimally invasive InjectrodeTM technology outlined in the parent award to treat pain, to target brain waste clearance and cerebral hemodynamics through cranial nerve stimulation as a potential prophylactic strategy to combat AD. The Injectrode consists of a polymer matrix which is liquid in a syringe but quickly cures into a solid form when injected into the body. This technology offers many advantages over traditionally made electrodes amenable to prophylactic use including minimally invasive implantation (a simple injection). The successful completion of these aims would provide pilot data demonstrating the Injectrode concept can be utilized to improve the clearance of molecules within the brain, while identifying likely physiological components driving CSF/ISF interchange for future optimization.