Timothy H. Lucas, M.D., Ph.D. - US grants

PI: Lucas, Timothy H.
Proposal Number: 1404041
Institution: University of Pennsylvania
Title: A wireless sensor-brain interface to restore finger sensation

The objective of this project is to develop a device, called a sensor-brain interface (SBI), which can restore the sense of touch and the sense of movement in a paralyzed hand. Considerable evidence suggests that these sensations will greatly improve a person?s ability to regain function of their hand. When combined with a therapy for restoring movement, the SBI has the potential to improve the quality of life of millions of people with hand paralysis due to spinal cord injury or other neurological conditions. The SBI has three components: sensors worn on the fingers, electronics that convert the sensor signals into appropriate electrical stimulation patterns, and stimulating electrodes to convey the signals directly to the brain. Novel designs are used for each of these components to achieve a system that is unobtrusive to wear and intuitive to use. The first two components have broader significance in the rapidly expanding field of wearable technology. The third component will inform the multitude of clinical therapies using electrical stimulation to modulate brain function. Collectively, the three components will yield a substantial vertical step towards reconnecting body and brain after paralysis.

Somatosensory signals are critical to normal motor function but their transmission, as with movement commands, is interrupted in paralysis. Neuroprosthetic devices are typically designed to restore movement but not sensation in the paralyzed limb. The resulting modest performance has not justified the use of these devices in a wide clinical population. To improve performance, the investigators will develop a sensor-brain interface (SBI) with the goal of restoring sensation to a paralyzed hand. The SBI has three components corresponding to the three aims of the project. The first aim is to make wearable tactile and motion sensors that are small and completely wireless and therefore unobtrusive to the user. The investigators will pursue two types of novel battery-free sensors of mechanical stimuli: (1) a battery-free active sensor of fingertip vibration powered by harvesting energy from emitted radio waves and (2) a fully-passive, circuit-free sensor using flexible radiofrequency identification tags to sense fingertip pressure and finger joint angle. The second aim is to design a body-area network (BAN) to wirelessly acquire and process the sensor output, configurably map the sensed signals to neural stimulation parameters, and wirelessly convey the parameters to a neural stimulator. The BAN will be accomplished with two, battery-powered, low-power circuits: (1) a sensor controller worn at the wrist and (2) a stimulation controller worn near the head. The third aim is to perform in-vivo tests to validate function of the SBI and evaluate the hypothesis that the cuneate nucleus (CN) of the brainstem is an advantageous site for encoding somatosensory information. The CN maximizes the amount of downstream neural circuitry available to process the artificial stimuli and to make the resulting percepts more intuitive to the user. The encoding performance will be compared to a more conventional, cortical encoding site. Finally, two different encoding paradigms will be compared to assess their relative merit. The scope of this project is to develop a functional SBI prototype and test the device in non-human primates. Following completion of the project, the investigators envision that the SBI could be combined with brain-controlled muscle stimulation for a complete, bidirectional, sensorimotor neuroprosthesis for reanimating a paralyzed hand.

PROJECT SUMMARY Paralysis following spinal cord injury is a devastating condition for which there is no adequate treatment. The injury disrupts motor and sensory communication between the brain and body. Re-establishing communication with a brain-machine interface (BMI) remains one of the most promising treatment strategies. A BMI establishes connections between (1) recorded brain signals and a device, e.g. a robotic hand, to provide motor output and (2) external sensors, e.g. of grasp force, and brain stimulation to provide sensory feedback. Recently, two independent studies have demonstrated that it is possible to reanimate an individual's own paralyzed hand, using brain-controlled muscle stimulation, instead of relying on a robotic device. This major advance provides a clear pathway toward naturalistic restoration of motor function after paralysis. However, the critical issue of how to provide a sense of touch for reanimated paralyzed hands has not been addressed. Ideally, tactile sensors for a reanimated human hand should be transparent to the user: implanted devices free from the constraints of gloves or wires. Previous tactile sensors for BMIs have been designed for robotic hands, where issues of size, power, and data transmission are less constrained. Thus, new technology is needed. In this project, we will develop an implantable, wireless tactile feedback system designed specifically for the human hand. First, we aim to develop a miniature, silica-based hermetic package with a built-in network of capacitors sensitive to normal and shear forces over a physiological range. Second, we aim to design an application-specific integrated circuit (ASIC) to be housed inside the implantable package to process the sensor capacitance changes and wirelessly transmit the data to a battery-powered base unit worn on the wrist. The base unit will also remotely power the ASIC through magnetic resonance at MHz frequencies, using the body as a communication channel. Third, we aim to test the complete, wireless sensor system in the non- human primate hand. The sensitive and stability of the implanted sensor output will be quantified and its function in the presence of simultaneous muscle stimulation assessed. This project leverages a strong collaboration between investigators with expertise in surgery, neuroengineering, microelectromechanical systems, low-power sensor electronics, and radiofrequency integrated circuits. The microfabricated sensor, hermetic packaging, wireless powering, and wireless read-out technology will provide important advances to the field of implantable medical devices. Ultimately, the sensor system could be combined with brain-controlled muscle stimulation to provide closed-loop hand reanimation in paralyzed subjects, with large expected gains in performance. The addition of tactile feedback to reanimation strategies would be a substantial step towards a clinical BMI allowing the thousands of newly paralyzed individuals each year to regain functional independence.

PROJECT SUMMARY Brain activity never ceases. When we are asleep, inattentive, or even under general anesthesia, networks of interconnected neurons in the human brain continue to spontaneously generate complex activity patterns. Sensory stimuli perturb this ongoing spontaneous neuronal activity. In order to be consciously detected, the effect of this perturbation needs to be large enough so as to engage thousands of neurons and persist for at least several hundred milliseconds. When we are awake and attentive, the smallest stimuli are sufficient to elicit a large perturbation. Under general anesthesia, however, even the most noxious stimuli do not reach the threshold for conscious perception. Here we address a fundamental question: why are sensory stimuli able to perturb neuronal activity in some states but not in others? We hypothesize that the ability of the sensory stimuli to perturb neuronal activity is related to the property of dynamical systems termed stability. If neuronal dynamics were unstable, the effect of any perturbation would grow over time without bounds and engage ever increasing number of neurons. Conversely, if the dynamics were too stable, then all perturbations will quickly dampen down and fail to reach threshold of perception. Thus, we hypothesize that conscious perception is most likely to occur when the neuronal dynamics are poised precisely between the stable and unstable regimes. We refer to this point as critical. To test the criticality hypothesis, we developed novel mathematical techniques and applied them to neurophysiological recordings in humans and in nonhuman primates. These preliminary findings strongly support the hypothesis. In the proposed project, we will rigorously test the criticality hypothesis using electrocorticography (ECoG) in human subjects implanted with electrodes for epilepsy localization. We will determine how the stability of spontaneous activity varies as a function of sleep and wake, attentiveness and drowsiness, as well as sedation and general anesthesia. We will validate the criticality hypothesis and our ability to estimate stability of neuronal activity by predicting responses to electrical brain stimulation. Using an auditory masked speech detection task, we will also determine whether stability of neuronal dynamics can be used to predict whether a natural stimulus presented at perceptual threshold will be consciously detected. While many other measures of neuronal activity have been previously associated with changes in arousal and perception, at present, it is not possible to apply the existing measures to unequivocally distinguish between activity in the conscious and unconscious brain. Hence, validating this criticality hypothesis would be a major advance. In addition to addressing a fundamental issue in neuroscience, finding an objective and quantifiable measure of sensory responsiveness has profound clinical significance in neurology and in anesthesiology where diagnoses of covert awareness under anesthesia or after brain injury cannot be made reliably with existing technology.

PROJECT SUMMARY/ABSTRACT The rapid development of novel molecular therapies for neurological disorders has led to a rapid progress in the translational pipeline: to date, there are multiple active clinical trials and one therapy has already been approved by FDA. Most commonly, gene therapies rely on Adeno Associated Virus (AAV) due to its safety, transduction efficiency, and long-term gene expression. In programs where AAV delivers cargo to restricted brain regions, it requires direct intracerebral injection. For instance, in Parkinson?s (PD) and Huntington?s disease (HD) a deep forebrain nucleus known as the putamen is often the target. However, complete coverage and efficient transduction of the entire putamen with AAV is challenging. Current delivery methods require multiple stereotactic injections through a single cannula. The serial nature of these injections is not only time consuming, but adds the risks of multiple brain penetrations and iterative displacement of the target. Furthermore, even in the most successful cases, the transduction efficiency of gene vectors delivered via single point injections is < 50%, which ultimately severely affects therapeutic efficacy. Beyond gene therapy, inadequate delivery is also critically affecting the efficacy of a number of other therapies relying on direct brain delivery, such as chemical and molecular platforms for treatment of glioblastoma. Inspired by this critical unmet need, we have developed a novel device for highly efficient intracerebral injections that minimizes risks. The Multipoint Injection Technology (MINT) consists in a central catheter integrating three moveable microcannulas connected to a central actuation mechanism for precise targeting and positioning, as well as maximization of volume coverage. Compared to current single cannula systems, MINT allows simultaneous injections from multiple microcannulas, thus eliminating the need for serial trajectories and potentially significantly reducing complexity, duration, and cost of the surgery. Furthermore, MINT is compatible with magnetic resonance imaging (MRI) and can be seamlessly integrated with the current surgical workflows based on MR-guidance and monitoring. Finally, the radial configuration and the multiple injections sites along each microcannula result in a more uniform distribution of the infusate in the tissue, thus maximizing the volume distribution and enabling targeting of different brain regions. In this project, we will advance this highly efficient intracerebral injection technology by validating it for MR-guided injections with benchtop tests and in vivo in non-human primates. Upon completion of this project, we expect to move the field forward by generating and validating a new delivery device that will significantly improve coverage, while reducing surgical time and number of transcortical trajectories. Overall this proposal will establish the future clinical potential of the multipoint injection device as a potentially transformative and enabling solution for highly efficient intracerebral delivery of gene-based, molecular, and pharmacological therapies and pave the way for fundamental innovations in the clinical care of neurological disorders.