Karunesh Ganguly - US grants

? DESCRIPTION (provided by applicant): Stroke is a major cause of disability. Despite significant advances in stroke rehabilitation methods there continue to be substantial long-term disability. Additional research is required to further our understanding and to develop new methods to facilitate recovery. Over the past decade, there have been impressive advances in electrophysiological recording technology and computational approaches. Studies using these methods in healthy animals support a conceptual framework for highly dynamic interactions between neurons and the broader motor networks. For motor recovery after stroke, the precise spatiotemporal dynamics at the single neuron, ensemble and network oscillation level remain unclear. Such knowledge can lead to the development of more targeted modulation of recovering circuits and the enhancement of motor recovery (e.g. physiological electrical stimulation or pharmacological activation of specific neural subtypes). We propose to use an in vivo electrophysiological framework to model the long-term network dynamics of the recovery process. We specifically aim to conduct multi-scale chronic monitoring in awake- behaving rodents recovering from a motor cortex stroke. Our preliminary data indicates that synchronous activity driven by oscillations in the ß-band (i.e. 12-30 Hz band in the local field potential) is important for the recovery process and that modulation of it can enhance recovery. The underlying hypothesis of this proposal is that synchronous spike-field interactions in the perilesional cortex is essential for motor recovery. We will pursue the following aims. 1) Determine the spike-field interactions in the perilesional cortex that predict motor recovery after stroke. 2). Assess if state-dependent stimulation during periods of elevated spike-field synchrony is more effective than constant direct current stimulation for motor recovery. 3). Determine the neuronal cell-types that drive the perilesional oscillatory dynamics. Completion of these aims will provide new directions for stroke rehabilitation as well as provide important career development. These lines of investigation have the possibility of discovering important knowledge about the network and the neurophysiological basis of motor recovery and can offer novel approaches to cortical neuromodulation and the enhancement of motor recovery.

? DESCRIPTION (provided by applicant): Patients with tetraplegia, or paralysis of all four limbs, are severely disabled. Surveys have found that restoration of upper-limb function is a high-priority for such patients. Brain-Machine Interfaces (BMIs) can eventually restore upper-limb reaching and grasping function by seamlessly merging the computational power of the brain with artificial prosthetic systems. A major challenge is robust translation of BMI technology to patient care. Two well-recognized limitations of current approaches are instability of recordings and the lack of proprioceptive feedback signals. This research proposal aims to conduct a pilot clinical study to test electrocorticography (ECoG) based control of an anthropomorphic exoskeleton in tetraplegic patients with residual proprioception. We specifically seek to translate BMI technology to the significant subset of tetraplegic patients with intact sensation (e.g. amyotrophic lateral sclerosis or incomplete spinal cord injury). Our approach would capitalize on both the well-recognized stability of ECoG recordings and the natural sensory feedback generated by passive movements of the subject's arm by the exoskeleton. The proposed research should greatly advance translational efforts by optimizing control under conditions that maximize neural learning mechanisms and provide natural sensory feedback.

ABSTRACT Stroke is the leading cause of disability in the United States, with approximately 700,000 new cases per year. Disability from upper limb impairment depends primarily on loss of hand function and finger dexterity. Despite advances in task-specific training for the upper limb, a large number of stroke patients do not regain full function of their hand. Somatosensory peripheral nerve stimulation (PNS) is a promising approach to target recovery of hand motor function in stroke patients. Both short-term and long-term improvements in hand function after stimulation of the peripheral nerves have been demonstrated in stroke patients. However, not all studies have found consistent effects and not all participants have experienced significant benefits. Improvements have also been linked to changes in central nervous system motor networks. Very little is known, however, about how PNS interacts with cortical neurophysiological dynamics. A systematic determination of dosing requirements and mechanisms of action is required for robust clinical translation and for maximal functional restoration in those with chronic motor deficits. Our proposal aims to take an innovative and comprehensive approach involving both human subjects and an animal model of stroke to better target perilesional cortical dynamics. Importantly, our preliminary data in both animals and human stroke subjects demonstrates a link between PNS and changes in resting state cortical dynamics. Our proposal is based on the overall hypothesis that dose titration to specifically target perilesional cortical activity will offer a more robust path to reliable translation and customization of parameters to individuals. Using a within subject study design and kinematic and neurophysiological outcome measures, we propose to conduct studies that will delineate how to modify and structure peripheral nerve stimulation to maximize functional restoration. Completion of our aims will provide essential guidance for the refinement and robust translation of peripheral neuromodulation to stroke patients. Our studies will allow us to: (1) definitively and causally determine how perilesional cortical activity is modified by PNS and (2) determine the link between perilesional cortical activity modulation and motor behavioral effects. We anticipate that we can develop a computational model of how cortical activity is modified in a gradual manner by ongoing PNS. This may allow us to develop novel approaches to PNS that are tailored to ongoing cortical dynamics and highly individualized for each stroke patient's specific pattern of injury.

PROJECT SUMMARY Stroke is the leading cause of motor disability in the United States, with approximately 700,000 new cases per year. Impaired hand and finger control are a leading cause of such disability. Despite advances in task- specific training for the upper limb, a large number of stroke patients do not regain full function of their hand; novel treatment methods are urgently required. We propose to use a systems neuroscience and `neural engineering' framework that captures the dynamic interactions between neurons and the distributed motor network to both characterize and develop novel neurophysiological based neuromodulation approaches to enhance motor function. Studies in healthy animals support a framework for dynamic interactions between local and distant areas through transient oscillations. Oscillations are defined by a frequency bandwidth, e.g. motor areas are known to have task-related low-frequency oscillations (0.5-4 Hz). How the recovery process affects neural activity and oscillatory dynamics in primates preforming dexterous tasks remains unknown? Our recent studies in rats (Ramanathan et al., Nature Medicine 2018; Lemke et al., Nature Neuroscience, 2019) demonstrated that population dynamics linked to low-frequency oscillatory activity (0.5-4Hz ?LFO?) are essential for movement control, track spontaneous recovery and can serve as a target for modulation using electrical stimulation. More specifically, cortical stimulation was found to both boost LFO power and augment motor function. Essential translational steps involve testing whether this approach also works for gyrated brains during the performance of dexterous tasks. This proposal aims to use in vivo electrophysiological methods to model the network dynamics of recovery. The underlying hypothesis is that synchronous LFO spike-field interactions in the perilesional cortex are important for recovery and its modulation can augment dexterous motor function. Importantly, our preliminary data provides strong support for our proposed research goals; we have found that low-frequency oscillatory dynamics drive coordination of sensory and motor areas during recovery and that artificial low-frequency electrical stimulation can boost dexterous function during recovery. Completion of these aims will provide critical information for designing therapeutic approaches that specifically target perilesional oscillatory activity with low frequency electrical stimulation. Focusing on targeted neuromodulation of such dynamic network interactions represents a new direction that could transform our ability to augment upper extremity function following stroke.

PROJECT SUMMARY Stroke is the leading cause of motor disability in the United States. While brain stimulation to enhance motor function after stroke has shown promise in small studies, two recent large stroke trials did not find evidence for significant benefits. A key uncertainty is about how to exactly tailor brain stimulation to effectively modulate neural dynamics associated with movement preparation and control. Our recent studies in rats (Ramanathan et al., Nature Medicine 2018; Lemke et al., Nature Neuroscience, 2019) demonstrated that population dynamics linked to low-frequency oscillatory activity (0.5-4Hz ?LFO?) are essential for movement control and can serve as a target for modulation using electrical stimulation. More specifically, cortical stimulation was found to both boost LFO power and augment motor function. We now also have substantial evidence in a non-human primate model that such an approach can be effective in more complex brains. However, it is essential to further optimize the delivery of such stimulation to specifically target cortical dynamics. We thus propose to optimize parameters for epidural stimulation to selectively modulate population dynamics in the intact motor network. Our approach entails simultaneous recording of single neurons in the non-human primate motor network along with electrical stimulation using a customized ?ring? of epidural cranial screw electrodes. Moreover, we will use computational analysis to determine how task-related neural dynamics in a reach-to-grasp task are modulated by electrical stimulation. More specifically, we will optimize and develop principles for large-scale electrical stimulation to selectively enhance ?neural modes? isolated to M1 or PMd or joint across both areas. This approach is built on the growing consensus that motor networks perform computations through coordinated ensemble activity or ?neural modes?, i.e. patterns of neural covariation measured with dimensionality reduction methods. Activation of neural modes (i.e. Neural Model Activation or NMA) appear to constitute building blocks for computations underlying movement control. Our specific aims are: 1) Determine optimal ACS parameters that increases both local and cross-area NMA between M1 and PMd during a reach-grasp task; 2) Determine optimal ACS parameters that increases both local and cross-area NMA between M1 and S1 during a reach-grasp task; 3) Determine parameters for ACS to enhance task NMA during time periods away from the task. Completion of these aims will provide critical information for designing therapeutic stimulation that selectively targets population dynamics in the distributed motor network. The information gained may also help improve methods for non- invasive brain stimulation.