Dynamic Functional Connectivity Between Cortex and Muscles

The motor-cortex is recognized as the origin of the major direct path from cortex to muscles. Although it has been studied for over a century, relatively little is known about how the motor cortex facilitates reach-to-grasp movements. We collected a rich dataset from monkeys trained to reach and grasp objects of different shapes, presented at various orientations and spatial locations. We simultaneously recorded single-unit activity from motor cortical areas (mainly the caudal bank of the pre-central gyrus), EMG activity from selected muscles (in the arm, wrist and hand) and high-resolution kinematic data from the wrist and hand. We show that motor-cortical neurons modulate their activity in an object specific manner, resulting in object specific co-activation of muscles and joint movements. We studied the multivariate relationships between the firing rates of individual neurons, EMG, joint angles and joint angle velocities and found that both EMG and kinematic features were encoded in the neural firing rates. Kinematic features were much better predictors of neural firing rates than EMG. We found that the best predictors of neural firing rates were neither individual muscles or joints, nor kinematic or EMG synergies extracted using PCA/ICA, but neuron-specific combinations of EMG and kinematic features. We show better predictions of both muscle activations and JA values by combining the activity of a few tens of sequentially recorded neurons; suggesting that neural activity contains synergistic information related to EMG, not independently present in individual neurons. By using functional connectivity, defined as the probability of observing changes in EMG following spikes from a trigger neuron, we further elucidated motor cortical activity to muscle activation. By studying both the short-time scale functional connectivity, on the order of milliseconds; and long-time scale functional connectivity, on the order of hundreds of milliseconds, we found that flexible long-time scale functional connections between individual neurons and muscles were modulated by kinematic features that could account for the relatively weaker neural firing rate relation to EMG. To support our findings, we show examples of simultaneous short-time scale functional connectivity and conclude that neuronal-muscular functional connectivity is flexible and task-dependent

A ventral root interface for neuroprosthetic control of locomotion

Recent advances in state of the art prosthetic limbs have demonstrated unprecedented levels of dexterity and control within the constraints of an anthropomorphic structure. Unfortunately, patients still struggle to naturally control and rely upon relatively simpler lower limb devices with just one or two joints. For patients living with the loss of a limb, functional motor circuitry is still intact through the spinal cord and into the peripheral nerves, transforming higher level control signals into discrete muscle activations. An interface at the spinal roots can take advantage of this final output of the nervous system to control the device, completely avoiding some of the context sensitivity issues in higher level structures. Further, the anatomical separation of motor and sensory signals into distinct ventral and dorsal components and the relative stability of the spinal column provide a path towards a targeted neuroprosthetic interface. This dissertation develops and validates methods to target motor axons in the ventral roots with multielectrode arrays. We demonstrate the ability to chronically record well-isolated signals from diverse populations of motor axons and develop techniques to identify the muscles they innervate. We subsequently use these motor signals to estimate kinematics during locomotion as accurately as estimations from simultaneously recorded muscle activity in the intact limb, demonstrating that a ventral root prosthetic interface is possible for patients living with loss of limb

New frontiers in population recording

The advent of reliable simultaneous recording of the activity of many neurons has enabled the study of interactions between neurons at a large scale: the number of observed pairwise interactions is proportional to the square of the number of recorded neurons. The dominant phenomenon in these pairwise interactions is synchronization, reflecting a system where many observed variables have in common a smaller set of latent variables. This permits the possibility that the complex signals observed in the brain might be reducible to a simpler system. We used this insight to design a better signal processing scheme for neuroprosthetics; to identify the same neurons in many recording sessions from their pairwise interactions; to show that the tuning functions of neurons in motor and premotor cortex do not reflect simple coordinate frame models; and to identify error as a dominant signal during continuous movements

Cortical control of intraspinal microstimulation to restore motor function after paralysis

Phd ThesisSpinal cord injury (SCI) is a devastating condition affecting the quality of life of many otherwise healthy patients. To date, no cure or therapy is known to restore functional movements of the arm and hand, and despite considerable effort, stem cell based therapies have not been proven effective. As an alternative, nerves or muscles below the injury could be stimulated electrically. While there have been successful demonstrations of restoration of functional movement using muscle stimulation both in humans and non-human primates, intraspinal microstimulation (ISMS) could bear benets over peripheral stimulation. An extensive body of research on spinal stimulation has been accumulated – however, almost exclusively in non-primate species. Importantly, the primate motor system has evolved to be quite different from the frog’s or the cat’s – two commonly studied species –, reecting and enabling changes in how primates use their hands. Because of these functional and anatomical differences, it is fair to assume that also spinal cord stimulation will have different effects in primates. is question – what are the movements elicited by ISMS in the macaque – will be addressed in chapters and . Chronic intraspinal electrode implants so far have been difficult to realise. In chapter we describe a novel use of oating microelectrode arrays (FMAs) as chronic implants in the spinal cord. Compared to implanted microwires or other arrays, these FMAs have the benet of a high electrode density combined with different lengths of electrodes. We were able to maintain these arrays in the cord for months and could elicit movements at low thresholds throughout. If we could build a neural prosthesis stimulating the spinal cord, how would it be controlled? Remarkable progress has been recently achieved in the eld of brain-machine interfaces (BMIs), for example enabling patients to control robotic arms with neural signals recorded from chronically implanted electrodes. Chapter of this thesis examines an approach that combines ISMS with cortical control in a macaque model for upper limb paralysis for the rst time and shows that there is a behavioural improvement. We have devised an experiment in which a monkey trained to perform a grasp-and-pull task receives a temporary cortically induced paralysis of the hand reducing task performance. At the same time, cortical recordings from a different area allow us to control ISMS at sites evoking hand movements – thus partially restoring function. Finally, in appendix A we describe a system we developed in order to introduce automated positive reinforcement training (aPRT) both at the breeding facility and in our animal houses. is system potentially reduces time spent on training animals, adds enrichment to the monkeys’ home environment, and allows for suitability screening of monkeys for behavioural neuroscience experiments

Encoding of Object Presence and Manipulation Affordances in the Frontoparietal Grasp Network

The ability to grasp and manipulate objects is a fundamental human capacity. Loss of this function due to injury or disease can result in the inability to independently perform tasks of daily living. Brain computer interfaces (BCIs), which decode neural activity to control assistive devices, represent a new class of potential therapies to restore arm and hand function. Recent efforts to implement BCI control of a robotic hand for grasping have been hindered by unexpected neural modulations in primary motor cortex (M1) related to the contextual factor of whether movements were made with or without an object present. We designed and carried out three experiments in healthy rhesus macaque monkeys to characterize the influence of various object-related contextual factors on movement features (MFs — kinematics and muscle activity of the arm and hand) and on neural activity in three grasp-related brain areas: M1, ventral premotor cortex (PMV) and anterior intraparietal area (AIP). A novel method was devised to implant intracortical microelectrode arrays in PMV and AIP for these experiments. In Experiment 1, monkeys performed similar reaching movements with or without an object present. In Experiment 2, monkeys performed similar grasps on a set of objects with different grip affordances (objects could be grasped in multiple ways). In Experiment 3, monkeys performed similar grasps on two objects with different use affordances (one was stationary and one could be lifted). All object-related contextual factors were found to evoke small but significant differences in MFs despite task requirements remaining constant across contexts. These context-dependent behavioral differences were accompanied by proportionately larger neural differences in all three brain areas. The presence or absence of an object resulted in changes in neuronal firing rates that could not be accounted for by linear encoding of MFs. This object presence signal was found to interact with MF encoding in M1 in a way that was detrimental for BCI-style MF decoding. Object grip affordance differences resulted in similar but smaller neural modulations that did not impact MF decoding. Neural modulations related to object use affordance were prominent only in PMV

Neurophysiological mechanisms of sensorimotor recovery from stroke

Ischemic stroke often results in the devastating loss of nervous tissue in the cerebral cortex, leading to profound motor deficits when motor territory is lost, and ultimately resulting in a substantial reduction in quality of life for the stroke survivor. The International Classification of Functioning, Disability and Health (ICF) was developed in 2002 by the World Health Organization (WHO) and provides a framework for clinically defining impairment after stroke. While the reduction of burdens due to neurological disease is stated as a mission objective of the National Institute of Neurological Disorders and Stroke (NINDS), recent clinical trials have been unsuccessful in translating preclinical research breakthroughs into actionable therapeutic treatment strategies with meaningful progress towards this goal. This means that research expanding another NINDS mission is now more important than ever: improving fundamental knowledge about the brain and nervous system in order to illuminate the way forward. Past work in the monkey model of ischemic stroke has suggested there may be a relationship between motor improvements after injury and the ability of the animal to reintegrate sensory and motor information during behavior. This relationship may be subserved by sprouting cortical axonal processes that originate in the spared premotor cortex after motor cortical injury in squirrel monkeys. The axons were observed to grow for relatively long distances (millimeters), significantly changing direction so that it appears that they specifically navigate around the injury site and reorient toward the spared sensory cortex. Critically, it remains unknown whether such processes ever form functional synapses, and if they do, whether such synapses perform meaningful calculations or other functions during behavior. The intent of this dissertation was to study this phenomenon in both intact rats and rats with a focal ischemia in primary motor cortex (M1) contralateral to the preferred forelimb during a pellet retrieval task. As this proved to be a challenging and resource-intensive endeavor, a primary objective of the dissertation became to provide the tools to facilitate such a project to begin with. This includes the creation of software, hardware, and novel training and behavioral paradigms for the rat model. At the same time, analysis of previous experimental data suggested that plasticity in the neural activity of the bilateral motor cortices of rats performing pellet retrievals after focal M1 ischemia may exhibit its most salient changes with respect to functional changes in behavior via mechanisms that were different than initially hypothesized. Specifically, a major finding of this dissertation is the finding that evidence of plasticity in the unit activity of bilateral motor cortical areas of the reaching rat is much stronger at the level of population features. These features exhibit changes in dynamics that suggest a shift in network fixed points, which may relate to the stability of filtering performed during behavior. It is therefore predicted that in order to define recovery by comparison to restitution, a specific type of fixed point dynamics must be present in the cortical population state. A final suggestion is that the stability or presence of these dynamics is related to the reintegration of sensory information to the cortex, which may relate to the positive impact of physical therapy during rehabilitation in the postacute window. Although many more rats will be needed to state any of these findings as a definitive fact, this line of inquiry appears to be productive for identifying targets related to sensorimotor integration which may enhance the efficacy of future therapeutic strategies