Using primary afferent neural activity for predicting limb kinematics in cat

Kinematic state feedback is important for neuroprostheses to generate stable and adaptive movements of an extremity. State information, represented in the firing rates of populations of primary afferent neurons, can be recorded at the level of the dorsal root ganglia (DRG). Previous work in cats showed the feasibility of using DRG recordings to predict the kinematic state of the hind limb using reverse regression. Although accurate decoding results were attained, these methods did not make efficient use of the information embedded in the firing rates of the neural population. This dissertation proposes new methods for decoding limb kinematics from primary afferent firing rates. We present decoding results based on state-space modeling, and show that it is a more principled and more efficient method for decoding the firing rates in an ensemble of primary afferent neurons. In particular, we show that we can extract confounded information from neurons that respond to multiple kinematic parameters, and that including velocity components in the firing rate models significantly increases the accuracy of the decoded trajectory. This thesis further explores the feasibility of decoding primary afferent firing rates in the presence of stimulation artifact generated during functional electrical stimulation. We show that kinematic information extracted from the firing rates of primary afferent neurons can be used in a 'real-time' application as a feedback for control of FES in a neuroprostheses. It provides methods for decoding primary afferent neurons and sets a foundation for further development of closed loop FES control of paralyzed extremities. Although a complete closed loop neuroprosthesis for natural behavior seems far away, the premise of this work argues that an interface at the dorsal root ganglia should be considered as a viable option

Studies on the mammalian muscle spindle

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The effects of peripheral nerve impairments on postural control and mobility among people with peripheral neuropathy

Approximately 20 million Americans are suffering Peripheral Neuropathy (PN). It is estimated that the prevalence of all-cause PN is about 2.4% in the entire adult population, whereas over 8-10% in the population segment over the age of 55 (Martyn & Hughes, 1997). Peripheral Neuropathy leads to a high risk of falling, resulting from the deficits of postural control caused by the impaired peripheral nerves, especially the degenerative somatosensory system. To date, there is no effective medical treatment for the disease but pain managements. The deficits of postural control decrease the life quality of this population. The degeneration of peripheral nerves reduces sensory inputs from the somatosensory system to central nervous system via spinal reflexive loop, which should provide valuable real-time information for balance correction. Therefore, it is necessary to investigate how PN affects the somatosensory system regarding postural control. Besides that, people with PN may develop a compensatory mechanism which could be reinforced by exercise training, ultimately to improve balance and mobility in their daily life. The neuroplasticity may occur within somatosensory system by relying on relative intact sensory resources. Hence, unveiling the compensatory mechanism in people with PN may help in understanding (a) essential sensations or function of peripheral nerves to postural control, (b) effective strategy of physical treatments for people with PN, and (c) task-dependent sensory information requirements. Therefore, this dissertation discussed the roles of foot sole sensation, ankle proprioception, and stretch reflex on balance as well as gait among people with PN. Furthermore, the discussion of the coupling between small and large afferent reflexive loops may spot the compensatory mechanism in people with PN

Development of a Functional Testing Platform for the Sensory Segment of the Neuromuscular Reflex Arc

Investigations of human biology and disease have been hindered by the use of animal models. The information obtained from such studies often results in clinically irrelevant results and drug trial failures. Additionally, several governing bodies have been formulating legislation to move away from animal models and toward more ethical and efficient testing platforms for drug discovery and cosmetic research. As an answer to these issues, body-on-a-chip systems have been a rapidly developing field which easily recapitulates in vivo functionality, providing a more relevant, repeatable, and ethical testing platform to better predict biology. These systems can be used as human-based testing platforms to evaluate human physiology, disease progression, and drug responsiveness for specific cell types and multi-organ systems. Diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) have significant research challenges, specifically with translating research findings into treatment plans. The complexity of the neuromuscular reflex arc, the biological system affected by these diseases, is difficult to study with traditional molecular techniques, namely because the many components of this disease system interact with each other using complex pathways. This work pushes the existing platform to a more complete human model of neuromuscular disease with the incorporation of gamma motoneurons, development of the first human induced pluripotent cell (iPSC) derived intrafusal fibers, and proposals to incorporate nociceptive neurons all on a functionally interrogative platform. The incorporation of these components will allow for a more complete, clinically relevant model to study neuromuscular disorders and for preclinical dug discovery

Neuromechanical Tuning for Arm Motor Control

Movement is a fundamental behavior that allows us to interact with the external world. Its importance to human health is most evident when it becomes impaired due to disease or injury. Physical and occupational rehabilitation remains the most common treatment for these types of disorders. Although therapeutic interventions may improve motor function, residual deficits are common for many pathologies, such as stroke. The development of novel therapeutics is dependent upon a better understanding of the underlying mechanisms that govern movement. Movement of the human body adheres to the principles of classic Newtonian mechanics. However, due to the inherent complexity of the body and the highly variable repertoire of environmental contexts in which it operates, the musculoskeletal system presents a challenging control problem and the onus is on the central nervous system to reliably solve this problem. The neural motor system is comprised of numerous efferent and afferent pathways with a hierarchical organization which create a complex arrangement of feedforward and feedback circuits. However, the strategy that the neural motor system employs to reliably control these complex mechanics is still unknown. This dissertation will investigate the neural control of mechanics employing a “bottom-up” approach. It is organized into three research chapters with an additional introductory chapter and a chapter addressing final conclusions. Chapter 1 provides a brief description of the anatomical and physiological principles of the human motor system and the challenges and strategies that may be employed to control it. Chapter 2 describes a computational study where we developed a musculoskeletal model of the upper limb to investigate the complex mechanical interactions due to muscle geometry. Muscle lengths and moment arms contribute to force and torque generation, but the inherent redundancy of these actuators create a high-dimensional control problem. By characterizing these relationships, we found mechanical coupling of muscle lengths which the nervous system could exploit. Chapter 3 describes a study of muscle spindle contribution to muscle coactivation using a computational model of primary afferent activity. We investigated whether these afferents could contribute to motoneuron recruitment during voluntary reaching tasks in humans and found that afferent activity was orthogonal to that of muscle activity. Chapter 4 describes a study of the role of the descending corticospinal tract in the compensation of limb dynamics during arm reaching movements. We found evidence that corticospinal excitability is modulated in proportion to muscle activity and that the coefficients of proportionality vary in the course of these movements. Finally, further questions and future directions for this work are discussed in the Chapter 5

ERR2 and ERR3 promote the development of gamma motor neuron functional properties required for proprioceptive movement control

The ability of terrestrial vertebrates to effectively move on land is integrally linked to the diversification of motor neurons into types that generate muscle force (alpha motor neurons) and types that modulate muscle proprioception, a task that in mammals is chiefly mediated by gamma motor neurons. The diversification of motor neurons into alpha and gamma types and their respective contributions to movement control have been firmly established in the past 7 decades, while recent studies identified gene expression signatures linked to both motor neuron types. However, the mechanisms that promote the specification of gamma motor neurons and/or their unique properties remained unaddressed. Here, we found that upon selective loss of the orphan nuclear receptors ERR2 and ERR3 (also known as ERR beta, ERR gamma or NR3B2, NR3B3, respectively) in motor neurons in mice, morphologically distinguishable gamma motor neurons are generated but do not acquire characteristic functional properties necessary for regulating muscle proprioception, thus disrupting gait and precision movements. Complementary gain-of-function experiments in chick suggest that ERR2 and ERR3 could operate via transcriptional activation of neural activity modulators to promote a gamma motor neuron biophysical signature of low firing thresholds and high firing rates. Our work identifies a mechanism specifying gamma motor neuron functional properties essential for the regulation of proprioceptive movement control

Stretching adversely modulates locomotor capacity following spinal cord injury via activation of nociceptive afferents.

Spinal cord injury (SCI) is the second leading cause of paralysis in the United States, affecting around 282,000 people with 17,000 new cases each year. Initial and secondary damage to the spinal cord disrupts multiple descending pathways that modulate the function of sympathetic preganglionic neurons and central pattern generating circuitry. Resulting loss of autonomic and locomotor functions, as well as decreased levels of physical activity, lead to a myriad of complications that affect multiple organ systems and significantly reduce both quality of life and life expectancy in individuals with SCI. Spasticity and muscle contractures are two common secondary conditions that develop in the chronic stages of SCI as a result of neurobiological and soft tissue adaptations. Stretching is the widely accepted initial therapy for the treatment of both spasticity and muscle contractures. Unlike humans, rats with experimental incomplete SCI have robust locomotor recovery and do not develop significant muscle contractures or spasticity. One of the long-standing operating principles in the Magnuson laboratory is that rats retrain or rehabilitate themselves through large amounts of in-cage activity. A previous graduate student in our lab, Krista Caudle, tested this hypothesis using custom designed wheelchairs to immobilize Sprague Dawley rats with mild-moderate SCIs. As expected, the immobilized SCI animals did not recover their locomotor function and, in addition, developed muscle contractures. To mimic the approach used in the clinic for the treatment of contractures, a hindlimb stretching protocol was developed and implemented as part of our daily care routine. As a control, non-immobilized SCI rats also received stretching therapy. Surprisingly, stretched rats and wheelchair immobilized rats showed similar impairments in locomotor recovery. This finding was alarming and warranted further studies. The work presented in this thesis is a continuation of the stretching projects in the Magnuson laboratory. Four major studies were carried out in order to improve our understanding of this stretching phenomenon and to begin uncovering the underlying physiological mechanisms. The following experiments revealed that hindlimb stretching disrupts locomotor function in rats with acute and chronic moderately-severe SCI. We also determined that dynamic “range of motion” stretching resulted in a similar pattern of locomotor impairment as our standard static stretch-and-hold protocol in rats with moderate sub-acute SCIs. Furthermore, using kinematics and electromyography (EMG), we determined that one of the most frequent responses to stretch in the rat hindlimbs is similar to human clonus. The significance of these findings are three-fold. First, to our knowledge, there has not been a specific description of clonus in the rat model of the SCI previously. Second, the similarity of the responses to stretch between rats and humans make a compelling argument for the clinical relevance of the stretching phenomenon. Finally, we determined that stretch-induced locomotor deficits depend on the presence of nociceptive afferents. Speculations about the specific physiological mechanisms of the stretching phenomenon and future directions are discussed. Comprehensive review of the stretching literature revealed a major problem in the rationale that is frequently provided for the use of stretching in the management of muscle contractures after SCI. In light of this work, a perspective on the future of stretching therapy in the rehabilitation after SCI is provided

An examination of agonist and antagonist motor unit firing properties

The interactions between opposing muscle (i.e. agonist and antagonist) groups can be extremely complex, task-dependent, and are still poorly understood. To identify possible origins of the coordination between antagonistic muscle groups, the common or shared sources of neural input need to be understood. The assessment and manipulation of motor unit firing properties, such as synchronization, can provide information regarding the common inputs to opposing muscles. PURPOSE: The purpose of this study was to introduce various interventions to systematically manipulate both agonist and antagonist motor unit firing properties, and obtain a better understanding of the interactions between the two. METHODS: Muscle activity was detected from the biceps brachii ("agonist") and the triceps brachii ("antagonist") during isometric forearm flexions. The signals from these muscles were decomposed into individual motor unit action potential trains. Subsequently, various firing properties such as mean firing rate, recruitment threshold, and synchronization were calculated. On two separate visits, either the agonist or antagonist muscle was fatigued. During another two visits, either the agonist or antagonist muscle underwent 18 minutes of prolonged stretching, which has been shown to significantly desensitize proprioceptors. RESULTS: During co-activation, the antagonist demonstrated significant motor unit synchronization, but to a lesser extent when compared to the agonist. The antagonist also exhibited a substantially smaller recruitment threshold range and higher average firing rates. Fatigue of the agonist did not show any changes to antagonist motor unit firing properties, despite a significant increase in co-activation. Fatigue of the antagonists produced effects on the motor unit behavior of the agonist, such as decreased motor unit synchronization. It was suggested that group III and IV muscle afferents originating from the antagonist were responsible for the change to the agonist. The stretching interventions provided some mixed results, often providing non-uniform changes across motor unit types. For example, agonist low-threshold motor unit pairs demonstrated an increase in short-term synchronization after agonist stretching, but the high-threshold motor unit pairs exhibited a decrease in synchronization. Future studies to help answer follow-up questions were suggested

Motor system plasticity induced by non-invasive stimuli

MD ThesisPrecisely timed paired stimulation protocols can change cortical and subcortical excitability. In the first study, induction of plastic changes in the long-latency stretch reflex (LLSR) by pairing non-invasive stimuli was attempted, at timings predicted to cause spiketiming dependent plasticity (STDP) in the brainstem. LLSR in human elbow muscles depends on multiple pathways; one possible contributor is the reticulospinal tract. The stimuli used are known to activate reticulospinal pathways. In healthy human subjects, reflex responses in flexor muscles were recorded following extension perturbations at the elbow. Subjects were then fitted with a portable device which delivered auditory click stimuli, and electrical stimuli to biceps muscle. The LLSR was significantly enhanced or suppressed in the biceps muscle depending on the intervention protocol. No changes were observed in the unstimulated brachioradialis muscle. Although contributions from the spinal or cortical pathways cannot be excluded, the results were consistent with STDP in reticulospinal circuits. In the second study, baseline TMS responses were recorded from two intrinsic hand muscles, flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC). In the first phase, paired associative stimulation (PAS) was delivered by pairing motor point stimulation of FDS or EDC with TMS. Responses were then remeasured. Increases were greatest in the hand muscles, smaller in FDS, and non-significant in EDC. In the second phase, intermittent theta-burst rapid-rate TMS was applied instead of PAS. In this case, all muscles showed similar increases in TMS responses. This study showed that potential plasticity in motor cortical output has a gradient: hand muscles > flexors > extensors. However, this was only seen in a protocol which requires integration of sensory input (PAS), and not when plasticity was induced purely by cortical stimulation (rapid rate TMS). In the third study, motor imagery was paired with TMS in healthy human subjects. They were asked to imagine wrist flexion or extension movement, while TMS was delivered to the motor cortex. Six different protocols were tested, but only flexor imagination with TMS and extensor imagination with TMS showed significant facilitation following the test. Flexor imagination with TMS increased motor evoked potential (MEP) in all four Abstract 2 muscles with maximum changes towards flexor, whereas extensor imagination with TMS increased MEP only in extensor. Above changes in the cortical or subcortical excitability evoked by non-invasive stimulation protocols were consistent with long term potentiation and long-term depression mediated plastic change