Remodeling Brain Activity by Repetitive Cervicothoracic Transspinal Stimulation after Human Spinal Cord Injury

Interventions that can produce targeted brain plasticity after human spinal cord injury (SCI) are needed for restoration of impaired movement in these patients. In this study, we tested the effects of repetitive cervicothoracic transspinal stimulation in one person with cervical motor incomplete SCI on cortical and corticospinal excitability, which were assessed via transcranial magnetic stimulation with paired and single pulses, respectively. We found that repetitive cervicothoracic transspinal stimulation potentiated intracortical facilitation in flexor and extensor wrist muscles, recovered intracortical inhibition in the more impaired wrist flexor muscle, increased corticospinal excitability bilaterally, and improved voluntary muscle strength. These effects may have been mediated by improvements in cortical integration of ascending sensory inputs and strengthening of corticospinal connections. Our novel therapeutic intervention opens new avenues for targeted brain neuromodulation protocols in individuals with cervical motor incomplete SCI

The Role of Supraspinal Structures for Recovery after SCI: From Motor Dysfunction to Mental Health

Neural circuitry controlling limbed locomotion is located in the spinal cord, known as Central Pattern Generators (CPGs). After a traumatic Spinal Cord Injury (SCI), ascending and descending tracts are damaged, interrupting the communication between CPGs and supraspinal structures that are fundamental to initiate, control and adapt movement to the environment. Although low vertebrates and some mammals regain some physiological functions after a spinal insult, the capacity to recover in hominids is rather limited. The consequences after SCI include physiological (sensory, autonomic and motor) and mental dysfunctions, which causes a profound impact in social and economic aspects of patients and their relatives Despite the recent progress in the development of therapeutic strategies for SCI, there is no satisfactory agreement for choosing the best treatment that restores the affected functions of people suffering the devastating consequences after SCI. Studies have described that patients with chronic SCI can achieve some degree of neurorestoration with strategies that include physical rehabilitation, neuroprosthesis, electrical stimulation or cell therapies. Particularly in the human, the contribution of supraspinal structures to the clinical manifestations of gait deficits in people with SCI and its potential role as therapeutic targets is not well known. Additionally, mental health is considered fundamental as it represents the first step to overcome daily adversities and to face progression of this unfortunate condition. This chapter focuses on the consequences of spinal cord disconnection from supraspinal structures, from motor dysfunction to mental health. Recent advancements on the study of supraspinal structures and combination of different approaches to promote recovery after SCI are discussed. Promising strategies are used alone or in combination and include drugs, physical exercise, robotic devices, and electrical stimulation

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

Tapping into rhythm generation circuitry in humans during simulated weightlessness conditions

An ability to produce rhythmic activity is ubiquitous for locomotor pattern generation and modulation. The role that the rhythmogenesis capacity of the spinal cord plays in injured populations has become an area of interest and systematic investigation among researchers in recent years, despite its importance being long recognized by neurophysiologists and clinicians. Given that each individual interneuron, as a rule, receives a broad convergence of various supraspinal and sensory inputs and may contribute to a vast repertoire of motor actions, the importance of assessing the functional state of the spinal locomotor circuits becomes increasingly evident. Air-stepping can be used as a unique and important model for investigating human rhythmogenesis since its manifestation is largely facilitated by a reduction of external resistance. This article aims to provide a review on current issues related to the "locomotor" state and interactions between spinal and supraspinal influences on the central pattern generator (CPG) circuitry in humans, which may be important for developing gait rehabilitation strategies in individuals with spinal cord and brain injuries

Investigation of the feasibility of using focal vibratory stimulation with robotic aided therapy for spasticity rehabilitation in spinal cord injury

The occurrence of a traumatic spinal cord injury is in hundreds of thousands of people every year. Survivors are left with loss of many bodily functions, loss of sensation below the point of injury and many more painful and uncomfortable repercussions which interfere with activities of daily living. Over 70% of people with SCI develop spasticity: abnormally increased muscle tone and connected joint stiffness that interfere with residual volitional control of the limbs. Treatments for spasticity include many pharmacological and non-pharmacological techniques, however many of them have severe sideeffects. Evidence suggest the use of vibratory stimulation to relieve repercussions of spasticity, despite not agreeing on the most advantageous protocol. This thesis evaluated effects that focal vibratory stimulation have on the muscle performance. Within two studies, focal muscle vibration is compared against different application conditions such as timing and location. The results suggests that if focal vibrations are applied to the relaxed muscle, the increase in muscle's force is observed. Analysis of the cortical waves indicates minimal cortical involvement in vibratory stimulation modulation. On the other hand, FV applied of the connected tendon/bone imposed to a contraction seems to have a potential to increase muscle's activation. There is evidence that motor cortex is responding to this stimulation to stabilise the muscle in order to perform the contraction. Within clinical trial, focal muscle vibratory stimulation is employed in total of 6 interventional sessions while a joint's spastic exor and extensor muscles were relaxed. Spasticity appears to be reduced as a consequence of the stimulation. Moreover, engaging the joint into robotic-aided therapy increase volitional control of the wrist, according to the analysis of the active range of motion, joint stiffness and kinematic parameters associated to the movement. The measurement and movement facilitation device used in the clinical trial was designed and developed in accordance to the spasticity and spinal cord injury repercussions consideration. The studies conducted for this thesis demonstrated feasibility and potential for the use of focal muscle vibratory stimulation to enhance muscle power in healthy muscles but also relieve consequences of spasticity. Vibrations combined with movement robotic-aided therapy have a prospects to enhance motor control

Tapping into rhythm generation circuitry in humans during simulated weightlessness conditions

An ability to produce rhythmic activity is ubiquitous for locomotor pattern generation and modulation. The role that the rhythmogenesis capacity of the spinal cord plays in injured populations has become an area of interest and systematic investigation among researchers in recent years, despite its importance being long recognized by neurophysiologists and clinicians. Given that each individual interneuron, as a rule, receives a broad convergence of various supraspinal and sensory inputs and may contribute to a vast repertoire of motor actions, the importance of assessing the functional state of the spinal locomotor circuits becomes increasingly evident. Air-stepping can be used as a unique and important model for investigating human rhythmogenesis since its manifestation is largely facilitated by a reduction of external resistance. This article aims to provide a review on current issues related to the ‘locomotor’ state and interactions between spinal and supraspinal influences on the central pattern generator circuitry in humans, which may be important for developing gait rehabilitation strategies in individuals with spinal cord and brain injuries

Closed-loop stimulation for upper limb rehabilitation following spinal cord injury and stroke

PhD ThesisInnovation is required to improve upper limb rehabilitation for neurological conditions such as stroke and spinal cord injury (SCI). There is growing appreciation of the importance of neural plasticity in recovery, and how this can be facilitated by synchronous activity in peripheral neural circuits and central brain areas. However, despite increasing scientific evidence, technological solutions that exploit associative plasticity have not yet been widely evaluated in clinical practice. In this thesis, I report the development and initial evaluation of a novel device which enabled a reaching and grasping motion in the affected limb by combining assistive functional electrical stimulation (FES) with inferred voluntary brain activity. The device was designed to enable translation from laboratory-to-clinic by overcoming common practical barriers to translational research, such as adaptability and ease of use. The device was demonstrated to be usable by individuals with either chronic stroke or SCI, and received positive qualitative feedback. Some participants showed modest improvements on assessments of upper limb function following a short intervention period. A study with healthy able-bodied volunteers indicated that after using the device, corticospinal pathways to the antagonist (flexor) muscle may be facilitated, and this facilitation might be increased by adjusting the relative timing of stimulation and inferred brain activity. The device could also deliver alternative stimulation techniques, and an exploratory study into transcutaneous spinal cord stimulation (tSCS) was conducted with healthy able-bodied volunteers. It was found that tSCS may activate peripheral and spinal pathways within acceptable comfort levels, but the parameters used in this study did not to generate functional contractions. An unexpected oscillatory motor response provided insights into how tSCS acts upon the motor system. Prior to a large scale evaluation of clinical effectiveness, further research is required to: further develop a theoretical basis for the intervention; demonstrate the mechanisms of action; and to evaluate the efficacy of the device.Wellcome Trust, postgraduate research studentship (2015 to 2018) • EPSRC Preparing for GCRF Award (PI: Dr Andrew Jackson) - Low cost rehabilitation of hand function following stroke (2016 to 2017

Doctor of Philosophy

dissertationHigh-count microelectrode arrays implanted in peripheral nerves could restore motor function after spinal cord injury or sensory function after limb loss via electrical stimulation. The same device could also help restore volitional control to a prosthesis-using amputee, or sensation to a Spinal cord Injury (SCI) patient, via recordings from the still-viable peripheral nerves. The overall objective of these dissertations studies is to improve the usefulness of intrafascicular electrodes, such as the Utah Slanted Electrode Array (USEA), for neuroprosthetic devices for limb loss or spinal cord injury patients. Previous work in cat sciatic nerve has shown that stimulation through the USEA can remain viable for months after implant. However, stimulation parameters were not stable, and recordings were lost rapidly and were subject to strong contamination by myoelectrical activity from adjacent muscles. Recent research has shown that even when mobility is restored to a patient, either through prosthesis or functional electrical stimulation, difficulties in using the affected limbs arise from the lack of sensory input. In the absence of the usual proprioceptive and cutaneous inputs from the limb, planning and executing motions can be challenging and sometimes lead to the user's abandonment of prostheses. To begin to address this need, I examined the ability of USEAs in cat hindlimb nerves to activate primary sensory fibers by monitoring evoked potentials in somatosensory cortex via skull-screw electrodes. I iv also monitored evoked EMG responses, and determined that it is possible to recruit sensory or motor responses independently of one another. In the second study of this dissertation, I sought to improve the long-term stability of USEAs in the PNS by physically and electrically stabilizing and protecting the array. To demonstrate the efficacy of the stabilization and shielding technique, I examined the recording capabilities of USEA electrodes and their selectivity of muscle activation over the long term in cat sciatic nerve. In addition to long-term viability, clinically useful neuroprosthetic devices will have to be capable of interfacing with complex motor systems such as the human hand. To extend previous results of USEAs in cat hindlimb nerves and to examine selectivity when interfacing with a complex sensorimotor system, I characterized EMG and cortical somatosensory responses to acute USEA stimulation in monkey arm nerves. Then, to demonstrate the functional usefulness of stimulation through the USEA. I used multi-array, multi-electrode stimulation to generate a natural, coordinated grasp

Spinal Control of Locomotion: Individual Neurons, Their Circuits and Functions

Systematic research on the physiological and anatomical characteristics of spinal cord interneurons along with their functional output has evolved for more than one century. Despite significant progress in our understanding of these networks and their role in generating and modulating movement, it has remained a challenge to elucidate the properties of the locomotor rhythm across species. Neurophysiological experimental evidence indicates similarities in the function of interneurons mediating afferent information regarding muscle stretch and loading, being affected by motor axon collaterals and those mediating presynaptic inhibition in animals and humans when their function is assessed at rest. However, significantly different muscle activation profiles are observed during locomotion across species. This difference may potentially be driven by a modified distribution of muscle afferents at multiple segmental levels in humans, resulting in an altered interaction between different classes of spinal interneurons. Further, different classes of spinal interneurons are likely activated or silent to some extent simultaneously in all species. Regardless of these limitations, continuous efforts on the function of spinal interneuronal circuits during mammalian locomotion will assist in delineating the neural mechanisms underlying locomotor control, and help develop novel targeted rehabilitation strategies in cases of impaired bipedal gait in humans. These rehabilitation strategies will include activity-based therapies and targeted neuromodulation of spinal interneuronal circuits via repetitive stimulation delivered to the brain and/or spinal cord