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Stroke is the leading cause of long-lasting disability in the United States and disproportionately affects adults in later life. Age-related decreases in dexterity and neural plasticity may contribute to the poorer prognosis of older stroke survivors, even following rehabilitative physical therapy. The goal of these dissertation studies is to determine how the cortical plasticity underlying motor skill learning, both before and after brain injury, changes in the aged brain. The general hypothesis of these studies is that age-related changes in motor performance and the limited ability to regain function following brain injury are associated with dysfunctional plasticity of the forelimb representation in the motor cortex. This hypothesis was tested in intact C57BL/6 mice by training them on a skilled reaching task and deriving intracortical microstimulation evoked motor cortical representations of the forelimb to determine training-induced changes in the function of the motor cortex. After ischemic lesions, age-dependencies in the effects of rehabilitative training in skilled reaching on forelimb motor cortical representations were investigated. Prior to injury, intact young and aged mice learned a skilled reaching task in similar time frames and with similar success rates. Training-induced reorganization in the young mouse motor cortex occurred in the caudal forelimb area, which is homologous to the primary motor cortex of primates. However, the rostral forelimb area, a potential premotor cortex, was larger in aged mice compared to young mice. Following focal ischemic lesions of the forelimb area of the sensorimotor cortex, aged mice had larger lesions and were more impaired than young mice, but both groups regained reaching ability after 9 weeks of rehabilitative training. Post-operative training resulted in plasticity of the rostral forelimb area in young mice, but we failed to see reorganization in the forelimb map of aged mice following rehabilitative training. These dissertation studies suggest that more severe brain damage in response to ischemia leads to poorer outcome in aged animals. Although the reorganization of motor cortex following initial skill learning and relearning following brain damage changes with age, the ability to learn motor tasks and improve function with rehabilitative training is maintained in healthy aging. / text

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<p>Brain Machine Interfaces (BMI) strive to restore motor and sensory functions lost due to paralysis, amputation, and neurological diseases by interfacing brain circuitry to external actuators in form of a cursor on a computer screen or a robotic limb. There is a strong clinical need for sensory restoration as lack of somatosensory feedback leads to loss of fine motor control and one of the most common preferences for improvements according to individuals with upper-limb loss is the ability to require less visual attention to perform certain functions and to have a better control of wrist movement. One way to restore sensory functions is using electrical microstimulation of brain sensory areas as an artificial sensory channel; however, the ways of creating such artificial sensory inputs are poorly understood. </p><p>This dissertation presents the use of intracortical microstimulation (ICMS) to the primary somatosensory cortex (S1) to guide exploratory arm movements without visual feedback. Two rhesus monkeys were chronically implanted with multielectrode arrays in S1 and primary motor cortex (M1). The monkeys used a hand-held joystick to reach targets with a cursor on a computer screen. ICMS patterns were delivered to S1 when the cursor was placed over the target, mimicking the sense of touch. After the target or the cursor was made invisible, monkeys relied on ICMS feedback instead of vision to perform the task. For an invisible cursor, a random offset was added to the position of the invisible cursor to rule out the possibility that monkeys relied on joystick position felt through proprioception. Learning to perform these tasks was accompanied by changes in both the parameters of arm movements and representation of those parameters by M1 and S1 neurons at a population and individual neuronal levels. </p><p>Offline decoding of single neurons and population of neurons showed that overlapping, but not identical subpopulations of neurons represented movements when ICMS provided feedback instead of vision.</p><p>These results suggest that ICMS could be used as an essential source of sensation from prosthetic limbs.</p> / Dissertation

<p>Brain-machine interfaces (BMIs) use recordings from the nervous system to extract volitional and motor parameters for controlling external actuators, such as prosthetics, thereby bypassing or replacing injured tissue. As such, they show enormous promise for restoring mobility, dexterity, or communication in paralyzed patients or amputees. Recent advancements to the BMI paradigm have made the brain -- machine communication channel bidirectional, enabling the prosthetic to inform the user about touch, temperature, strain, or other sensory information; these devices are hence called brain-machine-brain interfaces (BMBIs). </p><p>In the first chapter an intraoperative BMI is investigated in human patients undergoing surgery for implantation of a deep brain stimulation (DBS) treatment electrodes. While the BMI was marginally effective, we found high levels of behavioral and tremor tuning among cells recorded from the surgical targets, the subthalamic nucleus (STN) and ventral intermediate nucleus (VIM) of the thalamus. Notably, this tremor or behavior tuning was not mutually exclusive with oscillatory behavior, suggesting that physiological tuning persists even in the face of pathological oscillations. We then used nonlinear means for extracting tremor tuning, and found a significant population, consistent with double-frequency or co-modulation to tremor within the basal ganglia. Synchrony was then assessed over long and short timescales between pairs of neurons, and it was found that tremor tuning implies synchrony: all units exhibiting tremor tuning showed synchrony to at least one other unit. </p><p>BMBIs rely on a host of both scientific knowledge and technology for effective function, and this technology is currently in intensive research. In this dissertation two technologies for BMBIs, corresponding to the two directions of communication, are designed, described, and tested. The first one is a high compliance, digitally controlled, high-side current-regulated microstimulator for intracortical microstimulation (ICMS). The device is validated on the bench, tested in monkeys, and used for multiple experimental setups. Due to careful control of parasitic charge injection, the microstimulator is ideally suited for interleaving stimulation and recording as employed in some BMBIs. </p><p>The second technology described is a wireless, scalable, 128 channel neural recording system. The device features aggressive digital filtering to maximize signal quality, has spike sorting and compression on the transceiver, can be fully configured over the air through a custom wireless bridge and client software, and can run for over 30 hours on one battery. This system has been tested in a monkey while in its home cage, where the wireless system permitted unfettered, continuous recording and continuous access to a simplified BMI. A full description of the development and device is described, as well as results showing convincing 1D and suggestive 2D BMI control.</p> / Dissertation

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abstract: Intracortical microstimulation (ICMS) within somatosensory cortex can produce artificial sensations including touch, pressure, and vibration. There is significant interest in using ICMS to provide sensory feedback for a prosthetic limb. In such a system, information recorded from sensors on the prosthetic would be translated into electrical stimulation and delivered directly to the brain, providing feedback about features of objects in contact with the prosthetic. To achieve this goal, multiple simultaneous streams of information will need to be encoded by ICMS in a manner that produces robust, reliable, and discriminable sensations. The first segment of this work focuses on the discriminability of sensations elicited by ICMS within somatosensory cortex. Stimulation on multiple single electrodes and near-simultaneous stimulation across multiple electrodes, driven by a multimodal tactile sensor, were both used in these experiments. A SynTouch BioTac sensor was moved across a flat surface in several directions, and a subset of the sensor's electrode impedance channels were used to drive multichannel ICMS in the somatosensory cortex of a non-human primate. The animal performed a behavioral task during this stimulation to indicate the discriminability of sensations evoked by the electrical stimulation. The animal's responses to ICMS were somewhat inconsistent across experimental sessions but indicated that discriminable sensations were evoked by both single and multichannel ICMS. The factors that affect the discriminability of stimulation-induced sensations are not well understood, in part because the relationship between ICMS and the neural activity it induces is poorly defined. The second component of this work was to develop computational models that describe the populations of neurons likely to be activated by ICMS. Models of several neurons were constructed, and their responses to ICMS were calculated. A three-dimensional cortical model was constructed using these cell models and used to identify the populations of neurons likely to be recruited by ICMS. Stimulation activated neurons in a sparse and discontinuous fashion; additionally, the type, number, and location of neurons likely to be activated by stimulation varied with electrode depth. / Dissertation/Thesis / Videos of neuronal recruitment / Ph.D. Bioengineering 2013

Deal or no deal? Hold ‘em or fold ‘em? Buy, hold or sell? When faced with uncertainty, a wise decision-maker evaluates each option and chooses the one they deem most valuable. Scientists studying decision making processes have spent much theoretical and experimental effort formalizing a framework that captures how decision makers can maximize the amount of subjective value they accrue from such decisions. This thesis tested two hypotheses. The first was that subjective value guides our simplest and most common of motor actions similar to how it guides more deliberative economic decisions. The second was that subjective value is allocated across pre-motor regions of the brain to make our actions more efficient. To accomplish these goals, I adapted a paradigm used by behavioural economists for use in neurophysiological experiments in non-human primates. In our task, monkeys repeatedly make quick, orienting eye movements, known as saccades, to targets, which they learned through experience, had different values. In support of the hypothesis that subjective value influences simple motor actions, the speed with which monkeys responded, known as saccadic reaction time (SRT), and their saccadic choices to valued targets were highly correlated and therefore both acted as a behavioural measures of subjective value. Two complimentary results support the hypothesis that subjective value influences activity in the intermediate layers of the superior colliculus (SCi) – a well-studied brain region important to the planning and execution of saccades - to produce efficient actions. First, when saccades were elicited with microstimulation, we found that the timing and spatial allocation of pre-saccadic activity in the SC was shaped by subjective value. Second, the baseline preparatory activity and transient visual activity of SCi neurons prior to saccade generation was also influenced by subjective value. Our results can be incorporated into existing models of SC functioning that use dynamic neural field theory. I suggest that saccades of higher subjective value will result in higher activation of their associated neural field such that they will be more likely and more quickly selected. In summary, this thesis demonstrates that subjective value influences neural mechanisms, not only for deliberative decision making, but also for the efficient selection of simple motor actions. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2013-06-25 17:18:25.393

Spinal cord injury is a devastating neurological disorder partially characterized by a loss of motor function below the lesion. The dramatic loss of activity results in muscle atrophy and slow-to-fast transformation of contractile elements, producing smaller, weaker and more fatiguable muscles. Functional electrical stimulation (FES), has been proposed in order to induce muscular activity and reverse these changes. FES has primarily been applied in the periphery, either at the surface or implanted in or around a nerve or muscle. Although this can excite nervous tissue and produce muscular contractions, these systems often produce reversed recruitment of motor units leading to inappropriate force generation and increased fatigue. We applied intraspinal microstimulation (ISMS) through fine microwires implanted into the spinal cord of rats. Electrical stimulation through these microwires caused contractions of the quadriceps muscles in both acute and chronically spinalized animals. We showed that muscle recruitment is significantly more gradual with ISMS in intact rats compared to that produced by a standard nerve cuff. Our results further showed that this was due to preferential activation of fatigue resistant muscle fibers. Given this more orderly recruitment of motor units by ISMS, we tested the muscle phenotypes produced by ISMS or nerve cuffs after chronic stimulation. Surprisingly, over a 30 day stimulation period the quadriceps muscles chronically activated by either daily ISMS or nerve cuff stimulation underwent similar fast-to-slow transformations in fiber type and functional properties. This indicates that the recruitment order of motor units does not play the only role in determining the muscle phenotype. Other factors such as the total daily time of activity may be critically important to the phenotypic outcome of skeletal muscle. Finally, we demonstrated that quadriceps force recruitment by ISMS was unchanged following the 30 day stimulation period. In addition, 30 days of chronic ISMS did not cause observable damage in the spinal cord beyond that incurred by the implantation of sham microwires. These studies advance our understanding of the force recruitment properties, neuromuscular plasticity and damage incurred by ISMS and move us closer to developing a clinically viable ISMS procedure.

<p>Brain-machine interfaces (BMIs) use neuronal activity to control external actuators. As such, they show great promise for restoring motor and communication abilities in persons with paralysis or debilitating neurological disorders.</p><p>While BMIs aim to enact normal sensorimotor functions, so far they have lacked afferent feedback in the form of somatic sensation. This deficiency limits the utility of current BMI designs and may hinder the translation of future clinical BMIs, which will need a means of delivering sensory signals from prosthetic devices back to the user. </p><p>This dissertation describes the development of brain-machine-brain interfaces (BMBIs) capable of bidirectional communication with the brain. The interfaces consisted of efferent and afferent modules. The efferent modules decoded motor intentions from the activity of populations of cortical neurons recorded with chronic multielectrode recording arrays. The activity of these ensembles was used to drive the movements of a computer cursor and a realistic upper-limb avatar. The afferent modules encoded tactile feedback about the interactions of the avatar with virtual objects through patterns of intracortical microstimulation (ICMS).</p><p>I first show that a direct intracortical signal can be used to instruct rhesus monkeys about the direction of a reach to make with a BMI. Rhesus monkeys placed an actuator over an instruction target and obtained, from the target's artificial texture, information about the correct reach path. Initially these somatosensory instructions took the form of vibrotactile stimulation of the hands. Next, ICMS of primary somatosensory cortex (S1) in one monkey and posterior parietal cortex (PPC) in another was substituted for this peripheral somatosensory signal. Finally, the monkeys made direct brain-controlled reaches using the activity of ensembles of primary motor cortex (M1) cells, conditional on the ICMS cues. The monkey receiving ICMS of S1 was able to achieve the same level of proficiency with ICMS as with the stimulus delivered to the skin of the hand. The monkey receiving ICMS of PPC was unable to perform the task above chance. This experiment indicates that ICMS of S1 can form the basis of an afferent prosthetic input to the brain for guiding brain-controlled prostheses.</p><p>I next show that ICMS of S1 can provide feedback about the interactions of a virtual-reality upper-limb avatar and virtual objects, enabling active touch. Rhesus monkeys initially controlled the avatar with the movements of their arms and used it to search through sets of up to three objects. Feedback in the form of temporal patterns of ICMS occurred whenever the avatar touched a virtual object. Monkeys learned to use this feedback to find the objects with particular artificial textures, as encoded by the ICMS patterns, and select those associated with reward while avoiding selecting the non-rewarded objects. Next, the control of the avatar was switched to direct brain-control and the monkeys continued to move the avatar with motor commands derived from the extracellular neuronal activity of M1 cells. The afferent and efferent modules of this BMBI were temporally interleaved, and as such did not interfere with each other, yet allowed effectively concurrent operation. Cortical motor neurons were measured while the monkey passively observed the movements of the avatar and were found to be modulated, a result that suggests that concurrent visual and artificial somatosensory feedback lead to the incorporation of the avatar into the monkey's internal brain representation.</p><p>Finally, I probed the sensitivity of S1 to precise temporal patterns of ICMS. Monkeys were trained to discriminate between periodic and aperiodic ICMS pulse trains. The periodic pulse-trains consisted of 200 Hz bursts at a 10 Hz secondary frequency. The aperiodic pulse trains had a distorted periodicity and consisted of 200 Hz bursts at a variable instantaneous secondary frequency. The statistics of the aperiodic pulse trains were drawn from a gamma distribution with equal mean inter-burst intervals to the periodic pulse trains. The monkeys were able to distinguish periodic pulse trains from aperiodic pulse trains with coefficients of variation of 0.25 or greater. This places an upper-bounds on the communication bandwidth that can be achieved with a single channel of temporal ICMS in S1.</p><p>In summary, rhesus monkeys were augmented with a bidirectional neural interface that allowed them to make reaches to objects and discriminate them by their textures--all without making actual movements and without relying on somatic sensation from their real bodies. Both action and perception were mediated by the brain-machine-brain interface. I probed the sensitivity of the afferent leg of the interface to precise temporal patterns of ICMS. Moreover, I describe evidence that the BMBI controlled avatar was incorporated into the monkey's internal brain representation. These results suggest that future clinical neuroprostheses could implement realistic feedback about object-actuator interactions through patterns of ICMS, and that these artificial somatic sensations could lead to the incorporation of the prostheses into the user's body schema.</p> / Dissertation