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

Introduction: Bipolar disorder is associated with cortical abnormalities, including deficits in intracortical myelination. Intracortical myelin follows an inverted-U trajectory over the lifetime, but this trajectory is blunted in individuals with bipolar disorder. Little is understood about which genetic factors contribute to these deficits. Neuregulin-1, a cell-signalling protein, has been shown to contribute to cortical abnormalities and increase susceptibility to related disorders. Assessing the prevalence of neuregulin-1 polymorphisms, notably rs6994992, in bipolar disorder may elucidate the genetic contributors of intracortical myelin deficits and increase our understanding of factors causing susceptibility to bipolar disorder. Methods: 67 participants with bipolar disorder type I and 75 healthy control participants were included. T1-weighted MRI images were collected and processed to create R1 cortical maps, a proxy measure of intracortical myelin. Participant blood samples were genotyped at the rs6994992 locus. Linear models were used to test whether intracortical myelin can be predicted by age, bipolar diagnosis and NRG1 genotype. Results: Intracortical myelin is significantly predicted by age, diagnosis and genotype together in the motor cortex (left: R2 = 0.09, p < 0.01, right: R2 = 0.06, p < 0.05), the right premotor cortex (R2 = 0.095, p < 0.001), and the right inferior frontal cortex (R2 = 0.098, p < 0.001). Age is a significant individual predictor of intracortical myelin in the right dorsal anterior cingulate cortex, the bilateral motor cortex, the right premotor cortex, and the right inferior frontal cortex. Conclusions and Future Directions: Our study suggests that the right premotor, bilateral primary motor, and right inferior frontal cortices are regions of interest for understanding how intracortical myelin changes throughout the lifetime, especially in bipolar disorder. Future work should examine the impact of polygenic risk scores of bipolar disorder on intracortical myelin. / Thesis / Master of Science (MSc) / Bipolar disorder is associated with neurobiological changes, including cortical abnormalities, contributing to a greater disorder burden. Cortical myelination changes throughout the lifetime and larger deficits are found in individuals with bipolar disorder. However, the role of genetics in these intracortical myelin deficits is largely unknown. This thesis investigates how intracortical myelin content in various regions of the cortex is impacted by age, bipolar disorder diagnosis, and neuregulin gene variants. The goal of this research is to contribute to a better understanding of how genetics and age impact intracortical myelin in bipolar disorder to better understand the neurobiological changes of the disorder.

Humans possess the ability to generate an incredible degree of complex, highly skilled, and coordinated movements. Although much is known about the anatomical and physiological components of upper limb movement, the exact means by which these different areas coordinate is still far from understood. The ability to perform symmetrical, bimanual tasks with ease suggest a default coupling between mirror motor regions – a default coupling that is perceptible in unilateral movements. During intended unimanual movement in the upper limbs, bilateral changes to motor cortex output occur. The purpose of this study was to investigate the neural underpinnings of these bilateral changes and investigate the involvement of intracortical inhibitory circuits. Previous studies have shown that transcallosal connections between cortical representations of the intrinsic muscles of the hands are relatively sparser than the more proximal muscles of the upper limbs. It was hypothesized that differential responses in overall motor output or intracortical inhibition to ipsilateral muscle activation between the FDI and ECR could infer the involvement of transcallosal pathways; although interhemispheric transfer was not directly investigated in this thesis. Two studies used focal transcranial magnetic stimulation (TMS), specifically paired-pulse protocols, to investigate changes in short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) in response to contraction of contralateral homologous muscle groups to the inactive test muscle. Also, the response to activation of a non-homologous, but spatially close, muscle was investigated. Lastly, two muscle groups were investigated, a distal, intrinsic muscle of the hand (first dorsal interosseous) and a relatively more proximal muscle of the upper limb (extensor carpi radialis). These studies revealed that at low levels of force generation, unilateral isometric contractions facilitate ipsilateral mirror motor representations and reduce local GABA¬A receptor mediated inhibition. Notably, while similar facilitation occurred in both the distal and proximal effectors, decreases in SICI were much more robust in the ECR. Findings from this thesis provides insight into the neural mechanisms governing bilateral changes with unilateral movement and is important in the guiding the focus of future research.

Humans possess the ability to generate an incredible degree of complex, highly skilled, and coordinated movements. Although much is known about the anatomical and physiological components of upper limb movement, the exact means by which these different areas coordinate is still far from understood. The ability to perform symmetrical, bimanual tasks with ease suggest a default coupling between mirror motor regions – a default coupling that is perceptible in unilateral movements. During intended unimanual movement in the upper limbs, bilateral changes to motor cortex output occur. The purpose of this study was to investigate the neural underpinnings of these bilateral changes and investigate the involvement of intracortical inhibitory circuits. Previous studies have shown that transcallosal connections between cortical representations of the intrinsic muscles of the hands are relatively sparser than the more proximal muscles of the upper limbs. It was hypothesized that differential responses in overall motor output or intracortical inhibition to ipsilateral muscle activation between the FDI and ECR could infer the involvement of transcallosal pathways; although interhemispheric transfer was not directly investigated in this thesis. Two studies used focal transcranial magnetic stimulation (TMS), specifically paired-pulse protocols, to investigate changes in short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) in response to contraction of contralateral homologous muscle groups to the inactive test muscle. Also, the response to activation of a non-homologous, but spatially close, muscle was investigated. Lastly, two muscle groups were investigated, a distal, intrinsic muscle of the hand (first dorsal interosseous) and a relatively more proximal muscle of the upper limb (extensor carpi radialis). These studies revealed that at low levels of force generation, unilateral isometric contractions facilitate ipsilateral mirror motor representations and reduce local GABA¬A receptor mediated inhibition. Notably, while similar facilitation occurred in both the distal and proximal effectors, decreases in SICI were much more robust in the ECR. Findings from this thesis provides insight into the neural mechanisms governing bilateral changes with unilateral movement and is important in the guiding the focus of future research.

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

No description available.

No description available.

<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

The in-vivo observation of the neural activities generated by a large number of closely located neurons is believed to be crucial for understanding the nervous system. Moreover, the functional electrical stimulation of the central nervous system is an effective method to restore physiological functions such as limb control, sound sensation, and light perception. The Deep Brain Stimulation (DBS) is being successfully used in the treatment of tremor and rigidity associated with advanced Parkinson's disease. Cochlear implants have also been employed as an effective treatment for sensorineural deafness by means of delivering the electrical stimulation directly to the auditory nerve. The most significant contribution of this PhD study is the development of next-generation microprobes for the simultaneous stimulation and recording of the cortex and deep brain structures. For intracortical applications, millimetre length multisite microprobes that are rigid enough to penetrate into the cortex while integrated with flexible interconnection cables are demanded. In chronic applications, the flexibility of the cable minimizes the tissue damage caused by the relative micro-motion between the brain and the microprobe. Although hybrid approaches have been reported to construct such neural microprobes, these devices are brittle and may impose severe complications if they break inside the tissue. In this project, MEMS fabrication processes were employed to produce non-breakable intracortical microprobes with an improved structural design. These 32 channel devices are integrated with flexible interconnection cables and provide enough mechanical strength for penetration into the tissue. Polyimide-based flexible implants were successfully fabricated and locally reinforced at the tip with embedded 15 µm-thick gold micro-needles. In DBS applications, centimetre long microprobes capable of stimulating and recording the neural activity are required. The currently available DBS probes, manufactured by Medtronic, provide only four cylindrical shaped electrode sites, each 1.5 mm in height and 1.27 mm in diameter. Although suitable for the stimulation of a large brain volume, to measure the activity of a single neuron but to avoid measuring the average response of adjacent cells, recording sites with dimensions in the range of 10 - 20 µm are required. In this work, novel Three Dimensional (3D) multi channel microprobes were fabricated offering 32 independent stimulation and recording electrodes around the shaft of the implant. These microprobes can control the spatial distribution of the charge injected into the tissue to enhance the efficacy and minimize the adverse effects of the DBS treatment. Furthermore, the device volume has been reduced to one third the volume of a conventional Medtronic DBS lead to significantly decrease the tissue damage induced by implantation of the microprobe. For both DBS and intracortical microprobes, the impedance characteristics of the electrodes were studied in acidic and saline solutions. To reduce the channel impedance and enhance the signal to noise ratio, iridium (Ir) was electroplated on gold electrode sites. Stable electrical characteristics were demonstrated for the Ir and gold electrodes over the course of a prolonged pulse stress test for 100 million cycles. The functionality and application potential of the fabricated microprobes were confirmed by the in-vitro measurements of the neural activity in the mouse hippocampus. In order to reduce the number of channels and simplify the signal processing circuitry, multiport electrostatic-actuated switch matrices were successfully developed, fabricated, and characterized for possible integration with neural microprobes to construct a site selection matrix. Magnetic-actuated switches have been also investigated to improve the operation reliability of the MEMS switching devices.

The in-vivo observation of the neural activities generated by a large number of closely located neurons is believed to be crucial for understanding the nervous system. Moreover, the functional electrical stimulation of the central nervous system is an effective method to restore physiological functions such as limb control, sound sensation, and light perception. The Deep Brain Stimulation (DBS) is being successfully used in the treatment of tremor and rigidity associated with advanced Parkinson's disease. Cochlear implants have also been employed as an effective treatment for sensorineural deafness by means of delivering the electrical stimulation directly to the auditory nerve. The most significant contribution of this PhD study is the development of next-generation microprobes for the simultaneous stimulation and recording of the cortex and deep brain structures. For intracortical applications, millimetre length multisite microprobes that are rigid enough to penetrate into the cortex while integrated with flexible interconnection cables are demanded. In chronic applications, the flexibility of the cable minimizes the tissue damage caused by the relative micro-motion between the brain and the microprobe. Although hybrid approaches have been reported to construct such neural microprobes, these devices are brittle and may impose severe complications if they break inside the tissue. In this project, MEMS fabrication processes were employed to produce non-breakable intracortical microprobes with an improved structural design. These 32 channel devices are integrated with flexible interconnection cables and provide enough mechanical strength for penetration into the tissue. Polyimide-based flexible implants were successfully fabricated and locally reinforced at the tip with embedded 15 µm-thick gold micro-needles. In DBS applications, centimetre long microprobes capable of stimulating and recording the neural activity are required. The currently available DBS probes, manufactured by Medtronic, provide only four cylindrical shaped electrode sites, each 1.5 mm in height and 1.27 mm in diameter. Although suitable for the stimulation of a large brain volume, to measure the activity of a single neuron but to avoid measuring the average response of adjacent cells, recording sites with dimensions in the range of 10 - 20 µm are required. In this work, novel Three Dimensional (3D) multi channel microprobes were fabricated offering 32 independent stimulation and recording electrodes around the shaft of the implant. These microprobes can control the spatial distribution of the charge injected into the tissue to enhance the efficacy and minimize the adverse effects of the DBS treatment. Furthermore, the device volume has been reduced to one third the volume of a conventional Medtronic DBS lead to significantly decrease the tissue damage induced by implantation of the microprobe. For both DBS and intracortical microprobes, the impedance characteristics of the electrodes were studied in acidic and saline solutions. To reduce the channel impedance and enhance the signal to noise ratio, iridium (Ir) was electroplated on gold electrode sites. Stable electrical characteristics were demonstrated for the Ir and gold electrodes over the course of a prolonged pulse stress test for 100 million cycles. The functionality and application potential of the fabricated microprobes were confirmed by the in-vitro measurements of the neural activity in the mouse hippocampus. In order to reduce the number of channels and simplify the signal processing circuitry, multiport electrostatic-actuated switch matrices were successfully developed, fabricated, and characterized for possible integration with neural microprobes to construct a site selection matrix. Magnetic-actuated switches have been also investigated to improve the operation reliability of the MEMS switching devices.