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Description
Peripheral Vascular Disease (PVD) is a debilitating chronic disease of the lower extremities particularly affecting older adults and diabetics. It results in reduction of the blood flow to peripheral tissue and sometimes causing tissue damage such that PVD patients suffer from pain in the lower legs, thigh and buttocks after

Peripheral Vascular Disease (PVD) is a debilitating chronic disease of the lower extremities particularly affecting older adults and diabetics. It results in reduction of the blood flow to peripheral tissue and sometimes causing tissue damage such that PVD patients suffer from pain in the lower legs, thigh and buttocks after activities. Electrical neurostimulation based on the "Gate Theory of Pain" is a known to way to reduce pain but current devices to do this are bulky and not well suited to implantation in peripheral tissues. There is also an increased risk associated with surgery which limits the use of these devices. This research has designed and constructed wireless ultrasound powered microstimulators that are much smaller and injectable and so involve less implantation trauma. These devices are small enough to fit through an 18 gauge syringe needle increasing their potential for clinical use. These piezoelectric microdevices convert mechanical energy into electrical energy that then is used to block pain. The design and performance of these miniaturized devices was modeled by computer while constructed devices were evaluated in animal experiments. The devices are capable of producing 500ms pulses with an intensity of 2 mA into a 2 kilo-ohms load. Using the rat as an animal model, a series of experiments were conducted to evaluate the in-vivo performance of the devices.
ContributorsZong, Xi (Author) / Towe, Bruce (Thesis advisor) / Kleim, Jeffrey (Committee member) / Santello, Marco (Committee member) / Arizona State University (Publisher)
Created2014
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Description
Noninvasive neuromodulation could help treat many neurological disorders, but existing techniques have low resolution and weak penetration. Ultrasound (US) shows promise for stimulation of smaller areas and subcortical structures. However, the mechanism and parameter design are not understood. US can stimulate tail and hindlimb movements in rats, but not forelimb,

Noninvasive neuromodulation could help treat many neurological disorders, but existing techniques have low resolution and weak penetration. Ultrasound (US) shows promise for stimulation of smaller areas and subcortical structures. However, the mechanism and parameter design are not understood. US can stimulate tail and hindlimb movements in rats, but not forelimb, for unknown reasons. Potentially, US could also stimulate peripheral or enteric neurons for control of blood glucose.

To better understand the inconsistent effects across rat motor cortex, US modulation of electrically-evoked movements was tested. A stimulation array was implanted on the cortical surface and US (200 kHz, 30-60 W/cm2 peak) was applied while measuring changes in the evoked forelimb and hindlimb movements. Direct US stimulation of the hindlimb was also studied. To test peripheral effects, rat blood glucose levels were measured while applying US near the liver.

No short-term motor modulation was visible (95% confidence interval: -3.5% to +5.1% forelimb, -3.8% to +5.5% hindlimb). There was significant long-term (minutes-order) suppression (95% confidence interval: -3.7% to -10.8% forelimb, -3.8% to -11.9% hindlimb). This suppression may be due to the considerable heating (+1.8°C between US
on-US conditions); effects of heat and US were not separable in this experiment. US directly evoked hindlimb and scrotum movements in some sessions. This required a long interval, at least 3 seconds between US bursts. Movement could be evoked with much shorter pulses than used in literature (3 ms). The EMG latency (10 ms) was compatible with activation of corticospinal neurons. The glucose modulation test showed a strong increase in a few trials, but across all trials found no significant effect.

The single motor response and the long refractory period together suggest that only the beginning of the US burst had a stimulatory effect. This would explain the lack of short-term modulation, and suggests future work with shorter pulses could better explore the missing forelimb response. During the refractory period there was no change in the electrically-evoked response, which suggests the US stimulation mechanism is independent of normal brain activity. These results challenge the literature-standard protocols and provide new insights on the unknown mechanism.
ContributorsGulick, Daniel Withers (Author) / Kleim, Jeffrey (Thesis advisor) / Towe, Bruce (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Herman, Richard (Committee member) / Helms Tillery, Steven (Committee member) / Arizona State University (Publisher)
Created2015
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Description
A direct Magnetic Resonance (MR)-based neural activity mapping technique with high spatial and temporal resolution may accelerate studies of brain functional organization.

The most widely used technique for brain functional imaging is functional Magnetic Resonance Image (fMRI). The spatial resolution of fMRI is high. However, fMRI signals are highly influenced

A direct Magnetic Resonance (MR)-based neural activity mapping technique with high spatial and temporal resolution may accelerate studies of brain functional organization.

The most widely used technique for brain functional imaging is functional Magnetic Resonance Image (fMRI). The spatial resolution of fMRI is high. However, fMRI signals are highly influenced by the vasculature in each voxel and can be affected by capillary orientation and vessel size. Functional MRI analysis may, therefore, produce misleading results when voxels are nearby large vessels. Another problem in fMRI is that hemodynamic responses are slower than the neuronal activity. Therefore, temporal resolution is limited in fMRI. Furthermore, the correlation between neural activity and the hemodynamic response is not fully understood. fMRI can only be considered an indirect method of functional brain imaging.

Another MR-based method of functional brain mapping is neuronal current magnetic resonance imaging (ncMRI), which has been studied over several years. However, the amplitude of these neuronal current signals is an order of magnitude smaller than the physiological noise. Works on ncMRI include simulation, phantom experiments, and studies in tissue including isolated ganglia, optic nerves, and human brains. However, ncMRI development has been hampered due to the extremely small signal amplitude, as well as the presence of confounding signals from hemodynamic changes and other physiological noise.

Magnetic Resonance Electrical Impedance Tomography (MREIT) methods could have the potential for the detection of neuronal activity. In this technique, small external currents are applied to a body during MR scans. This current flow produces a magnetic field as well as an electric field. The altered magnetic flux density along the main magnetic field direction caused by this current flow can be obtained from phase images. When there is neural activity, the conductivity of the neural cell membrane changes and the current paths around the neurons change consequently. Neural spiking activity during external current injection, therefore, causes differential phase accumulation in MR data. Statistical analysis methods can be used to identify neuronal-current-induced magnetic field changes.
ContributorsFu, Fanrui (Author) / Sadleir, Rosalind (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Kleim, Jeffrey (Committee member) / Muthuswamy, Jitendran (Committee member) / Helms Tillery, Stephen (Committee member) / Arizona State University (Publisher)
Created2019
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Description
Proprioception is the sense of body position, movement, force, and effort. Loss of proprioception can affect planning and control of limb and body movements, negatively impacting activities of daily living and quality of life. Assessments employing planar robots have shown that proprioceptive sensitivity is directionally dependent within the horizontal plane

Proprioception is the sense of body position, movement, force, and effort. Loss of proprioception can affect planning and control of limb and body movements, negatively impacting activities of daily living and quality of life. Assessments employing planar robots have shown that proprioceptive sensitivity is directionally dependent within the horizontal plane however, few studies have looked at proprioceptive sensitivity in 3d space. In addition, the extent to which proprioceptive sensitivity is modifiable by factors such as exogenous neuromodulation is unclear. To investigate proprioceptive sensitivity in 3d we developed a novel experimental paradigm employing a 7-DoF robot arm, which enables reliable testing of arm proprioception along arbitrary paths in 3d space, including vertical motion which has previously been neglected. A participant’s right arm was coupled to a trough held by the robot that stabilized the wrist and forearm, allowing for changes in configuration only at the elbow and shoulder. Sensitivity to imposed displacements of the endpoint of the arm were evaluated using a “same/different” task, where participant’s hands were moved 1-4 cm from a previously visited reference position. A measure of sensitivity (d’) was compared across 6 movement directions and between 2 postures. For all directions, sensitivity increased monotonically as the distance from the reference location increased. Sensitivity was also shown to be anisotropic (directionally dependent) which has implications for our understanding of the planning and control of reaching movements in 3d space.

The effect of neuromodulation on proprioceptive sensitivity was assessed using transcutaneous electrical nerve stimulation (TENS), which has been shown to have beneficial effects on human cognitive and sensorimotor performance in other contexts. In this pilot study the effects of two frequencies (30hz and 300hz) and three electrode configurations were examined. No effect of electrode configuration was found, however sensitivity with 30hz stimulation was significantly lower than with 300hz stimulation (which was similar to sensitivity without stimulation). Although TENS was shown to modulate proprioceptive sensitivity, additional experiments are required to determine if TENS can produce enhancement rather than depression of sensitivity which would have positive implications for rehabilitation of proprioceptive deficits arising from stroke and other disorders.
ContributorsKlein, Joshua (Author) / Buneo, Christopher (Thesis advisor) / Helms-Tillery, Stephen (Committee member) / Kleim, Jeffrey (Committee member) / Santello, Marco (Committee member) / Arizona State University (Publisher)
Created2018
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Description
Vagal Nerve Stimulation (VNS) has been shown to be a promising therapeutic technique in treating many neurological diseases, including epilepsy, stroke, traumatic brain injury, and migraine headache. The mechanisms by which VNS acts, however, are not fully understood but may involve changes in cerebral blood flow. The vagus nerve plays

Vagal Nerve Stimulation (VNS) has been shown to be a promising therapeutic technique in treating many neurological diseases, including epilepsy, stroke, traumatic brain injury, and migraine headache. The mechanisms by which VNS acts, however, are not fully understood but may involve changes in cerebral blood flow. The vagus nerve plays a significant role in the regulation of heart rate and cerebral blood flow that are altered during VNS. Here, we examined the effects of acute vagal nerve stimulation on both heart rate and cerebral blood flow. Laser Speckle Contrast Analysis (LASCA) was used to analyze the cerebral blood flow of male Long\u2014Evans rats. Results showed two distinct patterns of responses whereby animals either experienced a mild or severe decrease in heart rate during VNS. Further, animals that displayed mild heart rate decreases showed an increase in cerebral blood flow that persisted beyond VNS. Animals that displayed severe decreases showed a transient decrease in cerebral blood flow followed by an increase that was greater than that observed in mild animals but progressively decreased after VNS. The results suggest two distinct patterns of changes in both heart rate and cerebral blood flow that may be related to the intensity of VNS.
ContributorsHillebrand, Peter Timothy (Author) / Kleim, Jeffrey (Thesis director) / Helms Tillery, Stephen (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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Description
Brain-machine interfaces (BMIs) were first imagined as a technology that would allow subjects to have direct communication with prosthetics and external devices (e.g. control over a computer cursor or robotic arm movement). Operation of these devices was not automatic, and subjects needed calibration and training in order to master this

Brain-machine interfaces (BMIs) were first imagined as a technology that would allow subjects to have direct communication with prosthetics and external devices (e.g. control over a computer cursor or robotic arm movement). Operation of these devices was not automatic, and subjects needed calibration and training in order to master this control. In short, learning became a key component in controlling these systems. As a result, BMIs have become ideal tools to probe and explore brain activity, since they allow the isolation of neural inputs and systematic altering of the relationships between the neural signals and output. I have used BMIs to explore the process of brain adaptability in a motor-like task. To this end, I trained non-human primates to control a 3D cursor and adapt to two different perturbations: a visuomotor rotation, uniform across the neural ensemble, and a decorrelation task, which non-uniformly altered the relationship between the activity of particular neurons in an ensemble and movement output. I measured individual and population level changes in the neural ensemble as subjects honed their skills over the span of several days. I found some similarities in the adaptation process elicited by these two tasks. On one hand, individual neurons displayed tuning changes across the entire ensemble after task adaptation: most neurons displayed transient changes in their preferred directions, and most neuron pairs showed changes in their cross-correlations during the learning process. On the other hand, I also measured population level adaptation in the neural ensemble: the underlying neural manifolds that control these neural signals also had dynamic changes during adaptation. I have found that the neural circuits seem to apply an exploratory strategy when adapting to new tasks. Our results suggest that information and trajectories in the neural space increase after initially introducing the perturbations, and before the subject settles into workable solutions. These results provide new insights into both the underlying population level processes in motor learning, and the changes in neural coding which are necessary for subjects to learn to control neuroprosthetics. Understanding of these mechanisms can help us create better control algorithms, and design training paradigms that will take advantage of these processes.
ContributorsArmenta Salas, Michelle (Author) / Helms Tillery, Stephen I (Thesis advisor) / Si, Jennie (Committee member) / Buneo, Christopher (Committee member) / Santello, Marco (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2015
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Description
Stromal cell-derived factor-1α (SDF-1α) and its key receptor, CXCR4 are ubiquitously expressed in systems across the body (e.g. liver, skin, lung, etc.). This signaling axis regulates a myriad of physiological processes that range from maintaining of organ homeostasis in adults to, chemotaxis of stem/progenitor and immune cell types after injury.

Stromal cell-derived factor-1α (SDF-1α) and its key receptor, CXCR4 are ubiquitously expressed in systems across the body (e.g. liver, skin, lung, etc.). This signaling axis regulates a myriad of physiological processes that range from maintaining of organ homeostasis in adults to, chemotaxis of stem/progenitor and immune cell types after injury. Given its potential role as a therapeutic target for diverse applications, surprisingly little is known about how SDF-1α mediated signaling propagates through native tissues. This limitation ultimately constrains rational design of interventional biomaterials that aim to target the SDF-1α/CXCR4 signaling axis. One application of particular interest is traumatic brain injury (TBI) for which, there are currently no means of targeting the underlying biochemical pathology to improve prognosis.

Growing evidence suggests a relationship between SDF-1α/CXCR4 signaling and endogenous neural progenitor/stem cells (NPSC)-mediated regeneration after neural injury. Long-term modulation of the SDF-1α/CXCR4 signaling axis is thus hypothesized as a possible avenue for harnessing and amplifying endogenous regenerative mechanisms after TBI. In order to understand how the SDF-1α/CXCR4 signaling can be modulated in vivo, we first developed and characterized a sustained protein delivery platform in vitro. We were the first, to our knowledge, to demonstrate that protein release profiles from poly(D,L,-lactic-co-glycolic) acid (PLGA) particles can be tuned independent of particle fabrication parameters via centrifugal fractioning. This process of physically separating the particles altered the average diameter of a particle population, which is in turn was correlated to critical release characteristics. Secondly, we demonstrated sustained release of SDF-1α from PLGA/fibrin composites (particles embedded in fibrin) with tunable burst release as a function of fibrin concentration. Finally, we contrasted the spatiotemporal localization of endogenous SDF-1α and CXCR4 expression in response to either bolus or sustained release of exogenous SDF-1α. Sustained release of exogenous SDF-1α induced spatially diffuse endogenous SDF-1/CXCR4 expression relative to bolus SDF-1 administration; however, the observed effects were transient in both cases, persisting only to a maximum of 3 days post injection. These studies will inform future systematic evaluations of strategies that exploit SDF-1α/CXCR4 signaling for diverse applications.
ContributorsDutta, Dipankar (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Kleim, Jeffrey (Committee member) / Nikkhah, Mehdi (Committee member) / Sirianni, Rachael (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2016
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Description
Transcranial electrical stimulation (tES) is a non-invasive brain stimulation therapy that has shown potential in improving motor, physiological and cognitive functions in healthy and diseased population. Typical tES procedures involve application of weak current (< 2 mA) to the brain via a pair of large electrodes placed on the scalp.

Transcranial electrical stimulation (tES) is a non-invasive brain stimulation therapy that has shown potential in improving motor, physiological and cognitive functions in healthy and diseased population. Typical tES procedures involve application of weak current (< 2 mA) to the brain via a pair of large electrodes placed on the scalp. While the therapeutic benefits of tES are promising, the efficacy of tES treatments is limited by the knowledge of how current travels in the brain. It has been assumed that the current density and electric fields are the largest, and thus have the most effect, in brain structures nearby the electrodes. Recent studies using finite element modeling (FEM) have suggested that current patterns in the brain are diffuse and not concentrated in any particular brain structure. Although current flow modeling is useful means of informing tES target optimization, few studies have validated tES FEM models against experimental measurements. MREIT-CDI can be used to recover magnetic flux density caused by current flow in a conducting object. This dissertation reports the first comparisons between experimental data from in-vivo human MREIT-CDI during tES and results from tES FEM using head models derived from the same subjects. First, tES FEM pipelines were verified by confirming FEM predictions agreed with analytic results at the mesh sizes used and that a sufficiently large head extent was modeled to approximate results on human subjects. Second, models were used to predict magnetic flux density, and predicted and MREIT-CDI results were compared to validate and refine modeling outcomes. Finally, models were used to investigate inter-subject variability and biological side effects reported by tES subjects. The study demonstrated good agreements in patterns between magnetic flux distributions from experimental and simulation data. However, the discrepancy in scales between simulation and experimental data suggested that tissue conductivities typically used in tES FEM might be incorrect, and thus performing in-vivo conductivity measurements in humans is desirable. Overall, in-vivo MREIT-CDI in human heads has been established as a validation tool for tES predictions and to study the underlying mechanisms of tES therapies.
ContributorsIndahlastari, Aprinda (Author) / Sadleir, Rosalind J (Thesis advisor) / Abbas, James (Committee member) / Frakes, David (Committee member) / Kleim, Jeffrey (Committee member) / Kodibagkar, Vikram (Committee member) / Arizona State University (Publisher)
Created2017
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Description
A current thrust in neurorehabilitation research involves exogenous neuromodulation of peripheral nerves to enhance neuroplasticity and maximize recovery of function. This dissertation presents the results of four experiments aimed at assessing the effects of trigeminal nerve stimulation (TNS) and occipital nerve stimulation (ONS) on motor learning, which was behaviorally characterized

A current thrust in neurorehabilitation research involves exogenous neuromodulation of peripheral nerves to enhance neuroplasticity and maximize recovery of function. This dissertation presents the results of four experiments aimed at assessing the effects of trigeminal nerve stimulation (TNS) and occipital nerve stimulation (ONS) on motor learning, which was behaviorally characterized using an upper extremity visuomotor adaptation paradigm. In Aim 1a, the effects of offline TNS using clinically tested frequencies (120 and 60 Hz) were characterized. Sixty-three participants (22.75±4.6 y/o), performed a visuomotor rotation task and received TNS before encountering rotation of hand visual feedback. In Aim 1b, TNS at 3 kHz, which has been shown to be more tolerable at higher current intensities, was evaluated in 42 additional subjects (23.4±4.6 y/o). Results indicated that 3 kHz stimulation accelerated learning while 60 Hz stimulation slowed learning, suggesting a frequency-dependent effect on learning. In Aim 2, the effect of online TNS using 120 and 60 Hz were characterized to determine if this protocol would deliver better outcomes. Sixty-three participants (23.2±3.9 y/o) received either TNS or sham concurrently with perturbed visual feedback. Results showed no significant differences among groups. However, a cross-study comparison of results obtained with 60 Hz offline TNS showed a statistically significant improvement in learning rates with online stimulation relative to offline, suggesting a timing-dependent effect on learning. In Aim 3, TNS and ONS were compared using the best protocol from previous aims (offline 3 kHz). Additionally, concurrent stimulation of both nerves was explored to look for potential synergistic effects. Eighty-four participants (22.9±3.2 y/o) were assigned to one of four groups: TNS, ONS, TNS+ONS, and sham. Visual inspection of learning curves revealed that the ONS group demonstrated the fastest learning among groups. However, statistical analyses did not confirm this observation. In addition, the TNS+ONS group appeared to learn faster than the sham and TNS groups but slower than the ONS only group, suggesting no synergistic effects using this protocol, as initially hypothesized. The results provide new information on the potential use of TNS and ONS in neurorehabilitation and performance enhancement in the motor domain.
ContributorsArias, Diego (Author) / Buneo, Christopher (Thesis advisor) / Schaefer, Sydney (Committee member) / Helms-Tillery, Stephen (Committee member) / Santello, Marco (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2023
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Description
Our ability to estimate the position of our body parts in space, a fundamentally proprioceptive process, is crucial for interacting with the environment and movement control. For proprioception to support these actions, the Central Nervous System has to rely on a stored internal representation of the body parts in space.

Our ability to estimate the position of our body parts in space, a fundamentally proprioceptive process, is crucial for interacting with the environment and movement control. For proprioception to support these actions, the Central Nervous System has to rely on a stored internal representation of the body parts in space. However, relatively little is known about this internal representation of arm position. To this end, I developed a method to map proprioceptive estimates of hand location across a 2-d workspace. In this task, I moved each subject's hand to a target location while the subject's eyes were closed. After returning the hand, subjects opened their eyes to verbally report the location of where their fingertip had been. Then, I reconstructed and analyzed the spatial structure of the pattern of estimation errors. In the first couple of experiments I probed the structure and stability of the pattern of errors by manipulating the hand used and tactile feedback provided when the hand was at each target location. I found that the resulting pattern of errors was systematically stable across conditions for each subject, subject-specific, and not uniform across the workspace. These findings suggest that the observed structure of pattern of errors has been constructed through experience, which has resulted in a systematically stable internal representation of arm location. Moreover, this representation is continuously being calibrated across the workspace. In the next two experiments, I aimed to probe the calibration of this structure. To this end, I used two different perturbation paradigms: 1) a virtual reality visuomotor adaptation to induce a local perturbation, 2) and a standard prism adaptation paradigm to induce a global perturbation. I found that the magnitude of the errors significantly increased to a similar extent after each perturbation. This small effect indicates that proprioception is recalibrated to a similar extent regardless of how the perturbation is introduced, suggesting that sensory and motor changes may be two independent processes arising from the perturbation. Moreover, I propose that the internal representation of arm location might be constructed with a global solution and not capable of local changes.
ContributorsRincon Gonzalez, Liliana (Author) / Helms Tillery, Stephen I (Thesis advisor) / Buneo, Christopher A (Thesis advisor) / Santello, Marco (Committee member) / Santos, Veronica (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2012