Matching Items (8)
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- All Subjects: Neurosciences
- Genre: Doctoral Dissertation
- Creators: Kleim, Jeffrey
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. 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
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 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
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 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.
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
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 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.
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
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 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
Description
Dexterous manipulation is a representative task that involves sensorimotor integration underlying a fine control of movements. Over the past 30 years, research has provided significant insight, including the control mechanisms of force coordination during manipulation tasks. Successful dexterous manipulation is thought to rely on the ability to integrate the sense of digit position with motor commands responsible for generating digit forces and placement. However, the mechanisms underlying the phenomenon of digit position-force coordination are not well understood. This dissertation addresses this question through three experiments that are based on psychophysics and object lifting tasks. It was found in psychophysics tasks that sensed relative digit position was accurately reproduced when sensorimotor transformations occurred with larger vertical fingertip separations, within the same hand, and at the same hand posture. The results from a follow-up experiment conducted in the same digit position-matching task while generating forces in different directions reveal a biased relative digit position toward the direction of force production. Specifically, subjects reproduced the thumb CoP higher than the index finger CoP when vertical digit forces were directed upward and downward, respectively, and vice versa. It was also found in lifting tasks that the ability to discriminate the relative digit position prior to lifting an object and modulate digit forces to minimize object roll as a function of digit position are robust regardless of whether motor commands for positioning the digits on the object are involved. These results indicate that the erroneous sensorimotor transformations of relative digit position reported here must be compensated during dexterous manipulation by other mechanisms, e.g., visual feedback of fingertip position. Furthermore, predicted sensory consequences derived from the efference copy of voluntary motor commands to generate vertical digit forces may override haptic sensory feedback for the estimation of relative digit position. Lastly, the sensorimotor transformations from haptic feedback to digit force modulation to position appear to be facilitated by motor commands for active digit placement in manipulation.
ContributorsShibata, Daisuke (Author) / Santello, Marco (Thesis advisor) / Dounskaia, Natalia (Committee member) / Kleim, Jeffrey (Committee member) / Helms Tillery, Stephen (Committee member) / McBeath, Michael (Committee member) / Arizona State University (Publisher)
Created2014
Description
Transcranial focused ultrasound (tFUS) is a unique neurostimulation modality with potential to develop into a highly sophisticated and effective tool. Unlike any other noninvasive neurostimulation technique, tFUS has a high spatial resolution (on the order of millimeters) and can penetrate across the skull, deep into the brain. Sub-thermal tFUS has been shown to induce changes in EEG and fMRI, as well as perception and mood. This study investigates the possibility of using tFUS to modulate brain networks involved in attention and cognitive control.Three different brain areas linked to saliency, cognitive control, and emotion within the cingulo-opercular network were stimulated with tFUS while subjects performed behavioral paradigms. The first study targeted the dorsal anterior cingulate cortex (dACC), which is associated with performance on cognitive attention tasks, conflict, error, and, emotion. Subjects performed a variant of the Erikson Flanker task in which emotional faces (fear, neutral or scrambled) were displayed in the background as distractors. tFUS significantly reduced the reaction time (RT) delay induced by faces; there were significant differences between tFUS and Sham groups in event related potentials (ERP), event related spectral perturbation (ERSP), conflict and error processing, and heart rate variability (HRV).
The second study used the same behavioral paradigm, but targeted tFUS to the right anterior insula/frontal operculum (aIns/fO). The aIns/fO is implicated in saliency, cognitive control, interoceptive awareness, autonomic function, and emotion. tFUS was found to significantly alter ERP, ERSP, conflict and error processing, and HRV responses.
The third study targeted tFUS to the right inferior frontal gyrus (rIFG), employing the Stop Signal task to study inhibition. tFUS affected ERPs and improved stopping speed. Using network modeling, causal evidence is presented for rIFG influence on subcortical nodes in stopping.
This work provides preliminarily evidence that tFUS can be used to modulate broader network function through a single node, affecting neurophysiological processing, physiologic responses, and behavioral performance. Additionally it can be used as a tool to elucidate network function. These studies suggest tFUS has the potential to affect cognitive function as a clinical tool, and perhaps even enhance wellbeing and expand conscious awareness.
The second study used the same behavioral paradigm, but targeted tFUS to the right anterior insula/frontal operculum (aIns/fO). The aIns/fO is implicated in saliency, cognitive control, interoceptive awareness, autonomic function, and emotion. tFUS was found to significantly alter ERP, ERSP, conflict and error processing, and HRV responses.
The third study targeted tFUS to the right inferior frontal gyrus (rIFG), employing the Stop Signal task to study inhibition. tFUS affected ERPs and improved stopping speed. Using network modeling, causal evidence is presented for rIFG influence on subcortical nodes in stopping.
This work provides preliminarily evidence that tFUS can be used to modulate broader network function through a single node, affecting neurophysiological processing, physiologic responses, and behavioral performance. Additionally it can be used as a tool to elucidate network function. These studies suggest tFUS has the potential to affect cognitive function as a clinical tool, and perhaps even enhance wellbeing and expand conscious awareness.
ContributorsFini, Maria Elizabeth (Author) / Tyler, William J (Thesis advisor) / Greger, Bradley (Committee member) / Santello, Marco (Committee member) / Kleim, Jeffrey (Committee member) / Helms Tillery, Stephen (Committee member) / Arizona State University (Publisher)
Created2020
Description
Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States each year and is a leading cause of death and disability for children and young adults in industrialized countries. Unfortunately, the molecular and cellular mechanisms of injury progression have yet to be fully elucidated. Consequently, this complexity impacts the development of accurate diagnosis and treatment options. Biomarkers, objective signatures of injury, can inform and facilitate development of sensitive and specific theranostic devices. Discovery techniques that take advantage of mining the temporal complexity of TBI are critical for the identification of high specificity biomarkers.
Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential.
My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate.
The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity.
Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential.
My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate.
The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity.
ContributorsMartinez, Briana Isabella (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Lifshitz, Jonathan (Committee member) / Sierks, Michael (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2020