Browsing by Subject "electrophysiology"

Now showing 1 - 9 of 9
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    Development of model-based and sensor-based programming techniques for optimizing directional deep brain stimulation therapy for movement disorders
    (2022-01) Brinda, AnneMarie
    Deep brain stimulation (DBS) therapy is a programmable neurosurgical intervention that can significantly improve quality of life for individuals with medication-refractory movement disorders, such as Essential Tremor and Parkinson’s Disease. However, clinical outcomes with DBS therapy still vary across patients, and the clinical time and effort necessary to program the stimulation settings to each patient’s symptoms presents practical challenges in the clinic. With the advent of directional lead technology and independent multi-channel current-controlled stimulation, the scope of possible DBS configurations is now substantially larger than it was even five years ago. This has greatly increased the time to determine the most effective electrode configuration, and in reality, much of the stimulation parameter space is left unexplored during a clinical visit. This thesis addressed the gap between the directional lead technology and its clinical implementation by developing three promising techniques to program directional DBS lead systems. The first programming technique involved developing subject-specific computational models of DBS based on individual MRI/CT scans. Comparing model predictions to clinical outcomes from patients with Essential Tremor revealed that lateral and medial parcellations of the motor-thalamic afferents of the cerebellothalamic tract were differentially associated with stimulation-induced therapy and side effects, respectively. Second, sensor-based evaluation of DBS in Essential Tremor patients revealed that directional contacts were superior to ring-mode contacts in providing optimized tremor reduction with reduced dysarthria. The third programming technique involved using neurophysiological feedback to guide the selection of which electrode(s) to use during DBS. In Parkinson’s disease, for example, stimulation through electrodes with higher resting-state beta-band oscillatory power in the subthalamic nucleus generally results in better clinical outcomes. Using a non-human primate model, we tracked how beta-band power changed spatially and temporally between intraoperative and chronic time points and showed that the strongest variability occurred within the first two weeks after lead implantation. This suggested that neurofeedback-based programming may be most consistent after the immune tissue response settles. Together, these results showed how model- and sensor-based programming techniques can limit the parameter space for programming directional DBS enabling more efficient and effective clinical outcomes in the future.
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    Disassociating Sensory, Choice, and Attentional Signals to Understand Feature Based Perception and Learning in Small Populations of Intermediate Visual Cortex
    (2019-05) Moore, Elisabeth
    Perception is integral to how we interact with our visual environment. How perception changes with experience is a function of learning, while how it occurs on a flexible, immediate time scale in relation to dynamic task demands, is mediated by attention. Both of these cognitive phenomena underpin how we perceive and interact with the world around us. Visual perceptual learning (VPL) is the improvement in the ability to perceive our visual environment, and is essential to how humans and other animals learn to interact with the world. Despite an extensive amount of research into the mechanisms of VPL, the neural mechanisms responsible for perceptual improvements remain controversial. A major challenge has been establishing that a particular physiological correlate of learning is actually responsible for learning, as opposed to merely reflecting changes in the properties or populations that are responsible. To address this issue, we employed a perceptual detection task in which neurons in a specific area, V4, are known to have task related responses on a scale of tens of milliseconds that reliably predict the timing and precision of shape detection. We followed population responses using a chronically implanted electrode array while non-human primates learned to detect shapes degraded by noise. Consistent with previous results that examined single neurons and neuronal ensembles, we found that, after the course of learning, variations in the local field potentials of individual electrodes over the course of tens of milliseconds reliably reflected the presentation of degraded shapes, and also predicted detection decisions made by the animal. Moreover, we found that variations in reliability of shape-related signals predicted the up-down fluctuations in performance seen over the course of learning in each animal. Together, these results demonstrate that population signals in area V4 are largely sufficient to explain the timing and reliability of shape detection and how that detection performance increases as a consequence of training. Endogenous feature-based visual attention involves an improvement in neural representations involving the attended feature that is dependent on immediate task dependent demands. How this happens in a specific population, and whether the involved populations overlap with those mediating perception, is not well understood. Due to previous work in our laboratory finding that feature based attention is targeted to specific, task appropriate neural populations in early visual cortex, we asked whether attention is similarly distributed in a task specific way in V4, how this depends on attentional state, and whether such neurons also signal the readout of the perceptual choice, given that choice signals have consistently been found in this area. We designed a demanding stimulus discrimination task where we directed subjects to attend to a specific feature of the task during high-field fMRI scanning. The stimulus alternated continuously at varying frequencies in low and high level features (spatial frequency and shape, due to their expected sensory activation of V1 and V4, respectively). Voxels were measured at high resolution, sampling 1mm of cortex, from V1 to V4, and the stimulus was presented near perceptual threshold in order to disassociate the stimulus from the choice. We used a linear regression analysis to compare continuous BOLD modulation of individual voxels to regressors modeling the continuous stimulus presentation when a given feature was attended to vs when it was not, and assessed how sensory and attention modulations overlapped with modulations containing a relationship to the ongoing perceptual choice. We found clear sensory attention effects in V4 that were specific to certain populations; however this did not appear to depend on initial sensitivity, and we did not see reliable choice signals or choice signals that overlapped with attention signals. We believe this may be due to the experimental design and recommend future approaches to disassociate sensory, attention, and choice signals in visual cortex.
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    Functional Characterization of Amino Acid Permeases in Rice and Liverwort
    (2015-12) Taylor, Margaret
    The amino acid permeases (AAPs) are a family of proton-coupled amino acid transporters that are found throughout the land plants but not in algae. Previously, the majority of research done on AAPs has been in Arabidopsis thaliana and other eudicots. There is a wide variation in the number of AAP genes between plant species, so some AAPs in non-eudicot species might have novel functions. The purpose of this thesis was to investigate the function of AAPs in rice, a model monocot, and liverwort, a basal land plant. The long-term goal of this project is to understand how differences in transport function in AAPs are related to differences in amino acid sequence. The main goal of this thesis work was to identify differences in AAP function. Electrophysiology was used to study the substrate specificity and substrate affinity of the rice and liverwort AAPs. Some of the rice and liverwort AAPs were found to have novel substrate specificities. Ancestral protein sequences were inferred and tested for function. Based on the results, the ability to transport basic amino acids is basal in AAPs. The inability to transport basic amino acids evolved independently at least twice in the AAP lineage.
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    G Protein Signaling In Astrocytes Regulates Neuronal Excitability And Synaptic Plasticity
    (2019-04) Durkee, Caitlin
    Accumulating evidence over the past few decades has revealed that astrocytes, a type of glial cell in the brain, are more involved in active brain communication than previously thought. In addition to serving a multitude of homeostatic roles in the brain, astrocytes also participate in bidirectional communication with neurons, a phenomenon that has important consequences for brain function. One way in which astrocytes communicate with neurons is through calcium-induced release of their own signaling molecules, termed gliotransmitters. A well-studied mechanism of calcium signaling in astrocytes is G protein-coupled receptor (GPCR) signaling, particularly Gq GPCR signaling. A less-studied calcium signaling pathway in astrocytes is through Gi/o GPCR activation. In neurons, activation of Gq GPCRs and Gi/o GPCRs leads to cellular excitation and inhibition, respectively. Whether the same effects occur in astrocytes, and the consequences of such signaling, is the focus of experiments in Chapter Two. I used both an endogenous and chemogenetic approach (i.e. DREADDs) to characterize the functional consequences of Gq and Gi/o GPCR signaling pathways in neurons and astrocytes. I found that activation of Gq GPCRs led to excitation in both neurons and astrocytes. In contrast, Gi/o GPCR activation led to cellular inhibition in neurons, but activation in astrocytes. Both Gq and Gi/o GPCR activation in astrocytes stimulated the release of glutamate that increased neuronal excitability. These results add additional complexity to neural communication in the brain and suggest that inhibitory signaling in particular may be a particular property of neurons. Chapter Three delves further into the consequences of GPCR signaling in astrocytes and whether it is involved in mediating long-term plasticity. While Chapter Two shows the consequences of activating astrocyte GPCRs exogenously, Chapter Three investigates the consequences of activating astrocyte GPCRs synaptically. In particular, I investigate the role of astrocytes in mediating long-term depression (LTD) at a subset of synapses in the dorsolateral striatum. Despite extensive research into neuronal circuitry in the striatum, little work has been done in elucidating the role of astrocytes in striatal function. I show that astrocytes respond to high-frequency stimulation-induced LTD through mGluR5, a type of glutamate Gq-coupled GPCR. In return, astrocytes release the gliotransmitter ATP, which is necessary for inducing LTD at corticostriatal synapses. Through both a loss of function and gain of function approach, I demonstrate that astrocytes are an integral participant of striatal plasticity. Taken together, these studies add to the growing evidence that astrocytes play active roles in information processing in the brain, a dogmatic shift in the previously-held notion that astrocytes serve strictly support functions.
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    Invasive and Noninvasive Brain Stimulation Strategies for the Treatment of Tinnitus
    (2014-06) Markovitz, Craig
    The central auditory system consists of a series of relay stations at which auditory information is processed in stages before reaching the auditory cortex for sound perception. However, descending projections and non-auditory inputs into the central auditory system also play a vital role in shaping neural coding along the auditory pathway. The work in this thesis seeks to investigate the organization and role of these modulatory pathways of the central auditory system, particularly to devise and improve upon existing neuromodulation strategies for treating neurological disorders related to the auditory system, including tinnitus and hyperacusis. Through animal studies, we have shown that the descending projections from primary auditory cortex to subcortical centers, particularly the central nucleus of the inferior colliculus, exhibit a precise spatial organization based on frequency coding, supporting the role of the corticofugal system for modulating specific and relevant coding features within the ascending auditory system. Further, by combining stimulation of auditory cortex with an irrelevant acoustic stimulus, we were able to suppress neural firing throughout the inferior colliculus, revealing at least one potential mechanism for gating relevant versus irrelevant sound inputs. Targeting this gating mechanism could provide a neuromodulation treatment for tinnitus and/or hyperacusis which are associated with hyperactivity across auditory centers. Finally, we introduce a new neuromodulation approach using simultaneous noninvasive stimulation of multimodal pathways, focusing initially on somatosensory and auditory inputs. We present our proof-of-concept studies showing the ability to modulate neural coding in the inferior colliculus up to auditory cortex in a systematic way depending on the stimulation parameters (e.g., interstimulus interval and body stimulation location). These invasive and noninvasive techniques for modulating the brain provide potential options for the treatment of hearing disorders as well as other neurological and neuropsychiatric conditions.
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    Investigating the effects of subthalamic nucleus stimulation on gait and pedunculopontine nucleus activity in a preclinical animal model of Parkinson’s disease
    (2022-02) Doyle, Alexandra
    Dopamine-replacement therapy and deep brain stimulation therapy can reliably manage several cardinal motor signs of Parkinson’s disease including tremor, rigidity, and bradykinesia. The efficacy of these treatments on gait and postural dysfunction, however, are often variable and wane over time. This doctoral dissertation advanced our understanding of parkinsonian gait dysfunction by (1) defining spatiotemporal progression of gait changes with increasing parkinsonian severity in the MPTP non-human primate model of Parkinson’s disease, (2) characterizing changes in gait parameters with targeted subthalamic deep brain stimulation, and (3) defining how targeted subthalamic deep brain stimulation differentially affects neuronal spike rate and pattern changes in the pedunculopontine nucleus, which is a key structure in the mesencephalic locomotor region. The major findings were that the MPTP non-human primate model displays progressive bradykinetic gait that align with severity of other cardinal motor signs; however, asymmetric and disordered gait patterns only appeared in the more advanced parkinsonian state. Deep brain stimulation of the subthalamic nucleus showed a spatial map in of improving and worsening bradykinetic gait, and this map aligned with a differential effect on pedunculopontine nucleus modulation. These results suggest that deep brain stimulation can impart therapeutic effects on gait symptoms, but the effects depend on how one modulates pathways involved in locomotion. Such findings will be useful for future efforts to optimize deep brain stimulation for individuals with Parkinson’s disease.
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    Linking topiramate exposure to changes in electrophysiological activity and behavioral deficits through quantitative pharmacological modeling
    (2019-05) Callisto, Samuel
    Topiramate is a broad-spectrum anti-epileptic drug used to treat a variety of conditions, including epilepsy, migraine, substance abuse, mood, and eating disorders. We investigated the effects of topiramate on the working memory system using population pharmacokinetic-pharmacodynamic modeling and unsupervised machine learning approaches. Working memory is the capacity-limited neurocognitive system responsible for simultaneous maintenance and manipulation of information in order to achieve a goal. Behavioral and electrophysiological indices of working memory function were measured using data collected during a double-blind, placebo-controlled crossover study in healthy volunteers. Subjects completed a Sternberg working memory task, during which accuracy and reaction time were measured, while subjects’ EEG was recorded. A pharmacokinetic-pharmacodynamic model was constructed which demonstrated that accuracy decreased linearly as a function of plasma concentration, and that the magnitude of individual deficits was predicted by working memory capacity. A separate pharmacokinetic-pharmacodynamic model was developed which showed that spectral power in the theta frequency band (4-8 Hz) recorded during the retention phase of the Sternberg task increased as a function of plasma concentration. Furthermore, a mixture model identified two subpopulations with differential sensitivity in topiramate-induced theta reactivity. In the subpopulation defined by lower reactivity, reaction times were 20% slower than in the high theta reactivity subpopulation. Principal component regression was used to quantify the relationship between changes in multiple measures of electrophysiological activity and behavioral deficits. Theta power during retention was found to be the best predictor of topiramate-related behavioral deficits. Performance on another working memory task, Digit Span Forward, was also predicted by theta power during retention, as well as alpha (8-12 Hz) power during encoding and retrieval stages. In conclusion, two treatment-independent factors that predict differences in behavioral and electrophysiological responses to topiramate administration were identified: working memory capacity and theta reactivity. Future research will be needed to determine the utility of these demographic factors in predicting risk of cognitive side effects in patients eligible for treatment with topiramate.
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    Neural Correlates of Phonetic Learning in Adult Listeners with Cochlear Implants
    (2015-08) Miller, Sharon
    Speech perception is a product of an individual's linguistic experience. Postlingually deafened cochlear implant (CI) recipients, persons who acquired speech and language with normal acoustic hearing, need to learn to remap degraded electric inputs provided by the implant to previously learned language patterns. The mechanisms underlying the perceptual remapping and whether formal auditory training can promote phonetic learning in CI users remain unclear. This dissertation used behavioral and auditory event-related potential (ERP) methods to examine phonetic learning of the difficult /ba/-/da/ and /wa/-/ja/ speech contrasts in adult CI recipients. Behavioral and neural measures were collected before and after high variability identification training. Behavioral experiments employed identification and discrimination tasks, and the ERP experiments used an oddball paradigm to elicit the mismatch negativity (MMN) response associated with preattentive phonetic categorization. The results indicated substantial neural plasticity for phonetic learning in adult postlingually deafened CI listeners can be induced by high variability identification training. The training protocol significantly improved perception of naturally produced speech in postlingually deafened CI recipients, and listeners generalized their learning to unfamiliar talkers. Fine scale behavioral and neural measures suggest enhanced phonetic categorization skills supported the observed improvements in phonetic perception. These findings have potential clinical implications related to the aural rehabilitation process following receipt of a cochlear implant device.
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    Utility of Monophasic Action Potentials in the Diagnosis and Treatment of Cardiac Arrhythmias
    (2018-04) Schmidt, Megan
    The object of this thesis was to investigate applications for monophasic action potential (MAP) recordings in the diagnosis and treatment of cardiac arrhythmias. To meet this objective, MAPs were measured in situ and in vitro, during sinus rhythm and cardiac arrhythmias. MAPs were analyzed for potential clinical applications and in novel cardiac mapping and ablation catheter concepts. MAPs are focal action potential recordings which are directly proportional to the electrical activities of cells adjacent to a contacting electrode. When sufficient force is applied between a contacting electrode and the myocardium, the cells directly beneath become mechanically depolarized; i.e. electrically inactive. As a transmembrane action potential passes through this region, a change in boundary currents between the active and inactive cells, via gap junctions, results in a waveform that is proportional to the original action potential. The Visible Heart® Apparatus provides us with the ability to study large mammalian hearts, including human, in an in vitro setting; allowing the testing of prototype catheter concepts prior to in situ or in vivo work. To validate MAPs from an in vitro working heart model a comparison study was conducted. Over the course of 2 hours in situ and 2 hours in vitro MAPs were recorded from the right atrium, left atrium, and right ventricle (endocardially and epicardially). Overall, there were no significant differences between recorded signals when compared to in situ baseline recordings. Based on these findings, systems like the Visible Heart® Apparatus can be used as a platform on which cardiac action potentials can be studied. The clinical application of MAP recordings, as they pertain to radiofrequency (RF) ablations, was also evaluated. To ensure proper lesion formation, RF ablation requires a catheter contact force (CF) of between 10-20 grams to be maintained throughout energy delivery. It was determined that MAP waveforms could only be recorded when at least 10-15 grams of CF was applied to the myocardium. In other words, the presence of MAP waveforms would indicate that sufficient CF has been applied prior to the delivery of RF energy. Additionally, MAP waveforms were found to correlate with RF lesion size. MAP amplitudes at baseline (pre-ablation) were significantly larger than amplitudes from lesions which matured to greater than 1 mm deep. MAPs were also able to distinguish between lesions between 1-2mm deep, and those deeper than 2mm. Moving forward, MAPs may be used in evaluating cardiac viability, both through recording from induced lesions, as well as in regions of scarred or ischemic myocardium.