Browsing by Subject "Neuromodulation"
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Item Embargo A bidirectional switch to treat colonic dysmotility(2023) Barth, Bradley BrighamSevere constipation can be life-threatening and disproportionately affects patients who may not benefit from conventional treatments. Sacral nerve stimulation (SNS) is an alternative to laxatives and pharmaceuticals, and it modulates propulsive action in the colon. Conventional SNS failed to treat slow-transit constipation. I hypothesized bursts of nerve stimulation interleaved by quiescent periods increase colonic transit more effectively than continuous nerve stimulation. I electrically stimulated the colon directly in computational models and the isolated mouse colon to characterize properties of the colonic motor complex (CMC), and I used optical and fluorescent imaging, electromyography, and manometry to compare the effect of pelvic and sacral nerve stimulation on colonic motility. I developed a computational model of colonic motility and compared the effects of burst and conventional nerve stimulation on pellet velocity and colonic emptying under normal and slow transit conditions. Burst nerve stimulation evoked more frequent calcium and pressure waves, and increased fecal pellet output than continuous nerve stimulation in the isolated mouse colon, anesthetized rat, and computational model, respectively. Burst nerve stimulation with optimized burst frequency, duration, and interval more effectively produced prokinetic motility than continuous nerve stimulation, suggesting that burst SNS may be a viable clinical treatment for severe and slow transit constipation.
Item Open Access Dopaminergic modulation of retinal processing from starlight to sunlight.(Journal of pharmacological sciences, 2019-05-04) Roy, Suva; Field, Greg DNeuromodulators such as dopamine, enable context-dependent plasticity of neural circuit function throughout the central nervous system. For example, in the retina, dopamine tunes visual processing for daylight and nightlight conditions. Specifically, high levels of dopamine release in the retina tune vision for daylight (photopic) conditions, while low levels tune it for nightlight (scotopic) conditions. This review covers the cellular and circuit-level mechanisms within the retina that are altered by dopamine. These mechanisms include changes in gap junction coupling and ionic conductances, both of which are altered by the activation of diverse types of dopamine receptors across diverse types of retinal neurons. We contextualize the modulatory actions of dopamine in terms of alterations and optimizations to visual processing under photopic and scotopic conditions, with particular attention to how they differentially impact distinct cell types. Finally, we discuss how transgenic mice and disease models have shaped our understanding of dopaminergic signaling and its role in visual processing. Cumulatively, this review illustrates some of the diverse and potent mechanisms through which neuromodulation can shape brain function.Item Open Access Investigating Potential Mechanisms of Subperception Spinal Cord Stimulation(2022) Titus, NathanSpinal cord stimulation (SCS) is a surgically implanted therapy for chronic pain that delivers electrical stimulation to the spinal cord. Recently, SCS paradigms have rapidly expanded to include more frequencies, amplitudes, and indications, but the therapeutic success of SCS remains stagnant(Titus et al., 2020). Many of the new SCS paradigms treat pain by applying stimulation at amplitudes less than the amount required for patients to perceive the treatments. However, there is little information regarding how these “subperception” SCS therapies effect analgesia. The work in this dissertation uses computational modeling and in vivo neural recordings to investigate and explore the potential analgesic mechanisms of subperception SCS.The combination of computational modeling and preclinical experimental data displayed in this dissertation provides many insights into the mechanisms of subperception SCS. A tool was built to design temporal patterns of SCS which predicted features of effective SCS patterns observed during in vivo single-unit recordings. A model was built to explain dorsal column responses to 10 kHz SCS, and this model accurately predicted in vivo single-unit recordings of dorsal column responses to low-amplitude, low-frequency SCS. This model was used to build a population of responses which was applied to a network model of SCS, and this modeling combination predicted in vivo multi-unit recordings of responses to a novel subperception SCS paradigm. Finally, models were developed which predicted the direct response of dorsal horn neurons to SCS. Feeding these responses into a network model of dorsal horn circuitry yielded similar changes in neural activity to measurements of neural activity obtained from post-mortem tissue of animals which had undergone SCS. Overall, this thesis work improved understanding of the mechanisms of action underlying multiple subperception SCS paradigms, provided models to predict and explain responses of neural elements to novel SCS paradigms, and developed a tool for designing new, effective patterns of SCS.
Item Open Access Model Based Optimization of Spinal Cord Stimulation(2015) Zhang, TianheChronic pain is a distressing, prevalent, and expensive condition that is not well understood and difficult to treat. Spinal cord stimulation (SCS) has emerged as a viable means of managing chronic pain when conventional therapies are ineffective, but the efficacy of SCS has improved little since its inception. The mechanisms underlying SCS, in particular the neuronal responses to SCS, are not well understood, and prior efforts to optimize SCS have focused on electrode design and spatial selectivity without considering how the temporal aspects of SCS (stimulation frequency, pattern) may affect neuronal responses to stimulation. The lack of a biophysical basis in prior attempts to optimize therapy may have contributed to the plateau in the clinical efficacy of SCS over time. This dissertation combines computational modeling and in vivo electrophysiological approaches to investigate the effects of SCS on sensory neuron activity in the dorsal horn and uses the insights gained from these experiments to design novel temporal patterns for SCS that may be more effective than conventional therapy.
To study the mechanisms underlying SCS, we constructed a biophysically-based network model of the dorsal horn circuit consisting of interconnected dorsal horn interneurons and a wide dynamic range (WDR) projection neuron and representations of both local and surround receptive field inhibition. We validated the network model by reproducing cellular and network responses relevant to pain processing including wind-up, A-fiber mediated inhibition, and surround receptive field inhibition. To quantify experimentally the responses of spinal sensory projection neurons to SCS, we recorded the responses of antidromically identified sensory neurons in the lumbar spinal cord during 1-150 Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). In a subset of rats, we additionally assessed the impact of GABAergic inhibition on spinal neuron responses to SCS by conducting SCS experiments following the intrathecal administration of bicuculline, a GABAA receptor antagonist, and CGP 35348, a GABAB receptor antagonist. Finally, we used the computational model to design non-regular temporal patterns capable of inhibiting sensory neuron activity more effectively than conventional SCS and at lower equivalent stimulation frequencies than clinical standard 50 Hz SCS, and we experimentally validated model predictions of the improved efficacy of select patterns against conventional SCS.
Computational modeling revealed that the response of spinal sensory neurons to SCS depends on the SCS frequency; SCS frequencies of 30-100 Hz maximally inhibited the model WDR neuron consistent with clinical reports, while frequencies under 30 Hz and over 100 Hz excited the model WDR neuron. SCS-mediated inhibition was also dependent on GABAergic inhibition in the spinal cord: reducing the influence GABAergic interneurons by weakening their inputs or their connections to the model WDR neuron reduced the range of optimal SCS frequencies and changed the frequency at which SCS had a maximal effect. Experimentally, we observed that the relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit described a subset of observed SCS-frequency dependent responses but was insufficient to account for the heterogeneous responses measured experimentally. In addition, intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, consistent with model predictions. Finally, computational modeling of dual frequency SCS, implemented by delivering two distinct frequencies simultaneously to distinct fiber populations, revealed frequency pairs that were more effective at inhibiting sensory neuron activity than equivalent conventional SCS and at lower average frequencies than clinically employed 50 Hz SCS. Experimental assessments of the effect of dual frequency SCS on spinal sensory neurons confirmed model predictions of greater efficacy at lower equivalent stimulation frequencies and suggest the use of non-regular temporal patterns as a novel approach to optimizing SCS. The outcomes of this dissertation are an improved understanding of the mechanisms underlying SCS, computational and experimental tools with which to continue the development and improvement of SCS. The insights and knowledge gained from the work described in this dissertation may result in translational applications that significantly improve the therapeutic outcomes of SCS and the quality of life of individuals affected by chronic pain.