In October 2017, the United States government declared a state of public health emergency in response to the burgeoning prescription opioid epidemic. Opioid analgesics are the gold standard of therapy for moderate to severe pain, but their clinical utility is greatly limited by analgesic tolerance – a primary driver of diminished pain control and opioid dose escalations. Integral in this process are primary afferent sensory neurons in dorsal root ganglia (DRG), the first-order components of nociceptive sensation. With surmounting evidence that morphine and other narcotics can alter gut microbial composition and promote bacterial translocation to other tissues, a question arises of whether the secondary release of bacterial products and pro-inflammatory cytokines can modulate antinociceptive tolerance development. This dissertation examines how gut bacteria depletion with antibiotics modulates the pharmacodynamic properties of chronic morphine in mice. Utilizing a “top-down” experimental approach, this is characterized at the whole-animal, single-cell, and molecular level via behavioral assays of antinociception, whole-cell patch-clamp recordings in DRG neurons, and analysis of tetrodotoxin-resistant (TTX-R) Na+ channel kinetics, respectively. Our findings collectively indicate that the gastrointestinal microbiome is an important modulator of antinociceptive tolerance development with chronic morphine administration.

This thesis focusses on the development and testing of optimization methods for parameter identification in cardiac electrophysiology models. Cardiac electrophysiology models are systems of differential equations representing the evolution of the trans-membrane potential of cardiac cells. The Mitchell-Schaeffer model is chosen for this thesis. The parameters included in the Mitchell-Schaeffer model are optimally adjusted so that the solution of the model has desired properties. Two optimization problems are formulated using least-square functions to identify parameters that match phase durations and parameters that fit entire potential recordings of swine heart tissue acquired via optical imaging techniques at different stimulation frequencies. The non-differentiable optimization methods (Compass Search and three other variants) are applied to solving both optimization problems for two reasons; First, the methods are studied to evaluate performance and second, the optimization process is evaluated to confirm its ability to identify parameters for the Mitchell-Schaeffer model.

Abstract not available

Introduction: Psychophysical and electrophysiological techniques have shown that chromatic contrast sensitivity improves between infancy and adolescence. In adults, electrophysiological and psychophysical methods usually agree. However, in infants electrophysiological techniques may underestimate ability to see chromatic contrast (Suttle et al., 2002). It is not known if the discrepancy between electrophysiological and psychophysical methods continues during childhood nor whether the chromatic VEP can be used as an indicator of colour perception in children. Purpose: To investigate the transient L-M chromatic visual evoked potential and its ability to indicate perception (psychophysical thresholds) of chromatic stimuli in children and adults. In particular, to determine whether a discrepancy between VEP and psychophysical L-M thresholds exists during childhood and if so, to gain some understanding about the nature of the discrepancy. Methods: Transient chromatic VEPs were recorded in children (aged 4.5-13 years) and adults (aged 20-40 years). VEP thresholds were compared with psychophysical thresholds (within-subjects comparison). Because the VEPs of the children were less intra-individually repeatable in morphology than those of the adults, post-hoc objective analysis of the VEPs, linear (Fourier) and nonlinear dynamical (Grassberger and Procaccia's (1983) correlation dimension) analyses, was conducted. Results: VEP and psychophysical estimates of chromatic contrast thresholds agreed using a variety of methods in the adults. In the children, however, the objective methods of assessment (extrapolation from Fourier-derived amplitudes and the correlation dimension) were more accurate than the methods that employed subjective evaluations of VEP morphology. Conclusion: The L-M transient chromatic VEPs of both children (aged 4.5-13 years) and adults appear to contain chromatic information, even in the absence of repeatable VEP morphology and should therefore be able to indicate chromatic perception (psychophysical thresholds). However, the chromatic information may be present as a nonlinear dynamical signal, which may require objective methods (Fourier analysis, the correlation dimension) to reveal the chromatic signal. The greater intra-individual variability of VEP morphology in children compared to adults may reflect poorer precision when switching between cortical states in children's brains. Alternatively, interactions between the immature visual system of the children and their general EEG may occur. Children's VEPs should therefore be interpreted differently to adult VEPs.

Background – Previous reports of abnormal auditory N2 and P3 event-related potentials (ERPs) suggest impaired discrimination, evaluation or context updating for infrequent target stimuli in post-traumatic stress disorder (PTSD). This study examines each of these processes by investigating high-resolution ERP topography during target detection for visual word stimuli. Method – ERPs were recorded at 124 electrodes from 10 PTSD patients and 10 matched controls. Target detection tasks comprised blocks of equally probable red and blue words, with low probability target events. Detection of fixed target words in one color provided the basis for measurement of selective attention for color, stimulus evaluation and target detection processing. Alternative task instructions, with the same stimuli, required detection of any consecutive word repeats in an attended color, which demands working memory updating for nontarget words. Comparison of attended non-target words from each task indicates the extra activity for updating working memory representations of target attributes. Thus, specific condition comparisons provide measures of stimulus discrimination and evaluation, working memory updating and target detection. Results – PTSD patients had slower and less accurate motor responses in both tasks, with greater inaccuracy during the variable target task. There was abnormal ERP activity in PTSD at 200-300 ms in the left posterior temporal region during stimulus discrimination and target recognition. During evaluation of attended non-target words, PTSD patients demonstrate deficits in frontal and parietal regions at 400-500 ms. During working memory updating, at 400-600 ms, there was a delay in frontal activation, followed by smaller activity in parietal areas in PTSD. During target word recognition, PTSD patients demonstrate deficits in frontal activity, with greater occipital and parietal activity. Conclusions – These findings indicate impaired evaluation and integration of new information in working memory. In particular, the results suggest failure in frontal executive systems, with greater dependence on visual processing for effective target detection. The current findings are consistent with neuropsychology studies that identify deficits of attention and memory for verbal information in PTSD. This study provides insight into the temporal components of attention and working memory in PTSD. It is proposed that working memory deficits arise from disruption to synchronized activity in distributed networks engaged in working memory processes.

This thesis reports on several new and innovative instrumentation developments to solve some of the problems of brain activity monitoring, particularly SSVEP (Steady State Visual Evoked Potentials) studies. SSVEP systems generate suitable stimuli and record the resulting brain biopotentials from scalp electrodes. The instrumentation is configured as a 'Neuropsychiatric Workstation', supporting up to 136 scalp electrodes. Operating in the SSVEP mode, the Neuropsychiatric Workstation reported here significantly improves upon the previously reported spatial resolution and accuracy of maps related to the generated stimuli. These maps allows insights to be gained into the cognitive workings of the brain. A significant component of the work reported here covers the development of the multielectrode EEG measurement modules and the associated techniques for minimising interference and cross-talk. The techniques for synchronising recordings from all electrodes with the stimulus, interfacing to a host computer and real-time storage of the very large amounts of data generated to hard disk, are all reported. The SSVEP paradigm uses a sinusoidal-modulated visual stimuli. A novel linearised LED (light emitting diode) head-up display was developed, in addition to more conventional stimuli, such as the alternating checker-board display, all with sinusoidal modulation capability over a range of frequencies. The Neuropsychiatric Workstation described in thesis has been replicated several times and is in regular use at Brain Sciences Institute (BSI) at Swinburne University of Technology, and other collaborative research institutes.

[by] Robert D. Hall and Roger Greenwood Mark. / Bibliography: p.80-83. / Contract no. DA36-039-AMC-03200(E).

Bibliographical note: p. 88. References: p. 89-93. / Contract DA36-039-AMC-03200(E). Grant DA-SIG-36-039-61-G14. Grant G-16526. Grant MH-04737-03.

No description available.

by Communications Biophysics Group of Research Laboratory of Electronics and William M. Siebert. / "July 7, 1959"--Cover. / Includes bibliographies. / Army Signal Corps Contract DA36-039-sc-78108. Dept. of the Army Task 3-99-06-108 and Project 3-99-00-100.