Background. Although treatments for dizziness as a result of visual-vestibular mismatch (VVM) exist, the lack of prognostic information about this population affects the quality of their rehabilitation care. Despite numerous studies showing that individuals presenting with non-specific dizziness are likely to have VVM, and despite VVM being recognized by to the international classification of vestibular disorders by the Bárány Society, it remains unknown how prevalent this condition is. The VVM diagnostic questionnaire has not yet been generally accepted as a useful tool for diagnosis. There are inadequate criteria for prescribed vestibular rehabilitation for individuals with VVM, and little evidence to support the selection of treatment programs among this population. Treatment outcomes are not particularly successful because of a lack of guidelines. Studies have been performed that address dizziness severity, but no reliable biometric measurement has been developed yet. A potential measure of VVM could be responses of the autonomic nervous system (ANS) during vestibulo-visual challenges given the anatomical relationship between the vestibular system and the ANS. Individuals with both peripheral and central vestibular dysfunction exhibit symptoms and signs of autonomic dysfunction as a result of vestibulo-autonomic interactions. Moreover, changes in postural sway are a tangible indicator of the balance during any disturbance to the vestibular system. In this dissertation the use of measures of electrodermal activity (EDA) of the ANS and postural acceleration are explored in vestibular migraine (VM) individuals both with and without VVM. Purpose. The aims of this dissertation were to examine, in VM adults: 1) the presence of VVM and visual dependency in individuals presenting with complaints of dizziness using the VVM questionnaire and the Rod and Frame protocol, respectively; 2) the potential of EDA activity and postural responses to differentiate between VM and healthy individuals when accommodating for postural instability and visual-vestibular conflict; and 3) the effect of exposure to different visual contexts of VR environments on EDA phasic and tonic responses and postural responses in identified VM adults with VVM. Participants. Seventy-four participants with dizziness were enrolled in Aim 1 (70% female, mean age 45.4 ± 14.8 years), and a total of 45 participants (23 healthy, 45.5% female, mean age 34± 9 years) and (22 VM adults, 61% female, mean age 34.4 ± 8, including 12 VM adults with VVM, 77% female, mean age 34±9) were enrolled in the experimental studies for Aims 2 and 3. Methods. In Aim 1, the VVM questionnaire and the Rod and Frame protocol were used to test the presence of VVM and visual dependency, respectively. In Aims 2 and 3, a Shimmer 3 IMU sensor accelerometer was used to assess trunk acceleration in the anterior-posterior, medial-lateral, and vertical directions with different VR environments (STREET and SPACE). EDA measurements were assessed with a wireless wearable Shimmer 3 GSR+. Clinical measures of dizziness and mobility were concurrently tested. A linear mixed model was used to examine the effect of VM with and without VVM on standing balance and EDA activity. Results. The presence of VVM, headache, and visual dependency demonstrated a strong association. EDA activity and postural acceleration significantly differed between VM and healthy individuals. Specific subjective reporting tools, including ABC, VSS-SF, VVAS, and DHI, were reliable for distinguishing between VM and healthy individuals. Lastly, VM individuals with VVM exhibited significantly greater NPL of trunk accelerations in the vertical plane than VM individuals without VVM with the STREET environment compared to the SPACE environment. Conclusion. VVM and visual dependency could be risk factors for developing vestibular migraine and should be included in the examination protocol of those populations. Combining measures of EDA and trunk acceleration may provide objective measures of the severity of dizziness related to VVM. Results of this dissertation suggest that the use of EDA measures combined with NPL-Vert could provide potential neurophysiological biomarkers in identifying VVM in adults with vestibular migraines. Further, the correlation between the characteristics of the visual environment and the subjective dizziness outcome measure may contribute to establishing a threshold-tolerance basis for designing a vestibular rehabilitation program that will more precisely target symptom severity. / Physical Therapy

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HRP applied to cut dorsal and ventral roots of the cat sacral spinal cord labeled afferent axons with swellings in close apposition to labeled preganglionic neurons (PGNs) in the sacral parasympathetic nucleus. Electron microscopy allowed characterization of synaptic contacts between afferents and PGNs. The results suggest that both the dorsal and ventral root afferents can directly activate autonomic preganglionic neurons.

Dysregulation of the autonomic cardiovascular control is a complication of diseases including diabetes, hypertension, sleep apnea, and aging. A common factor in these conditions is an increase in reactive oxygen species (ROS) in neural, cardiac, and endothelial tissues. Cu/Zn superoxide dismutase (SOD1) is an intracellular anti-oxidant enzyme that catalyzes dismutation of the superoxide anion (O2.-) to hydrogen peroxide (H2O2). Expression and function of this enzyme are diminished in pathologies that impair cardiovascular autonomic control. This study employed mice overexpressing a transgene for human SOD1 (hSOD1) to determine if its overexpression would alter autonomic regulation of BP, HR, and BRS in healthy animals, and if this animal line (C57B6SJL-Tg (SOD1)2 Gur/J) could be used in future studies to determine if hSOD1 overexpression can preserve cardiac autonomic function in disease models. To accomplish this aim, using anesthetized SOD1 and C57 (control) mice, we recorded HR, and aortic depressor nerve (ADN) activity changes in response to pharmacologically-induced BP changes in order to measure baroreflex and baroreceptor sensitivity, respectively. In order to identify any alterations in central, efferent, and cardiac components of the baroreflex arc, we electrically stimulated the left ADN and left cervical vagus and compared the reductions in BP and HR between the C57 and SOD1 mice. Time- and frequency-domain analysis of heart rate variability (HRV) was performed using pulse pressure recordings prior to pharmacologic or surgical procedures. We found that hSOD1 overexpression in the SOD1 mouse line, in comparison to C57 controls did not significantly affect resting HR (C57: 558 ± 8 vs. SOD1:553 ± 13 beats-per-minute) or blood pressure (C57: 88.8 ± 2.9 vs.SOD1: 85.8 ± 2.1 mmHg). hSOD1 overexpression did not affect the decrease in average mean arterial pressure (MAP) following injection of sodium nitroprusside (SNP) (C57: 38.7 ± 1.4 vs. SOD1: 39.5 ± 1.3 mmHg) or increase in average MAP (C57: 135.8 ± 3.1 vs. SOD1: 136.6 ± 3.5 mmHg) following injection of phenylephrine (PE). BRS, as measured by the averaged regression lines for ΔHR/ΔMAP for the SNP-induced tachycardic baroreflex (C57: 0.57 ± 0.06 bpm/mmHg, SOD1: 0.61 ± 0.08 bpm/mmHg)) and the PE-induced bradycardic baroreflex (C57: -2.9 ± 0.57 bmp/mmHg, SOD1: -4.3 ± 0.84 bpm/mmHg) are not significantly different between C57 and SOD1. Baroreceptor activation showed a significant increase in gain (C57: 5.4 ± 0.3 vs. SOD1: 7.4 ± 0.5 %/mmHg, P < 0.01) in the SOD1 transgenic mice. Heart rate depression in response to electrical stimulation of the left ADN and cervical vagus was comparable between C57 and SOD1, though MAP reduction in response to ADN stimulation is slightly, but significantly increased at 50 Hz in SOD1 animals. Time- domain analysis of HRV did not reveal any significant difference in beat-to-beat variability between SOD1 and C57 (SDNN: C57: 2.78 ± 0.20, SOD1: 2.89 ± 0.27), although frequency-domain analysis uncovered a significant reduction in the low-frequency power component of the HRV power spectral distribution (C57: 1.19 ± 0.11, SOD1: 0.35 ± 0.06, P < 0.001). This study shows that although hSOD1 overexpression does not affect overall baroreflex function, it does potentiate baroreceptor sensitivity and brain stem control of arterial pressure, and reduces low-frequency beat-to-beat variations in HR, without affecting total HRV.

The relationship between autonomic dysfunction and primary headache disorders has been established in the adult population. The aim of this retrospective study was to elucidate if there was a similar association in the pediatric primary headache population. Three groups were compared - migraine patients, tension-type headache patients and idiopathic scoliosis patients as a control group. Utilizing clinical data collected during patients' initial visits, prevalence of autonomic dysfunction symptoms were quantified. The headache groups also filled out the Functional Disability Index (FDI) as well as the Children's Depression Inventory (CDI) to help elucidate if there was a relationship between function disability, psychiatric state and primary headaches and/or autonomic dysfunction symptoms. It was found that the headache groups had significantly greater dysautonomia as compared to the control group. Only slight differences were found between the migraine and tension-type patients in regards to dysautonomia. No significant differences were found in total FDI or CDI scores. These results illuminate a relationship between autonomic nervous system dysfunction and primary headache disorders in the pediatric population studied. Prospective studies and the development of standardized dysautonomia questionnaires will allow a more detailed autonomic dysfunction profile to be built for this population.

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Chronic refractory gastrointestinal (GI) motility disorders are a significant burden on the healthcare system, acting as a large public health issue with significant impact on the quality of life in both the pediatric and adult population. Control systems of gastrointestinal motility are complex and involve coordination of smooth muscle contraction and relaxation, which the autonomic nervous system is largely responsible for. Gaps in the diagnosis process, such as overlooking autonomic function, has left patients with diminished quality of life and limited treatment options. Many patients in the clinic have experienced injury within the spinal cord and we hypothesized that GI symptoms might be related to spinal injury causing disruption of sensory and/or motor nerves of the autonomic nervous system. Our objective became to better understand the specific location and nature of spinal injuries and GI symptoms, as completed through the development of a self-report questionnaire. Main findings suggest symptoms indicative of T3-T9 and T10-L2 spinal pathology. COVID-19 did not allow for in-clinic neuromodulation with autonomic assessments, resulting in experiments remotely assessing at-home neuromodulation treatment for GI symptoms with suspected spinal autonomic dysfunction. At-home neuromodulation was not suitable for many patients, but those who were able to manage it showed highly promising results. After years of suffering, transcutaneous electrical nerve stimulation alleviated symptoms, particularly postprandial abdominal pain, constipation, vomiting and nausea. I discuss what we learned to set us up for successful at-home treatment, and we will use all information to design randomized controlled trials to prove the benefit of TENS. The present work offers significant information on the relationship of thoracolumbar spinal pathology and complex GI symptoms, which is now used in the clinic in the diagnosis process of GI dysmotility. In addition, we have learned how to conduct at-home treatment using TENS, which allows us to execute future studies. / Thesis / Master of Science (MSc) / There are gaps in the diagnosis process of complex gastrointestinal (GI) dysmotility disorders, including lack of testing of autonomic function, leaving patients suffering with diminished quality of life with unsuccessful treatment attempts. As many patients also experience injury or conditions of the spine, I have hypothesized that GI symptoms may be related to spinal injury-induced dysfunction of the autonomic nervous system. Experimental models aim to understand the location and nature of spinal pathology with GI symptoms for future diagnoses, as well as potential treatment options such as neuromodulation. Findings of this thesis suggest symptoms indicative of particular thoracolumbar spinal pathology and promising results of transcutaneous electrical nerve stimulation (TENS) to alleviate GI symptoms, including T3-T9 and T10-L2 spinal pathology-related postprandial abdominal pain, constipation, nausea, and vomiting. This work offers information for the diagnostic process of GI dysmotility and the future design of clinical trials of neuromodulation therapies.