Doctor of Philosophy
Shoemaker, Kevin J
Neurogenic Orthostatic Hypotension (NOH) is a cardinal feature of autonomic failure. Patients with NOH experience a persistent and consistent drop in blood pressure when standing due to failure of the autonomic nervous system to reflexively increase sympathetic outflow. NOH affects individuals worldwide, presenting as both a primary feature (i.e. Multiple Systems Atrophy, Pure Autonomic Failure) and secondary to several common disorders including diabetes and Parkinson’s Disease. However, there are still several gaps in our overall understanding and assessment of patients with NOH. Therefore, the six studies presented in this thesis aimed to address some of these gaps in our current knowledge.
Study 1 and 2 aimed to investigate activity within the central autonomic network (CAN) both at rest and during standardized autonomic challenges to determine whether patients have reduced activity relative to healthy controls. In this study we found patients had reduced activation in several CAN structures including the cingulate cortices, thalamus, hippocampus and cerebellum.
Based on study 1 and 2 results, study 3 and 4 aimed to determine whether patients also had reduced functional connectivity in two structures involved in postural blood pressure regulation: the brainstem and cerebellum. We found patients had significantly less connectivity between the brainstem and several CAN structures including the cerebellum, insula and cingulate cortices. Additionally, patients had significantly less intracerebellar connectivity, less cerebellar-brainstem connectivity and reduced connectivity to CAN structures including the insula, anterior cingulate, hippocampus, thalamus and putamen.
Finally, symptoms associated with NOH include postural light-headedness, dizziness and syncope. Proper diagnosis rests in the ability to accurately distinguish these non-specific symptoms as either orthostatic (postural) or non-orthostatic (non-postural). The purposes of studies 5 and 6 were to create a simple instrument capable of making this distinction, demonstrate its validity and reliability, sensitivity and specificity, and to test its ability to assess individuals based on symptomatology. In these studies, I found our questionnaire was valid, reliable and capable of positively predicting individuals with orthostatic intolerance related to autonomic dysfunction.
Overall, this thesis greatly expands our understanding of NOH pathophysiology and provides a new tool for assessing orthostatic symptomatology related to autonomic dysfunction.
Summary for Lay Audience
The autonomic nervous system (ANS) is a branch of the nervous system that regulates processes that occur without conscious effort, including: heart rate, breathing, blood pressure, sweating, digestion, sexual function, respiration, urination and defecation. The ANS has two major divisions: the sympathetic nervous system, primarily active during the “fight-or-flight” response, and the parasympathetic nervous system, primarily active during “rest-and-digest”.
When we stand up, the ANS ensures gravity does not pull our blood into our legs. However, when the ANS fails, this function is lost and as a result, individuals experience a significant drop in blood pressure when standing. ANS failure affects individuals worldwide, presenting as both a primary disorder (i.e. Pure Autonomic Failure) and secondary to several common disorders including diabetes and Parkinson’s Disease. However, there are still several gaps in our overall understanding and assessment of patients with autonomic failure. This thesis aimed to address these gaps.
The first half of the thesis focused to improve our understanding of autonomic failure by investigating brain activity in structures known to contribute to proper autonomic control. In addition, I investigated how these brain regions may be functionally connected to help regulate heart rate and blood pressure. I found patients with autonomic failure show reduced activity in several brain structures involved in blood pressure regulation and these structures showed reduced functional connectivity among each other.
The second half of the thesis aimed to improve the assessment of patients with ANS failure. When patients experience a significant blood pressure drop while standing, common symptoms include light-headedness and dizziness. Proper diagnosis rests in the ability to accurately distinguish these non-specific symptoms as either postural or non-postural. To identify and assess patients, we created a questionnaire capable of making this distinction. I evaluated several important parameters and found the questionnaire to be valid, reliable and capable of positively predicting individuals with autonomic dysfunction based on a symptom assessment.
This thesis greatly expands our understanding of autonomic failure and provides a new tool for assessing symptomatology related to autonomic dysfunction.
Baker, Jacquie, "Improving the Assessment and Understanding of Neurogenic Orthostatic Hypotension" (2019). Electronic Thesis and Dissertation Repository. 6298.
Available for download on Thursday, July 30, 2020