Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Clinical and Translational Science

First Advisor

Benjamin Littenberg


The term “migraine” is derived from the Greek hēmikrānía, meaning half skull – a reference to the unilateral headache which often accompanies migraine attacks. Today, unilateral headache remains a supportive feature of the clinical diagnosis of migraine. However, despite millennia of observations, the underpinnings of why headache in migraine is often unilateral are unknown. The overall goal of this research is to help clarify how the side in which head pain is experienced during migraine attacks relates to other aspects of the disease. I pursued this goal in the following three studies:

In the first study, a scoping review, I examine what is currently known about migraine with left- or right-sided headache during attacks. Of 5,428 abstracts screened, 26 met eligibility criteria and were included in the study. We found migraine with left-sided headache was associated with worse quality of life, psychiatric disease, and changes in the autonomic nervous system. Migraine with right-sided headache was associated with poorer performance on cognitive tests, anisocoria, changes in skin temperature, higher diastolic blood pressure, changes in cerebral blood flow, and changes on EEG. Most of these findings were based on single studies, without replication.

In the second study, I performed a cross-sectional analysis comparing patients with left- vs right-sided headache during attacks using the intake questionnaire of all patients seen through the UVM Headache Clinic over the prior 20 years. Of 5,627 patients screened, 340 met eligibility criteria. Patients with migraine with typically left-sided headache during attacks experienced 3.6 fewer headache-free days and 2.4 more severe headache days in the previous four weeks compared to patients with right-sided headache. No other differences in age, sex, handedness, migraine characteristics, or psychiatric comorbidities were identified.

In the third study, I conducted an observational cohort study in which subjects completed breath-hold functional MRI (fMRI) during a spontaneous migraine attack involving strictly left- or right-sided headache, then again when free of all migraine symptoms. This technique provides a measure of cerebrovascular reactivity, which is the ability of cerebral blood vessels to change in response to a vasoactive stimulus. Nineteen subjects completed the study. Cerebrovascular reactivity was decreased in the bilateral medial pulvinar nuclei. When the analysis was performed in subjects with left- (n = 12) or right-sided (n = 7) headache independently, the changes observed in the full cohort were explained by changes occurring in subjects with right-sided headache, suggesting vascular reactivity differed based on the side in which headache was experienced.

Taken together, we conclude there are clinical and neuroimaging differences between migraine with left- vs right-sided headache during attacks. These findings extend current knowledge and forge new paths toward a better understanding of the pathophysiology of migraine, which may ultimately lead to improved treatment of this pervasive and disabling disease.



Number of Pages

78 p.

Available for download on Tuesday, April 15, 2025