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Dissertation
Investigating brain-wide local field potential connectivity patterns underlying migraine
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007870
Abstract
Migraine is a debilitating disease, impacting over 1 billion people worldwide. Migraine consists of complex brain circuitry characterized by dysfunctional sensory-related brain circuits that intersect pain, sensation, and affect. Preclinical models of migraine have shed light on migraine-related phenotypes such as allodynia, facial grimace/squint, and light aversion. The calcitonin gene-related peptide (CGRP) model of migraine has emerged as one of the most clinically relevant models of migraine, leading to a number of therapeutic drugs targeting CGRP and its receptors. The ways in which different brain regions are coordinated during migraine is poorly understood. My thesis focused on answering this question by utilizing a systems-based approach using multi-site in vivo recordings to capture brain network activity in the form of local field potentials (LFP) during a CGRP-induced migraine-like brain state in rodents.
In Chapter 2, I tested the hypothesis that peripheral CGRP induces significant differences in LFP power and coherence across a migraine-related brain network when compared to vehicle and that treatment with an antimigraine drug would attenuate activity and coherence across the network. We found that peripheral CGRP decreased LFP power across the anterior cingulate cortex, basolateral amygdala, central amygdala, mediodorsal thalamus, posterior thalamus, ventral posteromedial thalamus, and bilateral parabrachial nuclei in a frequency and time-specific manner. CGRP disrupted coherence mainly in amygdala-related brain region pairings. I then hypothesized that treatment with an antimigraine drug, sumatriptan, would attenuate this response. We found that coadministration of CGRP and sumatriptan partially attenuated the changes in brain activity induced by CGRP alone.
In Chapter 3, I tested the hypothesis that early life stress (ELS) exacerbates migraine-related phenotypes and induces greater changes in LFP power and coherence across a migraine-related brain network in ELS animals compared to group-housed control animals. We found that ELS exacerbated migraine-related phenotypes in mice. ELS also impacted LFP power and coherence, especially in the central amygdala and posterior thalamus in the context of CGRP.
In Chapter 4, I tested the hypothesis that squint (spontaneous pain behavior) can be reliably and objectively quantified and could be paired with neurophysiological activity to reflect a spontaneous pain state in migraine. Using Deeplabcut, we were able to develop a low-cost model that is widely accessible and reliably detects squint in rodents. We simultaneously recorded squint behavioral responses and neurophysiological activity and generated a model characterizing the neurophysiological signatures during squint.
Overall, my thesis demonstrated that peripheral CGRP engages central activity, reflecting a migraine-related brain state. We characterized the changes in brain activity during migraine and assessed biological relevance through pharmacological manipulation and an environmental stressor. Such findings can be used to better understand the complex brain dynamics implicated in migraine.
Details
- Title: Subtitle
- Investigating brain-wide local field potential connectivity patterns underlying migraine
- Creators
- Micah Simone Johnson
- Contributors
- Rainbo Hultman (Advisor)Sanvesh Srivastava (Committee Member)Levi Sowers (Committee Member)Kathleen Sluka (Committee Member)Jan Wessel (Committee Member)Michelle Voss (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007870
- Publisher
- University of Iowa
- Number of pages
- xii, 152 pages
- Copyright
- Copyright 2025 Micah Simone Johnson
- Grant note
- University of Iowa funding sources: NIH T32 Training Grant, Graduate College Lulu Merle Johnson Fellowship, Graduate College Post-Comprehensive Exam Fellowship, and Ramon D. Buckley Graduate Student Award from the department of Molecular Physiology & Biophysics.
- Language
- English
- Date submitted
- 01/01/2025
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 139-152).
- Public Abstract (ETD)
- The brain works like a network of Christmas lights, with circuits communicating through electrical signals. If one light goes out, it’s easy to find and fix. But in the brain, when circuits malfunction—like during migraine—it’s much harder to pinpoint the problem. Migraine is characterized by not just headache pain but also symptoms like nausea, sensitivity to light, and trouble thinking, both during and between attacks. My research focused on understanding how brain circuits involved in migraine behave to better understand the disorder. I used a mouse model of migraine triggered by CGRP, a chemical that induces migraines in both humans and rodents. I found that CGRP causes certain brain regions—like the anterior cingulate cortex, amygdala, parabrachial nuclei, and thalamus—to become less active, especially in the first 10 minutes when pain is at its worst. CGRP also disrupted how these areas "talk" to each other, particularly connections involving the amygdala, which is linked to emotions and pain. When I treated the mice with the migraine drug sumatriptan, it partially restored normal brain activity. However, mice that experienced early life stress had worse migraine-like behavior and attenuated brain responses to CGRP. Finally, I discovered that eye squinting could be used as a sign of spontaneous pain. By linking squinting to brain activity, it may be possible to use it as a biomarker for migraine pain. This research brings us closer to understanding migraines and finding better ways to treat them.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984831024202771
Metrics
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