Headache: The Patient and the Mechanism

Abstract

Migraine is a highly prevalent and disabling primary headache disorder, and medication-overuse headache (MOH)—most often arising on a migraine background—represents a particularly severe, high-frequency phenotype associated with substantial functional impairment, psychiatric and sleep comorbidities, and elevated healthcare utilization. Despite major advances in acute and preventive therapies, many patients experience incomplete relief, relapse, or progression to chronic headache patterns, underscoring a need for mechanism-informed strategies and a clearer understanding of how headache phenotypes intersect with long-term brain health.Increasing attention has focused on the endocannabinoid system (ECS) as a modulatory network relevant to headache and pain. The ECS regulates synaptic signaling through the canonical endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), their cannabinoid receptors, and a set of synthetic and degradative enzymes that shape region- and context-specific lipid “tone.” Preclinical and clinical observations implicate altered endocannabinoid signaling during headache states, motivating therapeutic approaches that target endocannabinoid metabolism rather than direct receptor agonism. ABHD6, a key 2-AG hydrolyzing enzyme, is positioned to influence local lipid microdomains within pain-modulatory circuits and may represent a tractable lever for modifying headache-like hypersensitivity. The first arm tests whether ABHD6 inhibition can reverse MOH-like pain and characterizes accompanying ECS remodeling across pain circuits. In female Sprague–Dawley rats, 7-day sumatriptan infusion (0.6 mg/kg/day) produced robust periorbital allodynia, and acute ABHD6 inhibition via KT-182 (2 mg/kg, i.p.) transiently reversed established allodynia without affecting baseline sensitivity in saline controls, with effects emerging at ≈300–360 minutes post-dose. Naïve profiling showed KT-182 produced an ethanolamide-biased lipid signature with minimal monoacylglycerol effects, whereas chronic sumatriptan expanded monoacylglycerol pools and modestly remodeled ECS transcripts/proteins across cortex, periaqueductal gray, rostral ventromedial medulla, and trigeminal nucleus caudalis. In sumatriptan-exposed animals, KT-182 predominantly elevated ethanolamide-class and polyunsaturated endocannabinoid-like lipids in a region- and state-dependent manner, supporting ABHD6 as a circuit-relevant, lipid-centric target for MOH-like hypersensitivity. The second arm evaluates long-term neurological outcomes associated with migraine and MOH using matched cohorts in the PearlDiver Mariner database. In Study 1 (1,289,469 matched per group), “any migraine” was not associated with higher 10-year Alzheimer’s disease (AD) risk compared with controls (1.16% vs 1.28%), though modest elevations appeared in comorbidity-defined subgroups (e.g., migraine + IBS: 1.30% vs 1.10%; migraine + fibromyalgia: 1.10% vs 0.90%). In Study 2 (~42,000 per group), migraine cohorts had lower 10-year incidence than controls across AD, Parkinson’s disease (PD), and all-cause dementia, whereas MOH identified a higher-risk subset relative to migraine and showed outcome-specific divergence versus controls (vs controls: no difference for AD; higher PD; lower dementia). Exploratory stratification within MOH suggested higher 10-year dementia incidence with opioid and NSAID overuse than with triptan overuse (3.76% and 3.07% vs 1.08%), underscoring clinically meaningful heterogeneity. The third arm of this dissertation advances translational outreach by operationalizing a patient- and public-facing model for communicating “invisible” neurological signals. Hearing the Invisible (HTI) converted open-source EEG recordings into an immersive, multisensory installation integrating sound, light, and augmented reality. The centerpiece was a large-scale interactive brain with illuminated EEG “nodes” and an AR experience that enabled visitors to explore neural rhythms through movement and sonification, complemented by educational stations, live EEG-derived musical performance, and an academic poster component. Audience reflections and assessment data indicated strong engagement and suggested that multisensory presentation enhanced conceptual understanding of EEG and neurological disease while fostering empathy toward conditions that are not readily visible. In summary, this dissertation links mechanism, population evidence, and public translation to address headache as both a biological disorder and a lived experience. Mechanistically, the findings support ABHD6/endocannabinoid modulation as a state-dependent lever capable of reversing MOH-like hypersensitivity while reshaping lipid signaling across pain circuits. Epidemiologically, large, matched claims cohorts demonstrate that migraine-coded diagnoses are not uniformly associated with increased long-term neurodegenerative risk, whereas MOH and comorbidity-defined subgroups show distinct patterns that warrant targeted clinical attention. Finally, HTI provides a scalable framework for translating complex neurological data into accessible, emotionally resonant experiences that may improve understanding and empathy for invisible illness.