Headache & Pain*

Date/Time: Monday, September 11, 2023 - 4:15 PM – 5:45 PM
Track: Special Interest Group (SIG) Session
Room: Franklin Hall 2 (4th Floor)
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Session Evaluation Form: https://myana.org/form/ana2023-session-evaluation-heada

Chair: Charles Flippen II, MD, FANA, FAAN

Co-Chair: Seniha Ozudogru, MD

This session will focus on advances in understanding the mechanism(s) of cortical spreading depression, its influence on the clinical expression of migraine headache and how it informs potential migraine therapeutic targets. Several early and mid-career neuroscientists will present their recent work in this area along with selected abstracts submissions related to this topic.

Learning Objectives:

  • Effects of physiological processes (e.g. sleep) on CSD.
  • Effect of CSD on the clinical expression of migraine.
  • Regulation of neuropeptides related to migraine by delta opioid receptors.

PACAP as a therapeutic target for Medication Overuse Headache

Speaker: Amynah Pradhan, PhD

Opioids are still widely prescribed for migraine in the US. Chronic opioid use can cause medication overuse headache (MOH) which results in increased severity and frequency of migraine that is refractory to treatment. In preclinical models, our lab has demonstrated upregulation of pituitary adenylate cyclase activating polypeptide (PACAP) in both models of chronic opioid use and chronic migraine. We have recently confirmed these findings in novel translationally significant models of opioid-induced MOH. We found that the PACAP-PAC1 receptor antagonist, M65, reversed chronic allodynia in a model which combines morphine with the migraine trigger, nitroglycerin. Chronic opioids also exacerbated cortical spreading depression, a physiological correlate of migraine aura; and M65 inhibited this augmentation. Furthermore, in situ hybridization studies show a clear overlap between the mu opioid receptor and PACAP or PAC1 in migraine processing regions. This work suggests that the PACAPergic system facilitates the transition to chronic headache following opioid use, and strategies targeting this system may be particularly beneficial for MOH.

Progress in understanding cortical spreading depression

Speaker: Sinifunanya Nwaobi, MD, PhD

Cortical spreading depression is the putative substrate of the migraine aura. CSD is suspected to play a role in the development of migraine headache pain through activation of the trigeminovascular system and lead to the transformation of episodic migraine to chronic migraine (defined as 15 or more headache days per month). Clinical evidence suggests sleep modulates migraine both acutely and chronically. Our work utilizes novel micro-electronic technologies to understand the sleep-migraine connection with a focus on how sleep modulates CSD.

Cortical spreading depression link to migraine expression

Speaker: Andrea Harriott, MD, PhD

Cortical spreading depression (SD) is the underlying cause of migraine aura. Migraine is more prevalent in females, raising the possibility that sex and gonadal hormones play a role in disease mechanism. We recently demonstrated that minimally invasive optogenetic SD (opto-SD) can be used to model migraine aura in rodents and examine the causal relationship of SD to the headache of migraine and other migraine-associated phenotypes. During this presentation, data will be presented to demonstrate opto-SD induced trigeminal allodynia and mouse grimace. Sex differences in opto-SD behavior and the influence of estrus cycle stage on trigeminal allodynia, grimace and photosensitivity will also be presented.

Targeting the Photoreceptor Basis of Light Aversive Behavior in Mice

Oral Abstract Presenter: Eric Kaiser MD, PhD

Background: The characteristic photophobia of migraine may be mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs), which transmit melanopsin and cone signals. Light sensitization after calcitonin gene-related peptide (CGRP) administration has been used as a rodent model of migraine, but the photoreceptor basis of this behavior has not been studied. Here we measured light avoidance in mice to varying levels of broadband illumination and to chromatic variation designed to target melanopsin or the cones. Methods: Light aversion was tested in a modified light-dark box. Both zones were illuminated by narrow-band LEDs that targeted three different photopic opsins: 365 nm (UV; S-cone), 460 nm (blue; melanopsin), and 630 nm (red; ML-cone). During 30 minutes of habituation, the two zones had equilivant illumination (Expt 1: dark; Expt 2: UV+red at 30% intensity; Expt 3: blue at 30% intensity). During the subsequent 30 minutes, the zones were set to have differing illuminance (Expt 1: off vs. all LEDs set to ~log spaced intensity between 5% and 100%; Expt 2: blue 10% vs. 50% intensity in addition to the habituation background; Expt 3: UV+red 10% vs. 50% intensity in addition to the habituation background). Animals were studied initially, and then retested following peripheral CGRP or vehicle administration. Expt 4: c-Fos immunochemistry was measured in mice exposed to 100% intensity of all three LEDs following CGRP treatment. Results: Expt 1: wild-type C57BL/6J mice avoided the light zone, and the degree of aversion increased monotonically with increasing LED intensity following a sigmoidal functional form. Following either CGRP or vehicle treatment, there was increased light aversion at all light intensity levels. There was no overall difference in aversion between CGRP and vehicle treatments, although in post-hoc tests CGRP-treated animals showed greater light avoidance at the highest intensity levels. Expts 2 and 3: mice spent less time in the zone with the higher level of either blue or UV/red light. There were no reliable effects of treatment. Expt 4: Mice exposed to bright red/blue/UV light following peripheral CGRP administration demonstrated c-fos activation in lateral geniculate and visual cortex as well as the trigeminal nucleus caudalis and amygdala. Conclusions: We demonstrate that light avoidant behavior in the mouse can be measured as a psychometric function of light intensity. The aversive effect of both melanopsin and cone stimulation is consistent with the response properties of the ipRGCs and may provide a suitable model for evaluating mechanisms underlying migraine-associated photophobia.

Feasibility and Acceptability of Remote-Delivered Mindfulness-Based Cognitive Therapy (MBCT) for Patients with Migraine and Depressive Symptoms

Oral Abstract Presenter: Elizabeth Seng, PhD, FANA

Objective: This study evaluated the feasibility, acceptability, and fidelity of remotely-delivered MBCT for patients with migraine and comorbid depressive symptoms. Background:Migraine and depressive symptoms are comorbid. Depressive symptoms are associated with higher levels of disability. MBCT is an evidence-based treatment that has demonstrated efficacy to reduce depressive symptoms and headache disability. This study evaluated the feasibility, acceptability, and fidelity of remotely-delivered MBCT for patients with migraine and comorbid depressive symptoms. We also evaluated preliminary clinical signals for headache disability and depressive symptoms. Method: In a single-arm, open label clinical trial, participants were recruited from NYU’s electronic health record system. After an online prescreen and a phone screen, 16 eligible participants were assigned to receive either phone-delivered MBCT or video-delivered MBCT. The MBCT intervention was based on the standardized protocol and was abbreviated to 1hr/week (rather than 2.5 hrs/week) and was adapted for migraine. Primary outcomes were feasibility (session attendance), acceptability (Client Satisfaction Questionnaire (CSQ-8)), and fidelity (MBCT-T Adherence & Competence Scale). Homework adherence was also assessed. The treatment was considered feasible if average session attendance met or exceeded 75% (e.g., 6 of 8 sessions). The treatment was considered acceptable if the average CSQ-8 score met or exceeded 24. Optimal fidelity was considered a MBCT-T Adherence & Competence Scale score of greater than or equal to 2.5. Clinical outcomes were assessed pre- and post-intervention: headache disability (Headache Disability Inventory (HDI)) and depressive symptoms (Quick Inventory of Depressive Symptomatology - Self Report 16 (QIDS)). Related-Samples Wilcoxon Signed Rank Tests were used to evaluate changes in clinical outcomes from pre- to post-intervention. Results:Participants (n = 16) were all women with a mean age of 45 (SD = 13). The intervention met criteria for feasibility (M session attendance = 7.9/8, SD = 0.3), acceptability (M CSQ-8 = 28.8, SD = 3.3), and fidelity (MBCT-T Adherence & Competence Scale = 2.9). The average proportion of mindfulness homework activities completed was 0.65. When evaluating changes from pre- to post-intervention, we observed significant reductions in headache disability (HDI: p = .004) and depressive symptoms (QIDS: p = .003). Conclusion: The remotely-delivered MBCT for migraine and depressive symptoms intervention was feasible and acceptable to all participants. The intervention also exceeded the threshold for fidelity. We observed reductions in headache disability and depressive symptoms.