Effect of High-Definition Transcranial Direct Current Stimulation on Headache Severity and Central μ-Opioid Receptor Availability in Episodic Migraine

Abstract

Alexandre F DaSilva,1,2,* Dajung J Kim,1,2,* Manyoel Lim,1,2 Thiago D Nascimento,1,2 Peter JH Scott,3 Yolanda R Smith,4 Robert A Koeppe,3 Jon-Kar Zubieta,5 Niko Kaciroti6 1Headache and Orofacial Pain Effort (H.O.P.E.) Laboratory, Department of Biologic and Materials Sciences & Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA; 2Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA; 3Department of Radiology, University of Michigan, Ann Arbor, MI, USA; 4Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA; 5Department of Psychiatry, Mass General Brigham, Newton-Wellesley Hospital, Newton, MA, USA; 6Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA*These authors contributed equally to this workCorrespondence: Alexandre F DaSilva, Headache and Orofacial Pain Effort (H.O.P.E.) Laboratory, Michigan Neuroscience Institute, 205 Zina Pitcher PI, Room 1021, Ann Arbor, MI, 48109-5720, USA, Email [email protected]: The current understanding of utilizing HD-tDCS as a targeted approach to improve headache attacks and modulate endogenous opioid systems in episodic migraine is relatively limited. This study aimed to determine whether high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) can improve clinical outcomes and endogenous μ-opioid receptor (μOR) availability for episodic migraineurs.Methods: In a randomized, double-blind, and sham-controlled trial, 25 patients completed 10-daily 20-min M1 HD-tDCS, repeated Positron Emission Tomography (PET) scans with a selective agonist for μOR. Twelve age- and sex-matched healthy controls participated in the baseline PET/MRI scan without neuromodulation. The primary endpoints were moderate-to-severe (M/S) headache days and responder rate (≥ 50% reduction on M/S headache days from baseline), and secondary endpoints included the presence of M/S headache intensity and the use of rescue medication over 1-month after treatment.Results: In a one-month follow-up, at initial analysis, both the active and sham groups exhibited no significant differences in their primary outcomes (M/S headache days and responder rates). Similarly, secondary outcomes (M/S headache intensity and the usage of rescue medication) also revealed no significant differences between the two groups. However, subsequent analyses showed that active M1 HD-tDCS, compared to sham, resulted in a more beneficial response predominantly in higher-frequency individuals (> 3 attacks/month), as demonstrated by the interaction between treatment indicator and baseline frequency of migraine attacks on the primary outcomes. These favorable outcomes were also confirmed for the secondary endpoints in higher-frequency patients. Active treatment also resulted in increased μOR concentration compared to sham in the limbic and descending pain modulatory pathway. Our exploratory mediation analysis suggests that the observed clinical efficacy of HD-tDCS in patients with higher-frequency conditions might be potentially mediated through an increase in μOR availability.Conclusion: The 10-daily M1 HD-tDCS can improve clinical outcomes in episodic migraineurs with a higher baseline frequency of migraine attacks (> 3 attacks/month). This improvement may be, in part, facilitated by the increase in the endogenous μOR availability.Clinical Trial Registration: www.ClinicalTrials.gov, identifier - NCT02964741.Keywords: HD-tDCS, neuromodulation, migraine, headache, pain, mu-opioid receptor

Keywords

• hd-tdcs
• neuromodulation
• migraine
• headache
• pain
• mu-opioid receptor