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

Abstract

Objective

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

Data Sharing Statement

The data supporting this study’s findings are available from the corresponding author ([email protected]) upon reasonable request.

Ethics Approval and Informed Consent

The study protocol was approved by the University of Michigan Institutional Review Boards (HUM00107286) and registered at ClinicalTrials.gov (NCT02964741). We conducted the study under the Declaration of Helsinki. All study participants provided written informed consent.

Acknowledgments

We thank the patients who participated in this randomized trial, previous research coordinators (Ifeyinwa Arinze and Dalya Saleem) who performed administrative, technical, or material support, and staff at the PET Center of the University of Michigan hospital and fMRI Lab for providing core facilities and services throughout the study.

Disclosure

The contents described within this study, PainTrek and H.O.P.E. M1 HD-tDCS, have been developed at the University of Michigan and disclosed to the University of Michigan Office of Technology Transfer. All intellectual property rights, including but not limited to patents/patent applications, trademarks, and copyright of software, algorithms, reports, displays, and visualizations, are owned by the Regents of the University of Michigan. Dr. DaSilva is the main inventor of the mobile technology now called PainTrek (previously GeoPain, MoxyTech), which is owned by the University of Michigan. Other authors declare no conflict of interest in this work. Present address for Manyoel Lim: Food Convergence Research Division, Korea Food Research Institute, Republic of Korea.

Additional information

Funding

This research was supported by grant 1-R01-NS094413 from the National Institute of Neurological Disorders and Stroke (Dr. DaSilva). The funding agency had no role in the design and conduct of the study.