Dorso lateral prefrontal cortex stimulation with TMS in chronic migraine individuals refractory to anti-CGRP monoclonal antibodies: Clinical, neuropsychological and neurophysiological effects

Background People with high-frequency episodic migraine or chronic migraine may have resistant or refractory forms. The lack of efficacy of pharmacologic therapies is a major clinical challenge that requires alternative strategies, including neuromodulation and exploration of new targets to improve disease management. The present study aimed to test the effectiveness of an accelerated protocol of theta burst stimulation (iTBS) via the dorso lateral prefrontal cortex (DLPFC) in a group of chronic migraine individuals who did not respond to monoclonal antibodies against calcitonin gene-related peptide (CGRP). The co-primary outcomes were the reduction in monthly headache frequency, use of symptomatic medication and perceived pain intensity. In parallel we wanted to understand the possible role of the prefrontal cortex in the emotional and cognitive functions likely responsible for treatment failure and to offer a possible non-pharmacologic option to individuals with difficult-to-treat migraine. To this end, we measured clinical outcomes along with an electroencephalogram (EEG) and behavioral responses to cognitive and emotional tests related to prefrontal functions. Methods This study was conducted in a controlled, single-blind design in 12 people with chronic refractory migraine. An accelerated protocol of iTBS on DLPFC was preceded by a sham session and followed by a two-month follow-up. Clinical data were collected and a neuropsychological assessment including anxiety, depression and cognitive profile was performed. Cognitive and emotional Stroop testing was performed at baseline, after sham and real stimulation, and at follow-up during high-density EEG recording to obtain event-related potentials (N2, N400 and late sustained potential (LP)). Stroop data from an age- and sex-matched control group were compared with those of migraine individuals. Results Monthly headache days, monthly medication days and headache intensity improved after real stimulation. A similar trend emerged for anxiety, depression, and cognitive performance. The Stroop test was impaired in the baseline, as evidenced by an increase in reaction time and a decrease in N2 and LP in the cognitive task, which returned to normal after real iTBS and at follow-up. Conclusions The results support the efficacy of iTBS as a non-invasive neuromodulation approach for the treatment of chronic, refractory migraine. They tentatively point to the role of cognitive fog and psychopathological symptoms in refractoriness to anti-CGRP drugs, which should be confirmed in larger multicenter studies, and suggest this non-pharmacological approach as another promising therapeutic option for people with difficult-to-treat migraine.