Avoid or seek light - a randomized crossover fMRI study investigating opposing treatment strategies for photophobia in migraine

Abstract

Background: Photophobia, the aberrantly increased sensitivity to light, is a common symptom in migraine patients and light discomfort is frequently found as a trigger for migraine attacks. In behavioral studies, planned exposure to light was found to reduce headache in migraine patients with photophobia, potentially by increasing habituation to this migraine trigger. Here, we aimed to elucidate neurophysiological mechanisms of light exposure versus light deprivation in migraine patients using functional magnetic resonance imaging (fMRI).

Methods: Ten migraine patients (9 female, age = 28.70 ± 8.18 years) and 11 healthy controls (9 female, age = 23.73 ± 2.24 years) spent one hour on 7 consecutive days exposed to flashing light (Flash) or darkness (Dark) using a crossover design with a wash-out period of 3 months. Study participants kept a diary including items on interictal and ictal photophobia, presence and severity of headache 7 days before, during and 7 days after the interventions. One week before and one day after both interventions, fMRI using flickering light in a block design was applied. Functional activation was analyzed at whole-brain level and habituation of the visual cortex (V1) was modeled with the initial amplitude estimate and the corrected habituation slope.

Results: Mean interictal photophobia decreased after both interventions, but differences relative to the baseline did not survive correction for multiple comparisons. At baseline, flickering light induced activation in V1 was higher in the patients compared to the controls, but activation normalized after the Flash and the Dark interventions. V1 habituation indices correlated with headache frequency, headache severity and ictal photophobia. In the Flash condition, the individual change of headache frequency relative to the baseline corresponded almost perfectly to the change of the habituation slope compared to the baseline.

Conclusions: On average, light exposure did not lead to symptom relief, potentially due to the short duration of the intervention and the high variability of the patients' responses to the intervention. However, the strong relationship between visual cortex habituation and headache symptoms and its modulation by light exposure might shed light on the neurophysiological basis of exposure treatment effects.

Trial registration: NCT05369910 (05/06/2022, retrospectively registered).

Keywords: Functional magnetic resonance imaging; Habituation; Headache; Migraine; Photophobia.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Individual habituation curves in the primary visual cortex (V1), illustrated for patient P07. Visual activation was induced by a flickering light task (10 runs, block design, FWE-corr. 0.05, activation displayed in red to yellow). Mean beta values within the V1 region of interest (blue) were extracted for each run and linearized using the natural log transform, resulting in uncorrected individual habituation curves per session

Fig. 2

Mean interictal photophobia (a) and mean headache frequency (b) at baseline, during the intervention (Flash or Dark) and post intervention, plotted for all patients (P01-P10) individually. Interictal photophobia scores dropped after the Flash and after the Dark intervention in most of the patients. Regarding headache frequency, individual responses to the interventions were heterogenous but returned to baseline levels after the interventions

Fig. 3

Functional activation induced by flickering light in patients and controls at baseline, and after Flash and Dark intervention, contrasted to the baseline (FWE 0.05 corr., cluster threshold = 10). At baseline, patients display higher activation in the primary visual cortex than controls. When contrasting Flash vs. baseline, patients show higher activation in the bilateral anterior insula compared to controls, while no difference was found for the contrast Dark vs. baseline

Fig. 4

Initial activation amplitude (a) and corrected habituation slope (b’) in the patients and controls for the baseline, Flash and Dark intervention. Patients exhibited a significantly higher initial activation amplitude at baseline compared to Flash and Dark

Fig. 5

Correlations between primary visual cortex (V1) activation habituation estimates and diary variables in the patients. The initial amplitude was significantly correlated with headache severity and ictal photophobia, while the corrected habituation slope was significantly correlated with headache frequency and severity, and with ictal photophobia

Fig. 6

Corrected habituation slope (b’) for the primary visual cortex (V1) in all migraine patients individually. In the Flash condition, an increased habituation slope was found in 6 patients (P01, P02, P05, P06, P08, P10) and a decrease in 4 patients (P03, P04, P07, P09) compared to the baseline. In the Dark condition, 6 patients showed an increased b’ (P01, P03, P05, P08, P09, P10) and 4 a declined b’ (P02, P04, P06, P07) relative to the baseline