Functional disability in migraine in adolescents is associated with changes in amygdala connectivity

Background & Aims

Migraine in youth has a high prevalence worldwide (>11%)1. It is often associated with comorbidities. It is one of the leading causes of disability, impacting the affected children and their families1. A better understanding of the mechanisms underlying migraine is essential to improve its treatment.
Previous results from our lab highlighted (1) increased functional connectivity between the amygdala and brain areas previously associated with pain in adolescents with migraine2, (2) changes in brain activation and amygdala connectivity at rest following Cognitive Behavioral Therapy (CBT) and associated with headache frequency reduction3,4. Little is known about the potential mechanisms underlying functional disability associated with migraine.
Our aim is to characterize such mechanisms, which could contribute to the definition of new therapeutic targets. We hypothesize that functional disability will be associated with changes in amygdala connectivity.

Methods

97 adolescents with migraine (age: 13.80 +/- 2.07; 72F/24M/1 non-binary) were enrolled in an ongoing study. Participants completed a 28-day baseline headache diary and a baseline visit including Quantitative Sensory Testing (QST) and fMRI including 2 resting-state BOLD series. Questionnaires were also collected, including PedMIDAS5, a measure of functional disability in migraine for children and adolescents.
Resting-state data were preprocessed using an FSL pipeline and aCompCor denoising. First-level analyses were performed on individual time series and included the demeaned individual time courses of the right, respectively left, amygdala seeds as regressors of interest. Second-level analyses were completed to combine the two individual first-level images. Group-level analyses were performed to define the relationship of functional disability with amygdala connectivity by using demeaned individual scores of the PedMIDAS as a regressor of interest.

Results

Average scores at the PedMIDAS were 49.9 (sd: 30.9), indicating moderate to severe disabilities. The average headache frequency measured during the 28 days of the headache diary was 14.6 days (sd: 6.0 days).
Results of the functional connectivity at a z threshold of 3.1 showed a negative relationship between functional disability, i.e. individual PedMIDAS scores, and functional connectivity between the left amygdala seed and two clusters including the bilateral caudate nuclei and thalamus. Similarly, a negative relationship was found between the individual PedMIDAS scores and functional connectivity between the right amygdala seed and a cluster encompassing the right caudate nucleus/thalamus.

Conclusions

Our results strongly suggest that the amygdala is intimately associated with brain mechanisms underlying functional disability in migraine. These results could be important clinically: functional disability is the number one complaint in the clinic and has been shown to have a greater and faster decrease than pain sensations over the course of individualized CBT. However, the lack of knowledge of mechanisms underlying functional disability is likely to hinder the efficiency of treatment for migraine and associated functional disabilities. Our results are a first step in improving this knowledge.
Further studies are needed to bridge this gap of knowledge and translate it into clinical practices better targeting functional disability in migraine. A better understanding of mechanisms underlying the evolution of functional disabilities during treatment could contribute to the definition of new treatment targets.

References

1. Onofri, A. et al. Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis. J. Headache Pain 24, 8 (2023).
2. Nahman?Averbuch, H. et al. New insight into the neural mechanisms of migraine in adolescents: Relationships with sleep. Headache: J. Head Face Pain 62, 668–680 (2022).
3. Nahman-Averbuch, H. et al. Alterations in Brain Function After Cognitive Behavioral Therapy for Migraine in Children and Adolescents. Headache: The Journal of Head and Face Pain 33, Cd003968-18 (2020).
4. Nahman-Averbuch, H. et al. Identification of neural and psychophysical predictors of headache reduction after cognitive behavioral therapy in adolescents with migraine. Pain 162, 372–381 (2021).
5. Hershey, A. D. et al. PedMIDAS: development of a questionnaire to assess disability of migraines in children. Neurology 57, 2034–2039 (2001).
6. Lynch-Jordan, A. M. et al. Differential changes in functional disability and pain intensity over the course of psychological treatment for children with chronic pain. Pain 155, 1955–1961 (2014).