New Insight Into the Neural Mechanisms of Migraine in Adolescents: Relationships With Sleep

Hadas Nahman-Averbuch PhD; Victor J. Schneider II MSc; Gregory R. Lee PhD; James L. Peugh PhD; Andrew D. Hershey MD, PhD, FAAN, FAHS; Scott W. Powers PhD, ABPP, FAHS; Massimiliano de Zambotti PhD; Robert C. Coghill PhD; Christopher D. King PhD


Headache. 2022;62(6):668-680. 

In This Article

Abstract and Introduction


Objective: This case-control study examines if measures of subjective and objective (actigraphic) sleep difficulties mediate alterations in amygdalar connectivity in adolescents with migraine compared to healthy adolescents.

Background: Adolescents with migraine have different functional connectivity of the amygdala compared to individuals without migraine. Sleep is often disturbed in adolescents with migraine, and could contribute to the alterations in functional connectivity.

Methods: Twenty adolescents with migraine and 20 healthy controls were recruited from Cincinnati Children's Hospital. Participants completed surveys about their headaches and overall sleep quality, sleep hygiene, and perceived sleep difficulties (Insomnia Severity Scale [ISI]); completed wrist-worn actigraphy; and underwent a magnetic resonance imaging scan.

Results: Adolescents with migraine differed from healthy controls only in perceived difficulty in sleep initiation and maintenance (ISI: 8.5 ± 4.7 and 4.5 ± 3.7 [mean ± standard deviation], −4.00 [95% confidence: −6.7 to −1.3], p = 0.005) and had greater functional connectivity between the amygdala and the posterior cingulate cortex, precuneus, dorsolateral prefrontal, sensorimotor, and the occipital cortexes. The differences in functional connectivity of the amygdala were not mediated by the subjective/objective sleep measures (ISI/wake minutes after sleep onset).

Conclusions: Adolescents with migraine have greater connectivity between the amygdala and areas involved in sensory, affective, and cognitive aspects of pain. These alterations may not be due to higher levels of sleep difficulties in adolescents with migraine, suggesting that both amygdala and sleep alterations may play an independent role in migraine pathophysiology. This advances the understanding of the mechanisms underlying pediatric migraine and can potentially advance migraine management.


Brain structure and function are altered in patients with migraine compared to healthy controls,[1–4] but only a few studies have examined neural alterations in youth with migraine.[5–7] These studies found alterations in the function of brain regions such as the amygdala, insula, primary somatosensory cortex (S1), and thalamus but were somewhat limited by a wide age range (including young adults) and by having participants on preventive medications. Thus, the neural mechanisms involved in migraine in adolescents remain to be fully characterized.

One factor that has frequently been associated with elevated pain in adolescents is sleep.[8–11] In adolescents, sleep is a particularly important variable because it is often short and poorly timed.[12,13] In pediatric patients with migraine, disturbed sleep (e.g., short sleep duration, poorer sleep quality) is often associated with greater headache frequency and disability.[14,15] However, the extent to which and the neurobiological mechanisms by which sleep disruption exacerbates pain in people with migraine remain almost wholly unexplored.

The amygdala is one brain region that has been implicated in nociceptive processing,[16,17] migraine pathophysiology,[18–20] and sleep disturbance.[21–24] In adult patients with migraine, amygdalar functional connectivity with the whole brain is related to the severity of sleep disturbances (measured as categorical four-grade sleep disturbance scale ranging from normal to serious sleep disturbance).[25] Thus, the impact of disrupted sleep on amygdalar connectivity might shape the alterations in amygdalar connectivity between patients with migraine and healthy controls.

The current study aims were to (1) evaluate subjective and objective (actigraphic) sleep in adolescents with and without migraine, (2) evaluate resting-state functional connectivity of the amygdala in adolescents with and without migraine, and (3) determine whether measures of subjective and objective sleep mediate differences in amygdalar connectivity. We hypothesized that adolescents with migraine would report greater subjective and objective sleep disruption and would have alterations in resting-state functional connectivity of the amygdala compared to controls. Additionally, we hypothesized that sleep disruption would mediate the differences between the groups in amygdalar connectivity.