Acute sleep deprivation enhances susceptibility to the migraine substrate cortical spreading depolarization

• Published in: Journal of headache and pain Vol. 21; no. 1; p. 86
• Main Authors: Negro, Andrea, Seidel, Jessica L., Houben, Thijs, Yu, Esther S., Rosen, Ike, Arreguin, Andrea J., Yalcin, Nilufer, Shorser-Gentile, Lea, Pearlman, Lea, Sadhegian, Homa, Vetrivelan, Ramalingam, Chamberlin, Nancy L., Ayata, Cenk, Martelletti, Paolo, Moskowitz, Michael A., Eikermann-Haerter, Katharina
• Format: Journal Article
• Language: English
• Published: Milan Springer Milan 06-07-2020; Springer Nature B.V; BMC
• Subjects: Animal models; Animals; Cortical spreading depolarization; Cortical Spreading Depression - physiology; CSD; Depolarization; Disease Models, Animal; Diurnal; Headache; Hypothalamus; Internal Medicine; Male; Medicine; Medicine & Public Health; Migraine; Migraine without Aura - physiopathology; Neurology; Neuronal-glial interactions; Pain Medicine; Potassium chloride; Rats; Rats, Sprague-Dawley; Research Article; Risk factors; Sleep and wakefulness; Sleep deprivation; Sleep Deprivation - physiopathology; Sleep disorders; Spreading depression; Susceptibility; Therapeutic applications; Ventrolateral preoptic (VLPO) nucleus; Ventrolateral preoptic nucleus; VLPO; Cortical spreading depolarization; CSD; VLPO; Migraine; Sleep deprivation; Ventrolateral preoptic (VLPO) nucleus
• ISSN: 1129-2369; 1129-2377
• DOI: 10.1186/s10194-020-01155-w

Background
Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models.
Methods
Acute
sleep deprivation was achieved using the “gentle handling method”, chosen to minimize stress and avoid confounding bias. Sleep deprivation was started with onset of light (diurnal lighting conditions), and assessment of CSD was performed at the end of a 6 h or 12 h sleep deprivation period. The effect of
chronic
sleep deprivation on CSD was assessed 6 weeks or 12 weeks after lesioning of the hypothalamic ventrolateral preoptic nucleus. All experiments were done in a blinded fashion with respect to sleep status. During 60 min of continuous topical KCl application, we assessed the total number of CSDs, the direct current shift amplitude and duration of the first CSD, the average and cumulative duration of all CSDs, propagation speed, and electrical CSD threshold.
Results
Acute
sleep deprivation of 6 h (
n
 = 17) or 12 h (
n
 = 11) duration significantly increased CSD frequency compared to controls (17 ± 4 and 18 ± 2, respectively, vs. 14 ± 2 CSDs/hour in controls;
p
 = 0.003 for both), whereas other electrophysiological properties of CSD were unchanged.
Acute
total sleep deprivation over 12 h but not over 6 h reduced the electrical threshold of CSD compared to controls (
p
 = 0.037 and
p
 = 0.095, respectively).
Chronic
partial sleep deprivation in contrast did not affect CSD susceptibility in rats.
Conclusions
Acute
but not
chronic
sleep deprivation enhances CSD susceptibility in rodents, possibly underlying its negative impact as a migraine trigger and exacerbating factor. Our findings underscore the importance of CSD as a therapeutic target in migraine and suggest that headache management should identify and treat associated sleep disorders.