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

Andrea Negro, Jessica L Seidel, Thijs Houben, Esther S Yu, Ike Rosen, Andrea J Arreguin, Nilufer Yalcin, Lea Shorser-Gentile, Lea Pearlman, Homa Sadhegian, Ramalingam Vetrivelan, Nancy L Chamberlin, Cenk Ayata, Paolo Martelletti, Michael A Moskowitz, Katharina Eikermann-Haerter, Andrea Negro, Jessica L Seidel, Thijs Houben, Esther S Yu, Ike Rosen, Andrea J Arreguin, Nilufer Yalcin, Lea Shorser-Gentile, Lea Pearlman, Homa Sadhegian, Ramalingam Vetrivelan, Nancy L Chamberlin, Cenk Ayata, Paolo Martelletti, Michael A Moskowitz, Katharina Eikermann-Haerter

Abstract

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.

Keywords: CSD; Cortical spreading depolarization; Migraine; Sleep deprivation; VLPO; Ventrolateral preoptic (VLPO) nucleus.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Experimental setup for electrophysiological recordings. CSD, cortical spreading depolarization; E, electrode; μC, micro coulomb
Fig. 2
Fig. 2
Effect of acute sleep deprivation on electrical CSD threshold. CSD threshold was reduced after 12 h but not 6 h of sleep deprivation. Each circle represents the CSD threshold of an individual rat. All controls (6 h controls and 12 h controls) were pooled for statistical analysis, as no significant difference was found between the two control groups. * p < 0.01 vs. control
Fig. 3
Fig. 3
Effect of acute sleep deprivation on CSD frequency. Both 6 h and 12 h of sleep deprivation increased the frequency of CSD during topical continuous application of KCl. Each circle represents the CSD frequency of an individual rat. All controls (6 h controls and 12 h controls) were pooled for statistical analysis, as no significant difference was found between the two control groups. * p = 0.03 vs. control
Fig. 4
Fig. 4
CSD threshold and frequency in VLPO-lesioned rats. Electrical CSD threshold (a) and CSD frequency upon topical continuous KCl (b) were not altered in rats after chronic sleep deprivation, 6 or 12 weeks after lesioning of the ventrolateral preoptic nucleus. The x-axis indicates the number of intact VLPO neurons after the lesioning procedure. The number of VLPO neurons for sham animals was set to > 800

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