Abstract
Huntington’s disease (HD) is characterised by progressive symptoms including cognitive deficits and sleep/wake disturbances reflected in an abnormal electroencephalography (EEG). Modafinil, a wake-promoting and cognitive-enhancing drug, has been considered as a treatment for HD. We used HD (R6/2) mice to investigate the potential for using modafinil to treat sleep-wake disturbance in HD. R6/2 mice show sleep-wake and EEG changes similar to those seen in HD patients, with increased rapid eye movement sleep (REMS), decreased wakefulness/increased non-REMS (NREMS), and pathological changes in EEG spectra, particularly an increase in gamma power. We recorded EEG from R6/2 and wild-type mice treated with modafinil acutely (with single doses between 25 and 100 mg/kg; at 12 and 16 weeks of age), or chronically (64 mg/kg modafinil/day from 6 to 15 weeks). Acutely, modafinil increased wakefulness in R6/2 mice and restored NREMS to wild-type levels at 12 weeks. It also suppressed the pathologically increased REMS. This was accompanied by decreased delta power, increased peak frequency of theta, and increased gamma power. At 16 weeks, acute modafinil also restored wakefulness and NREMS to wild-type levels. However, whilst REMS decreased, it did not return to normal levels. By contrast, in the chronic treatment group, modafinil-induced wakefulness was maintained at 15 weeks (after 9 weeks of treatment). Interestingly, chronic modafinil also caused widespread suppression of power across the EEG spectra, including a reduction in gamma that increases pathologically in R6/2 mice. The complex EEG effects of modafinil in R6/2 mice should provide a baseline for further studies to investigate the translatability of these result to clinical practice.
Highlights
Huntington’s disease (HD) is a complex progressive genetic neurodegenerative disorder characterised by motor, cognitive, and affective symptoms [1]
We showed previously using a combination of modafinil (Provigil) and alprazolam that treating sleep-wake deficits in R6/2 mice has a beneficial effect on cognitive performance and arousability [9, 21]
We found that acutely modafinil was wake-promoting in R6/2 mice and reduced the pathologically increased rapid eye movement sleep (REMS), the effect waned as the disease progressed
Summary
Huntington’s disease (HD) is a complex progressive genetic neurodegenerative disorder characterised by motor, cognitive, and affective symptoms [1]. Disturbances of sleep-wake behaviour, including sleep fragmentation [2, 3], abnormality of rapid eye movement sleep (REMS) [4, 5], and daytime sleepiness [6, 7] are widespread problems in HD patients that frequently appear early in the course of the disease [8, 9]. Pathological EEG spectral abnormalities are seen in HD patients [3, 9, 10]. We used the R6/2 line for our studies [18] These mice show a phenotype mirroring important symptoms seen in HD patients, including deteriorating motor and cognitive functions [19, 20]. R6/2 mice show progressive changes in quantitative EEG (qEEG), in particular a pathological increase in gamma oscillation power [11, 12]
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