Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington’s disease

Abstract

Deficits in sleep and circadian organization have been identified as common early features in patients with Huntington's disease that correlate with symptom severity and may be instrumental in disease progression. Studies in Huntington's disease gene carriers suggest that alterations in the electroencephalogram may reflect underlying neuronal dysfunction that is present in the premanifest stage. We conducted a longitudinal characterization of sleep/wake and electroencephalographic activity in the R6/2 mouse model of Huntington's disease to determine whether analogous electroencephalographic 'signatures' could be identified early in disease progression. R6/2 and wild-type mice were implanted for electroencephalographic recordings along with telemetry for the continuous recording of activity and body temperature. Diurnal patterns of activity and core body temperature were progressively disrupted in R6/2 mice, with a large reduction in the amplitude of these rhythms apparent by 13 weeks of age. The diurnal variation in sleep/wake states was gradually attenuated as sleep became more fragmented and total sleep time was reduced relative to wild-type mice. These genotypic differences were augmented at 17 weeks and evident across the entire 24-h period. Quantitative electroencephalogram analysis revealed anomalous increases in high beta and gamma activity (25-60 Hz) in all sleep/wake states in R6/2 mice, along with increases in theta activity during both non-rapid eye movement and rapid eye movement sleep and a reduction of delta power in non-rapid eye movement sleep. These dramatic alterations in quantitative electroencephalographic measures were apparent from our earliest recording (9 weeks), before any major differences in diurnal physiology or sleep/wake behaviour occurred. In addition, the homeostatic response to sleep deprivation was greatly attenuated with disease progression. These findings demonstrate the sensitivity of quantitative electroencephalographic analysis to identify early pathophysiological alterations in the R6/2 model of Huntington's disease and suggest longitudinal studies in other preclinical Huntington's disease models are needed to determine the generality of these observations as a potential adjunct in therapeutic development.

Sleep deficits but no metabolic deficits in premanifest Huntington's disease

“…This suggests that even in the presence of sufficient sleep duration, the restorative effects may be compromised during the premanifest stage. These results of fragmented sleep are in line with a recent paper showing major sleep disturbances in manifest HD patients that were also characterized by increased arousals and awakenings55 and data from transgenic animal models of HD showing that sleep quality as well as oscillatory brain activity (EEG) and circadian rhythmicity becomes gradually more disrupted as the disease progresses 11, 12, 14. Furthermore, it has recently been shown that resting EEG alterations in pre‐HD individuals may be related to the course of the pathological process and to HD endophenotype 43.…”

“…Our study therefore is the first qEEG study performed during sleep in premanifest and manifest patients with HD and indicates alterations in the NREM‐ and particularly the REM‐dependent oscillatory activity of the brain associated with disease burden in gene carriers. Some of our findings such as the decrease in the 3 to 8Hz range and the increase in the high‐frequency (32–36Hz) range in the early HD group are somewhat similar to findings in transgenic animal studies reporting a progressive decrease in low‐frequency (delta) and increase in high‐frequency (beta–gamma) activity in sleep 11, 12, 58. The REM‐dependent increase in the 1 to 2Hz range is unexpected and could be related to increased REM intensity (density of REM), a hypothesis that remains to be tested.…”

“…These results are intriguing, because EEG activity reflects characteristics of cortical and subcortical neural activity and has the potential to become a biomarker for HD onset and progression in the future 56. Whereas there are a number of quantitative EEG (qEEG) studies of waking brain activity in HD (for a review see Nguyen et al56), there are only a couple of studies looking at spectral features of EEG during sleep, and only in transgenic animal models of HD,11, 12, 14, 57, 58 with no studies in humans. Our study therefore is the first qEEG study performed during sleep in premanifest and manifest patients with HD and indicates alterations in the NREM‐ and particularly the REM‐dependent oscillatory activity of the brain associated with disease burden in gene carriers.…”

“…Although pathogenic pathways are beginning to be unraveled offering targets for treatment,8 the precise pathophysiological mechanisms of HD are poorly understood 9. Previously we have shown that sleep disturbances are present in early manifest disease,10 and several studies on transgenic animal models of HD have shown that sleep progressively worsens as the disease develops11, 12, 13, 14 dependently on age and gene dosage 15. However, we do not know whether sleep problems are present during the premanifest stage in individuals carrying the HD gene mutation.…”

A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity

“…The results obtained in baseline recordings using abdominally placed telemeters were discordant from those previously published in the same strain (19). Consequently, we replicated our study of nNOS KO and WT mice using tethered EEG and electromyographic (EMG) recordings, which more closely approximated the previously published procedures and which we have also used previously in both rats (20) and mice (21). Because the results from these two types of recordings in our laboratory were largely coincident (compare Fig.…”