Perivascular space diffusivity and brain microstructural measures are associated with circadian time and sleep quality.

The glymphatic system is centred around brain cerebrospinal fluid flow and is enhanced during sleep, and the synaptic homeostasis hypothesis proposes that sleep acts on brain microstructure by selective synaptic downscaling. While so far primarily studied in animals, we here examine in humans if brain diffusivity and microstructure is related to time of day, sleep quality and cognitive performance. We use diffusion weighted images from 916 young healthy individuals, aged between 22 and 37 years, collected as part of the Human Connectome Project to assess diffusion tensor image analysis along the perivascular space index, white matter fractional anisotropy, intra-neurite volume fraction and extra-neurite mean diffusivity. Next, we examine if these measures are associated with circadian time of acquisition, the Pittsburgh Sleep Quality Index (high scores correspond to low sleep quality) and age-adjusted cognitive function total composite score. Consistent with expectations, we find that diffusion tensor image analysis along the perivascular space index and orbitofrontal grey matter extra-neurite mean diffusivity are negatively and white matter fractional anisotropy positively correlated with circadian time. Further, we find that grey matter intra-neurite volume fraction correlates positively with Pittsburgh Sleep Quality Index, and that this correlation is driven by sleep duration. Finally, we find positive correlations between grey matter intra-neurite volume fraction and cognitive function total composite score, as well as negative interaction effects between cognitive function total composite score and Pittsburgh Sleep Quality Index on grey matter intra-neurite volume fraction. Our findings propose that perivascular flow is under circadian control and that sleep downregulates the intra-neurite volume in healthy adults with positive impact on cognitive function.

Haplotype of the astrocytic water channel AQP4 is associated with slow wave energy regulation in human NREM sleep.

Cerebrospinal fluid (CSF) flow through the brain parenchyma is facilitated by the astrocytic water channel aquaporin 4 (AQP4). Homeostatically regulated electroencephalographic (EEG) slow waves are a hallmark of deep non-rapid eye movement (NREM) sleep and have been implicated in the regulation of parenchymal CSF flow and brain clearance. The human AQP4 gene harbors several single nucleotide polymorphisms (SNPs) associated with AQP4 expression, brain-water homeostasis, and neurodegenerative diseases. To date, their role in sleep-wake regulation is unknown. To investigate whether functional variants in AQP4 modulate human sleep, nocturnal EEG recordings and cognitive performance were investigated in 123 healthy participants genotyped for a common eight-SNP AQP4-haplotype. We show that this AQP4-haplotype is associated with distinct modulations of NREM slow wave energy, strongest in early sleep and mirrored by changes in sleepiness and reaction times during extended wakefulness. The study provides the first human evidence for a link between AQP4, deep NREM sleep, and cognitive consequences of prolonged wakefulness.