Evidence for wakefulness-related changes to extracellular space in human brain white matter from diffusion-weighted...

Recently, several magnetic resonance imaging (MRI) studies have reported time-of-day effects on brain structure and function. Due to the possibility that time-of-day effects reflect mechanisms of circadian regulation, the aim of this prospective study was to assess these effects while under strict experimental control of variables that might influence biological clocks, such as caffeine intake and exposure to blue-emitting light. In addition, the current study assessed whether time-of-day effects were driven by changes to extracellular space, by including estimations of non-Gaussian diffusion metrics obtained from diffusion kurtosis imaging, white matter tract integrity and the spherical mean technique, in addition to conventional diffusion tensor imaging -derived parameters. Participants were 47 healthy adults who underwent diffusion-weighted imaging in the morning and evening of the same day. Morning and evening scans were compared using voxel-wise tract based spatial statistics and permutation testing. A day of wakefulness was associated with widespread increases in fractional anisotropy, indices of kurtosis and indices of the axonal water fraction. In addition, wakefulness was associated with widespread decreases in radial diffusivity, both in the single compartment and in extra-axonal space. These results suggest that an increase in the intra-axonal space relative to the extra-axonal volume underlies time-of-day effects in human white matter, which is in line with activity-induced reductions to the extracellular volume. These findings provide important insight into possible mechanisms driving time-of-day effects in MRI.