White matter structural differences in OSA patients experiencing residual daytime sleepiness with high CPAP use: a non-Gaussian diffusion MRI study.

OBJECTIVES: To investigate factors associated with residual sleepiness in patients who were highly adherent to continuous positive airway pressure (CPAP). Nocturnal inactivity, comorbidities, concomitant medications, and, in particular, white matter (WM) differences using diffusion magnetic resonance imaging (MRI) were explored using a continuous-time random-walk (CTRW) model. METHODS: Twenty-seven male patients (30-55 years of age) with obstructive sleep apnea (OSA) received CPAP as the only treatment (CPAP ≥ 6 h/night) for at least 30 days. Based on the Psychomotor Vigilance Task (PVT) results, participants were divided into a non-sleepy group (lapses ≤ 5; n = 18) and a sleepy group (lapses > 5; n = 9). Mean nocturnal inactivity (sleep proxy) was measured using actigraphy for one week. Diffusion-weighted imaging (DWI) with high b-values, as well as diffusion tensor imaging (DTI), was performed on a 3 T MRI scanner. The DWI dataset was analyzed using the CTRW model that yielded three parameters: temporal diffusion heterogeneity α, spatial diffusion heterogeneity β, and an anomalous diffusion coefficient D(m). The differences in α, β, and D(m) between the two groups were investigated by a whole-brain analysis using tract-based spatial statistics (TBSS), followed by a regional analysis on individual fiber tracts using a standard parcellation template. Results from the CTRW model were compared with those obtained from DTI. The three CTRW parameters were also correlated with the clinical assessment scores, Epworth Sleepiness Scale (ESS), PVT lapses, and PVT mean reaction time (MRT) in specific fiber tracts. RESULTS: There were no differences between groups in mean sleep duration, comorbidities, and the number or type of medications, including alerting and sedating medications. In the whole-brain DWI analysis, the sleepy group showed higher α (17.27% of the WM voxels) and D(m) (17.14%) when compared to the non-sleepy group (P < 0.05), whereas no significant difference in β was observed. In the regional fiber analysis, the sleepy and non-sleepy groups showed significant differences in α, β, or their combinations in a total of 12 fiber tracts; whereas similar differences were not observed in DTI parameters, when age was used as a covariate. Additionally, moderate to strong correlations between the CTRW parameters (α, β, or D(m)) and the sleepiness assessment scores (ESS, PVT lapses, or PVT MRT) were observed in specific fiber tracts (|R| = 0.448-0.654, P = 0.0003-0.019). CONCLUSIONS: The observed differences in the CTRW parameters between the two groups indicate that WM alterations can be a possible mechanism to explain reversible versus residual sleepiness observed in OSA patients with identical high level of CPAP use. The moderate to strong correlations between the CTRW parameters and the clinical scores suggest the possibility of developing objective and quantitative imaging markers to complement clinical assessment of OSA patients.