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

Abstract

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 ≥ 6hr./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 Tesla 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 Dm. The differences in α, β, Dm, and the combination of α and β 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 Dm (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 twelve 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 Dm) 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.

Novel Aspects of CPAP Treatment and Interventions to Improve CPAP Adherence

“…As a final note, providers should be aware that about 20% of patients who are highly adherent to treatment remain sleepy. Mechanisms for this have been proposed, and there is evidence of white matter compromise, with myelin diffusivity affected along with axonal shrinkage, in those who are sleepy compared with adherent patients who are not [33]. Fortunately, in these cases, there are medications that increase alertness with better sustained attention and quality of life [34,35].…”

Excessive Daytime Sleepiness in Obstructive Sleep Apnea. Mechanisms and Clinical Management

“…These changes suggest possible myelin and/or axonal damage. In contrast, whole-brain fractional anisotropy (FA) and axial diffusivity in patients with OSA did not differ between patients with and without EDS ( 32 , 33 ). In the same studies, differences in regional DTI parameters were reported, with higher regional MD (primarily related to increased radial diffusivity) and lower regional FA in patients with EDS compared with those without EDS.…”

“…In the same studies, differences in regional DTI parameters were reported, with higher regional MD (primarily related to increased radial diffusivity) and lower regional FA in patients with EDS compared with those without EDS. These differences are suggestive of decreased axonal and myelin integrity ( 32 , 33 ). Specifically, these regional differences were observed in fibers of the corpus callosum, internal and external capsule, corona radiata, and sagittal stratum, with most changes seen in the left hemisphere ( 32 ).…”

“…Green: mean fractional anisotropy (FA) skeleton (threshold = 0.2) without significant change. Red-yellow: voxels with significantly increased parameters values in the sleepy group as compared to the nonsleepy group with P < 0.05 as shown in the color bar ( 33 ). ( C ) Whole-brain α, β, and D m maps showing the presence or absence of differences between sleepy and nonsleepy patients with OSA ( 33 ).…”

Advances in pathophysiology and neuroimaging: Implications for sleep and dementia

“…Continuous positive airway pressure (CPAP) therapy has been shown to alter DTI metrics on treatment‐naïve subjects when acquired before and after treatment, as well as on measures of cortical blood flow and blood volume . DTI studies have also now been employed to understand why some treatment‐compliant patients remain symptomatic with daytime sleepiness, with such studies revealing persistent white matter changes on DTI which may explain ongoing symptoms, as well as potentially highlight a subgroup at higher risk of future cognitive decline . A longer term study that evaluated brain morphology after 18 months of CPAP therapy in OSA patients found longer treatment correlated with volume increases in the hippocampal dentate gyrus and cerebellar dentate nucleus, and in those with severe OSA, with volume increases in the pre‐frontal cortex .…”