White matter microstructure and sleep-wake disturbances in individuals at ultra-high risk of psychosis

Jesper Ø Rasmussen; Dorte Nordholm; Louise B Glenthøj; Marie A Jensen; Anne H Garde; Jayachandra M Ragahava; Poul J Jennum; Birte Y Glenthøj; Merete Nordentoft; Lone Baandrup; Bjørn H Ebdrup; Tina D Kristensen

doi:10.3389/fnhum.2022.1029149

White matter microstructure and sleep-wake disturbances in individuals at ultra-high risk of psychosis

Front Hum Neurosci. 2022 Oct 28:16:1029149. doi: 10.3389/fnhum.2022.1029149. eCollection 2022.

Authors

Jesper Ø Rasmussen¹, Dorte Nordholm², Louise B Glenthøj^{2

3}, Marie A Jensen⁴, Anne H Garde^{4

5}, Jayachandra M Ragahava^{1

6}, Poul J Jennum^{7

8}, Birte Y Glenthøj^{1

8}, Merete Nordentoft^{2

8}, Lone Baandrup^{1

8

9}, Bjørn H Ebdrup^{1

8}, Tina D Kristensen¹

Affiliations

¹ Centre for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.
² Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.
³ Department of Psychology, Faculty of Social Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ The National Research Centre for the Working Environment, Copenhagen, Denmark.
⁵ Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
⁶ Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁷ Danish Centre for Sleep Medicine, Department of Clinical Neurophysiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁸ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹ Mental Health Centre Copenhagen, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.

Abstract

Aim: White matter changes in individuals at ultra-high risk for psychosis (UHR) may be involved in the transition to psychosis. Sleep-wake disturbances commonly precede the first psychotic episode and predict development of psychosis. We examined associations between white matter microstructure and sleep-wake disturbances in UHR individuals compared to healthy controls (HC), as well as explored the confounding effect of medication, substance use, and level of psychopathology.

Methods: Sixty-four UHR individuals and 35 HC underwent clinical interviews and diffusion weighted imaging. Group differences on global and callosal mean fractional anisotropy (FA) was tested using general linear modeling. Sleep-wake disturbances were evaluated using the subjective measures disturbed sleep index (DSI) and disturbed awakening index (AWI) from the Karolinska Sleep Questionnaire, supported by objective sleep measures from one-night actigraphy. The primary analyses comprised partial correlation analyses between global FA/callosal FA and sleep-wake measures. Secondary analyses investigated multivariate patterns of covariance between measures of sleep-wake disturbances and FA in 48 white matter regions of interest using partial least square correlations.

Results: Ultra-high risk for psychosis individuals displayed lower global FA (F = 14.56, p < 0.001) and lower callosal FA (F = 11.34, p = 0.001) compared to HC. Subjective sleep-wake disturbances were significantly higher among the UHR individuals (DSI: F = 27.59, p < 0.001, AWI: F = 36.42, p < 0.001). Lower callosal FA was correlated with increased wake after sleep onset (r = -0.34, p = 0.011) and increased sleep fragmentation index (r = -0.31, p = 0.019) in UHR individuals. Multivariate analyses identified a pattern of covariance in regional FA which were associated with DSI and AWI in UHR individuals (p = 0.028), but not in HC. Substance use, sleep medication and antipsychotic medication did not significantly confound these associations. The association with objective sleep-wake measures was sustained when controlling for level of depressive and UHR symptoms, but symptom level confounded the covariation between FA and subjective sleep-wake measures in the multivariate analyses.

Conclusion: Compromised callosal microstructure in UHR individuals was related to objectively observed disruptions in sleep-wake functioning. Lower FA in ventrally located regions was associated with subjectively measured sleep-wake disturbances and was partly explained by psychopathology. These findings call for further investigation of sleep disturbances as a potential treatment target.

Keywords: diffusion weighted imaging; psychopathology; sleep; substance use; ultra-high risk of psychosis; white matter.