Contents lists available at ScienceDirect Psychiatry Research: Neuroimaging journal homepage: www.elsevier.com/locate/psychresns Functional connectivity of the circadian clock and neural substrates of sleep- wake disturbance in delirium Sunghyon Kyeong a , Soo-Hee Choi b , Jung Eun Shin b,c , Woo Suk Lee d , Kyu Hyun Yang d , Tae-Sub Chung e , Jae-Jin Kim a,c,f, ⁎ a Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea b Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea c Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea d Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea e Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea f Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea ARTICLE INFO Keywords: Delirium Suprachiasmatic nucleus Functional connectivity ABSTRACT A possible mechanism of disrupted circadian rhythms in delirium was identified using resting-state functional connectivity. Thirty-four delirious patients and 38 non-delirious controls were scanned for resting-state functional MRI. Seed-based connectivity of the suprachiasmatic nucleus was compared between the groups. In delirious patients functional connectivity from the circadian clock was increased to the dorsal anterior cingulate cortex and decreased to the posterior cingulate cortex, parahippocampal gyrus, cerebellum, and thalamus. A dysregulation of the default mode network and mental coordination processing areas by the circadian clock may be the underlying pathophysiology of sleep-wake cycle disturbance and symptom fluctuation in delirium. 1. Introduction Delirium tends to fluctuate in severity during the course and includes disruption in the sleep-wake cycle, such as daytime sleepiness, difficulty falling asleep, and nighttime agitation and wakefulness (Inouye, 2006). This disruption can be caused by a loss of normal circadian rhythm that displays endogenous oscillation, which is facili- tated by the circadian clocks (Figueroa-Ramos et al., 2009). Among various biological clocks, the master clock is located in the suprachias- matic nucleus of the hypothalamus (SCN), which receives light information via the retinohypothalamic tract and coordinates the peripheral circadian clocks (Moore, 1997). Previous studies have shown that advanced age is associated with reduced volume and lower cell number in the SCN (Hofman et al., 1988; Roozendaal et al., 1987). Therefore, it is likely that abnormal SCN activity may be also associated with dysregulation of the circadian rhythm in delirious patients. Our group studied the resting-state brain network in delirium using fMRI (Choi et al., 2012), demonstrating abnormal connection of the posterior cingulate cortex (PCC) with the dorsolateral prefrontal cortex and disconnections among subcortical nuclei. In fact, functional con- nectivity within the default mode network (DMN) and subcortical regions plays an essential role in controlling arousal levels and maintaining alertness (Sämann et al., 2011). Despite evidence for these associations with dysfunction in consciousness-related regions in delir- ium, the underlying mechanisms of sleep-wake cycle disturbance regarding malfunction of biological clocks remains unclear. In the present study, we aimed to account for the neural basis of sleep-wake cycle disturbances in delirious patients. For this purpose, we compared resting-state functional connectivity of the circadian clock between delirious patients and non-delirious controls and then exam- ined correlations between connectivity strength and delirium severity. Under the hypothesis that neural interaction of the circadian clock with cortical regions, including the DMN, would be disrupted in delirium, we used the SCN as a seed region for connectivity analysis. 2. Methods 2.1. Participants Thirty-four delirious patients who had various underlying medical diseases [77.8 ± 9.7 years old (71-91); 17 male] were recruited from the inpatient units of various clinical departments. This study was approved by the institutional review board of Yonsei University Gangnam Severance Hospital. We obtained written informed consent http://dx.doi.org/10.1016/j.pscychresns.2017.03.017 Received 14 November 2016; Received in revised form 18 March 2017; Accepted 20 March 2017 ⁎ Correspondence to: Department of Psychiatry, Yonsei University Gangnam Severance Hospital, 211 Eonju-ro Gangnam-gu, Seoul 06273, Republic of Korea. E-mail address: jaejkim@yonsei.ac.kr (J.-J. Kim). Psychiatry Research: Neuroimaging 264 (2017) 10–12 Available online 04 April 2017 0925-4927/ © 2017 Elsevier B.V. All rights reserved. MARK