Research: brain structural differences are associated with unrefreshing sleep in CFS | 04 July 2017

Published in NMR in Biomedicine, 29 June 2017.

RESEARCH ARTICLE
Medial cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome

Zack Y. Shan, Richard Kwiatek, Richard Burnet, Peter Del Fante, Donald R. Staines, Sonya M. Marshall‐Gradisnik, Leighton R. Barnden.

National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia.

Abstract
Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited.

All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT‐T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities. We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure.

In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT‐T1w intensities (family‐wise error corrected cluster, PFWE< 0.05) and between PSQI and T1w intensities (PFWE< 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001).

This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.

Main Paper (Extracts)
Sleep plays an important role in human health and well‐being, with its recuperative, restorative, and learning consolidation properties. Unrefreshing sleep is a hallmark of ME/CFS that causes patients to wake up feeling tired even after extended periods of sleep, to experience excessive daytime sleepiness, and to have difficulty falling asleep and staying asleep. Therefore, unrefreshing sleep results at least in worsening fatigue symptoms and adds to the ‘illness burden’ in CFS patients.

Roughly 91% of CFS patients report unrefreshing sleep regardless of adequate sleep duration. The effect of unrefreshing sleep is of importance in CFS aetiology because sleep disturbance can cause fatigue, myalgia, and poor attention. A recent path analysis study, exploring the interrelationship of different symptoms in CFS, found that poor sleep quality directly impacted on both mental and physical quality of life. Similarly, another study found that subjective‐ but not actigraphy‐defined sleep quality predicts next‐day fatigue in patients with CFS.

Given that unrefreshing sleep is a hallmark of CFS, we hypothesized that brain changes would be associated with unrefreshing sleep in patients with CFS. Interrogation of brain structure associations with sleep disturbance can provide direct in vivo evidence on whether there is brain involvement in unrefreshing sleep in CFS. To the best of our knowledge, there is no study of brain structure correlations with sleep quality in patients with CFS. Therefore, this study investigates if there are brain structural changes associated with unrefreshing sleep in CFS using MRI.

Subjects
Thirty‐eight CFS subjects from community based specialist and general practice, meeting Canadian Consensus Criteria for CFS, were assessed. Fourteen healthy, normal controls (NCs), unrelated to the CFS subjects, were recruited by public advertisement. The CFS group included 27 females and 11 males aged 34.8 ± 10.1 (mean ± SD) years. The NC group included 10 females and 4 males aged 34.7 ± 8.4 years old. There was no significant difference in age (P = 0.26) between the CFS and NC groups. No CFS or NC subject had developed a significant medical condition, including hypertension, or psychiatric illness during the research period. No subject was taking centrally acting medication. All subjects were right handed, not smokers, and not substance abusers, ascertained during clinician (RK) interview.

Discussion
(Abbreviations: CFQ, Chalder Fatigue Scale, GM, grey matter, IFOF, inferior frontooccipital fasciculus, mPFC, medial prefrontal cortex, PSQI, Pittsburgh Sleep Quality Index, WM, white matter)

This is the first brain MRI study in CFS to test for brain structure associations with the frequent complaint of unrefreshing sleep as measured by the PSQI. There were three novel findings: (i) In the mPFC, MT‐T1w and T1w intensities are significantly correlated with the sleep quality measure PSQI. Furthermore, the mPFC MT‐T1w and T1w intensities were lower in patients with CFS than in NCs. (ii) The regional WM volumes in the left IFOF are significantly lower in patients with CFS than in NCs. In CFS subjects WM volumes in the left IFOF correlated with PSQI. (iii) The MT‐T1w and T1w intensities in the right internal capsule were significantly correlated with PSQI both in the CFS group alone and in the combined CFS + NC groups, but not in the NC group alone. The T1w intensities in the right insula were significantly correlated with the CFS severity measure CFQ both in the CFS group and in the combined group. MT‐T1w intensities in the right IFOF were also significantly correlated with PSQI in both the CFS and combined groups. However, no inter‐group difference in MT‐T1w or T1w level measures was observed in the corresponding regions.

Unrefreshing sleep is a defining characteristic of CFS. However, lack of objective evidence has led to questioning of subjective patient reports. This study not only established negative correlations of MT‐T1w with PSQI and T1w with PSQI in the mPFC, but also found lower mPFC MT‐T1w and T1w intensities in CFS patients than in NCs. These two findings together confirmed that changes in MRI characteristics in the mPFC were associated with unrefreshing sleep in CFS patients, although causality between them could not be determined. It is not necessary, therefore, to resort to subject misperceptions to explain unrefreshing sleep in CFS. Our findings suggest that traditional sleep measures may not be able to detect sleep abnormality in CFS patients. The reasons for the changed MRI characteristics in the mPFC in CFS could not be determined in this study, although it is noteworthy that mPFC reduction of serotonin transporters and mPFC hypoperfusion were observed in previous studies of CFS.

Regional IFOF WM volumes were significantly decreased here in patients with CFS compared with NCs. This finding supports our previous observation of progressive WM atrophy in the left IFOF in CFS, although 15 of the 40 CFS patients and 10 of the 14 NCs in this study were also used in that longitudinal study. WM atrophy in the left IFOF also correlated with PSQI. To the best of our knowledge, the left IFOF does not play a role in mediating sleep, although a recent study found that frontoparietal connection strength predicts individual resistance to sleep deprivation. Therefore, left IFOF WM atrophy could exacerbate poor sleep quality in patients with CFS.

Conclusion
This is the first study to investigate brain structure associations with unrefreshing sleep in CFS. We found that mPFC MRI measures correlate with CFS and the objective instrumental measures most likely arises because traditional sleep monitoring methods do not respond to the mechanism that causes unrefreshing sleep in CFS. This study warrants the exploration in more depth of unrefreshing sleep in CFS patients.

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