Reduced Creatine Concentrations in Severe Short-sleep Insomnia Disorder
Christopher B Miller1, Caroline D Rae2, Michael Green2, Brendon Yee1,3, Christopher J Gordon1,4, Nathaniel S Marshall1, Simon D Kyle5, Colin A Espie5, Ronald R Grunstein1, and Delwyn J Bartlett1

1NeuroSleep and Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia, 2The University of New South Wales, Randwick, Australia, 33 Department of Respiratory and Sleep Medicine, RPAH, Sydney, Australia, 4Sydney Nursing School, Sydney, Australia, 5Nuffield Department of Clinical Neurosciences and Sleep & Circadian Neuroscience Institute, The University of Oxford, Oxford, United Kingdom

Synopsis

We investigated 31 subjects with Insomnia Disorder grouped by hierarchical cluster analysis into long (N = 19) or short (N = 12) sleep duration insomnia and 16 healthy, good sleeping controls using an aymmetric PRESS MRS sequence at 3T in the left occipital cortex. A super metabolite variable constructed from creatine, Asp, Glu and Gln separated short sleeping insomnia from long sleeping and controls, positively correlated with total sleep duration and negatively with wake-time after sleep onset. Short sleep is associated with reduced creatine concentration.

Introduction

Insomnia is heterogeneous disorder associated with impaired GABA/Creatine concentrations [1]; however the direction of the association relative to healthy good sleeping controls (GSC) is unclear [2]. From an overnight sleep study, two discrete objective groups of insomnia have been proposed: short (SSI) and long (LSI) sleep duration insomnia. The SSI group is more severe with associations to a range of adverse health outcomes [3]. Our aim was to evaluate Creatine and closely coupled measures of brain metabolism (Aspartate, Glutamate and Glutamine) between SSI and LSI patients in the left occipital cortex (LOCC), a group of GSC serve as a comparison.

Methods

Patients with Insomnia Disorder (n=31) completed an overnight assessment only and hierarchical cluster analysis empirically grouped patients into either SSI (n=12) or LSI (n=19). Two weeks later, patients and GSC (n=16) underwent 1H Magnetic Resonance Spectroscopy (MRS) with an asymmetric PRESS (A-PRESS) sequence for resolution in the LOCC at 3T (Achieva TX, Philips, Best, The Netherlands) using a 32 channel head coil. Spectra were fitted using jMRUI (v 4, build 162) using the QUEST algorithm [4] with metabolite basis sets simulated for the appropriate sequence timings using NMRSCOPE. Standard deviations estimated by jMRUI of the estimate for each metabolite were obtained for each fit.

Results

MANCOVA revealed a statistically significant effect of group (Wilks’ λ (.652), F(8, 74) = 2.21; p =.036; partial η2 = .193. Follow-up univariate analyses (Fig. 1) revealed differences for Creatine - lower in the SSI relative to GSC (p <.05, d = 0.75) and LSI groups (p =.05, d = 0.58). Aspartate displayed a trend also in SSI (lower) compared to LSI (p =.08, d = 0.80). The 4 coupled metabolites (Creatine, Aspartate, Glutamate and Glutamine) formed a single super metabolite variable (SMV) from the raw canonical coefficients (ws) of the MANCOVA. ANCOVA of the SMV was highly significant (F(2, 40) = 9.72, p <.001; partial η2 = .327) with Bonferroni comparisons revealing differences between LSI vs. SSI (p <.001, d = 1.41) and SSI vs. Controls (p <.01, d = 1.22; Fig. 2). SMV was positively correlated with total sleep duration (r2 = .31, p <.01, Fig. 3) and negatively correlated with wake-time after sleep onset (r2 = -.15, p <.01). No overall differences were found between Insomnia Disorder and GSC (Wilks’ λ (.943), F(4, 38) = .579; p =.680; partial η2 = .057).

Discussion

These findings indicate that severe SSI is associated with reduced creatine concentrations in the LOOC relative to both LSI and GSC. No overall differences were found between heterogeneous Insomnia Disorder and GSC. Creatine and closely coupled metabolites combined into a single MCV can discriminate SSI from LSI and GSC groups. Impaired metabolism is significantly correlated with objective insomnia severity (sleep duration and wake-time after sleep onset).

Acknowledgements

This research was supported by the National Health and Medical Research Council (NHMRC, Australia) Centre for Integrated Research Understanding of Sleep (CIRUS), 571421; NeuroSleep 1060992 and the Cooperative Research Centre for Alertness, Safety and Productivity, Australian Commonwealth Government.

References

1. Winkelman, J. W., Buxton, O. M., Jensen, J. E., Benson, K. L., O'Connor, S. P., Wang, W., & Renshaw, P. F. (2008). Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). Sleep, 31(11), 1499.

2. Spiegelhalder, K., Regen, W., Baglioni, C., Nissen, C., Riemann, D., & Kyle, S. D. (2015). Neuroimaging Insights into Insomnia. Current neurology and neuroscience reports, 15(3), 1-7.

3. Vgontzas, A. N., Fernandez-Mendoza, J., Liao, D., & Bixler, E. O. (2013). Insomnia with objective short sleep duration: the most biologically severe phenotype of the disorder. Sleep medicine reviews, 17(4), 241-254.

4. Ratiney, H, Sdika, M, Coenradie, Y et al., NMR in Biomed, 2005. 18: 1-13.

Figures

Fig. 1. MRS measures (± s.d.) in insomnia phenotypes vs controls

Fig. 2. Super metabolite variable levels (± s.d.) in insomnia subtypes and controls

Fig. 3. Relationship between total sleep time and super metabolite variable levels.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
4096