In this review, the authors detail our current understanding of the crucial role that sleep and its disturbances play in bipolar disorder. Multiple lines of evidence suggest that impaired sleep can induce and predict manic episodes. Similarly, treatment of sleep disturbance may serve as both a target of treatment and a measure of response in mania. The depressive phase of bipolar illness is marked by sleep disturbance that may be amenable to somatic therapies that target sleep and circadian rhythms. Residual insomnia in the euthymic period may represent a vulnerability to affective relapse in susceptible patients. Given the importance of sleep in all phases of bipolar disorder, appropriate evaluation and management of sleep disturbance in patients with bipolar illness is further detailed.

Insomnia is closely related to major depressive disorder (MDD) both cross-sectionally and longitudinally, and as such, offers potential opportunities to refine our understanding of the neurobiology of both sleep and mood disorders. Clinical and basic science data suggest a role for reduced γ-aminobutyric acid (GABA) in both MDD and primary insomnia (PI). Here, we have utilized single-voxel proton magnetic spectroscopy (1H-MRS) at 4 Tesla to examine GABA relative to total creatine (GABA/Cr) in the occipital cortex (OC), anterior cingulate cortex (ACC), and thalamus in 20 non-medicated adults with PI (12 women) and 20 age- and sex-matched healthy sleeper comparison subjects. PI subjects had significantly lower GABA/Cr in the OC (p=0.0005) and ACC (p=0.03) compared with healthy sleepers. There was no significant difference in thalamic GABA/Cr between groups. After correction for multiple comparisons, GABA/Cr did not correlate significantly with insomnia severity measures among PI subjects. This study is the first to demonstrate regional reductions of GABA in PI in the OC and ACC. Reductions in GABA in similar brain regions in MDD using 1H-MRS suggest a common reduction in cortical GABA among PI and mood disorders.

Winkelman JW; Plante DT; Schoerning L; Benson K; Buxton OM; O'Connor SP; Jensen JE; Renshaw PF; Gonenc A. Increased rostral anterior cingulate cortex volume in chronic primary insomnia. 2013;36(7):991-998.

Background Sleep disturbance is a common and important component of affective illness. Fitness activity trackers are emerging as alternative means to estimate sleep in psychiatric patients; however, their ability to quantify sleep in mood disorders has not been empirically evaluated. Thus, this study sought to evaluate the utility of the Fitbit Flex (FBF) to estimate sleep in patients with major depressive disorder (MDD) relative to gold standard polysomnography (PSG) and a widely-used actigraph (Actiwatch-2; AW-2). Methods Twenty-one patients with unipolar MDD wore the FBF and AW-2 during in-laboratory PSG. Bland-Altman analysis compared sleep variables among devices. Epoch-by-epoch analysis further evaluated sensitivity, specificity, and accuracy for the FBF and AW-2 relative to PSG. Results The FBF demonstrated significant limitations in quantifying sleep and wake, relative to PSG. In the normal setting, the FBF significantly overestimated sleep time and efficiency, and displayed poor ability to correctly identify wake epochs (i.e. low specificity). In the sensitive setting, the FBF significantly underestimated sleep time and efficiency relative to PSG. Performance characteristics of the FBF were more similar to the AW-2 in the normal compared to sensitive setting. Limitations Participants were young to middle aged and predominantly female, which may limit generalizability of findings. Study design also precluded ability to assess longitudinal performance of FBF. Conclusions The FBF is not an adequate substitute for PSG when quantifying sleep in MDD, and the settings of the device sizably impact its performance relative to PSG and other standard actigraphs. The limitations and capabilities of the FBF should be carefully considered prior to clinical and research implementation.

These results suggest that even during the deepest stage of sleep, sensory and sensorimotor areas in insomnia subjects may still be relatively active compared to control subjects and to the rest of the sleeping brain.

The impact of advances in sleep and circadian sciences over the last 20 years on medicine, health, and public safety has been limited in part by the lack of availability of objective tools capable of quantifying sleep and circadian function in point-of-care (p-o-c) settings. This whitepaper is a product of a workshop that was designed to bring together thoughtleaders in biomarker development, experts in sleep-circadian biology and sleep disorders to identify barriers and opportunities informing the future development of p-o-c diagnostic tools. The workshop entitled, "Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health," was held in Bethesda April 27-28 2015, and was jointly sponsored by the National Heart Lung and Blood Institute, National Institute on Aging and the Sleep Research Society (hereafter referred to as the biomarker workshop, (http:// www.nhlbi.nih.gov/research/reports). The Sleep Research Society supported a number of early career investigators to attend the workshop. They contributed to the writing of this whitepaper. A biomarker is a "biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, condition or disease." 1,2 For the purpose of this whitepaper, "biomarkers" include quantifiable molecules and chemical properties of easily accessible biological samples (e.g., blood, urine, saliva). An ultimate goal is the development of robust and practical approaches for p-o-c or contact implementation in population-based research and most importantly, for clinical applications to enhance sleep and circadian health.Biomarkers to assess current alertness status, sleep health and circadian function are needed for: research to further understanding of sleep and circadian health science, p-o-c diagnosis of sleep and circadian disorders, for prognosis and to evaluate the risk of associated heart, lung, blood, and aging diseases and disorders, and to assess the adequacy of therapy. The ideal biomarker would show high sensitivity (correctly identify the state and degree of acute sleep loss, and possibly even duration that such a status has been ongoing), specificity (correctly identify the presence/absence of a chronic sleep deficiency, such as would be useful in an annual primary care medical visit). However, the field is currently without any viable biomarkers measurable in easily accessible bio-specimens. The availability of objective platforms capable of quantifying

Background Sleep spindles are believed to mediate several sleep-related functions including maintaining disconnection from the external environment during sleep, cortical development, and sleep-dependent memory consolidation. Prior studies that have examined sleep spindles in major depressive disorder (MDD) have not demonstrated consistent differences relative to control subjects, which may be due to sex-related variation and limited spatial resolution of spindle detection. Thus, this study sought to characterize sleep spindles in MDD using high-density electroencephalography (hdEEG) to examine the topography of sleep spindles across the cortex in MDD, as well as sex-related variation in spindle topography in the disorder. Methods All-night hdEEG recordings were collected in 30 unipolar MDD participants (19 women) and 30 age and sex-matched controls. Topography of sleep spindle density, amplitude, duration, and integrated spindle activity (ISA) were assessed to determine group differences. Spindle parameters were compared between MDD and controls, including analysis stratified by sex. Results As a group, MDD subjects demonstrated significant increases in frontal and parietal spindle density and ISA compared to controls. When stratified by sex, MDD women demonstrated increases in frontal and parietal spindle density, amplitude, duration, and ISA; whereas MDD men demonstrated either no differences or decreases in spindle parameters. Limitations Given the number of male subjects, this study may be underpowered to detect differences in spindle parameters in male MDD participants. Conclusions This study demonstrates topographic and sex-related differences in sleep spindles in MDD. Further research is warranted to investigate the role of sleep spindles and sex in the pathophysiology of MDD.

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