David T. Plante

Sleep Disturbance in Bipolar Disorder: Therapeutic Implications

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.

Reduced γ-Aminobutyric Acid in Occipital and Anterior Cingulate Cortices in Primary Insomnia: a Link to Major Depressive Disorder?

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.

Topographic and sex-related differences in sleep spindles in major depressive disorder: a high-density EEG investigation.

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.

Sex-related differences in sleep slow wave activity in major depressive disorder: a high-density EEG investigation

BackgroundSleep disturbance plays an important role in major depressive disorder (MDD). Prior investigations have demonstrated that slow wave activity (SWA) during sleep is altered in MDD; however, results have not been consistent across studies, which may be due in part to sex-related differences in SWA and/or limited spatial resolution of spectral analyses. This study sought to characterize SWA in MDD utilizing high-density electroencephalography (hdEEG) to examine the topography of SWA across the cortex in MDD, as well as sex-related variation in SWA topography in the disorder.MethodsAll-night recordings with 256 channel hdEEG were collected in 30 unipolar MDD subjects (19 women) and 30 age and sex-matched control subjects. Spectral analyses of SWA were performed to determine group differences. SWA was compared between MDD and controls, including analyses stratified by sex, using statistical non-parametric mapping to correct for multiple comparisons of topographic data.ResultsAs a group, MDD subjects demonstrated significant increases in all-night SWA primarily in bilateral prefrontal channels. When stratified by sex, MDD women demonstrated global increases in SWA relative to age-matched controls that were most consistent in bilateral prefrontal regions; however, MDD men showed no significant differences relative to age-matched controls. Further analyses demonstrated increased SWA in MDD women was most prominent in the first portion of the night.ConclusionsWomen, but not men with MDD demonstrate significant increases in SWA in multiple cortical areas relative to control subjects. Further research is warranted to investigate the role of SWA in MDD, and to clarify how increased SWA in women with MDD is related to the pathophysiology of the disorder.

Effects of sleep deprivation on sleep homeostasis and restoration during methadone-maintenance: A [31]P MRS brain imaging study

Insomnia afflicts many individuals, but particularly those in chronic methadone treatment. Studies examining sleep deprivation (SD) have begun to identify sleep restoration processes involving brain bioenergetics. The technique ([31])P magnetic resonance spectroscopy (MRS) can measure brain changes in the high-energy phosphates: alpha-, beta-, and gamma-nucleoside triphosphate (NTP). In the present study, 21 methadone-maintained (MM) and 16 control participants underwent baseline (BL), SD (40 wakeful hours), recovery1 (RE1), and recovery2 (RE2) study nights. Polysomnographic sleep was recorded each night and ([31])P MRS brain scanning conducted each morning using a 4T MR scanner (dual-tuned proton/phosphorus head-coil). Interestingly, increases in total sleep time (TST) and sleep efficiency index (SEI) commonly associated with RE sleep were not apparent in MM participants. Analysis of methadone treatment duration revealed that the lack of RE sleep increases in TST and SEI was primarily exhibited by short-term MM participants (methadone <12 months), while RE sleep in long-term MM (methadone >12 months) participants was more comparable to control participants. Slow wave sleep increased during RE1, but there was no difference between MM and control participants. Spectral power analysis revealed that compared to control participants; MM participants had greater delta, theta, and alpha spectral power during BL and RE sleep. ([31])P MRS revealed that elevations in brain beta-NTP (a direct measure of ATP) following RE sleep were greater in MM compared to control participants. Results suggest that differences in sleep and brain chemistry during RE in MM participants may be reflective of a disruption in homeostatic sleep function.

Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health

Janet M. Mullington, PhD1; Sabra M. Abbott, MD, PhD2; Judith E. Carroll, PhD3; Christopher J. Davis, MS, PhD4; Derk-Jan Dijk, PhD5; David F. Dinges, PhD6; Philip R. Gehrman, PhD7; Geoffrey S. Ginsburg, MD, PhD8; David Gozal, MD, MBA9; Monika Haack, PhD1; Diane C. Lim, MD10; Madalina Macrea, MD, MPH, PhD11,12; Allan I. Pack, MBChB, PhD, FRCP13; David T. Plante, MD14; Jennifer A. Teske, PhD15; Phyllis C. Zee, MD, PhD2

Seasonal trends in restless legs symptomatology: evidence from Internet search query data

OBJECTIVE Patients with Willis-Ekbom disease (restless legs syndrome [RLS]) frequently report seasonal worsening of their symptoms; however, seasonal patterns in this disorder have not been systematically evaluated. The purpose of our investigation was to utilize Internet search query data to test the hypothesis that restless legs symptoms vary by season, with worsening in the summer months. METHODS Internet search query data were obtained from Google Trends. Monthly normalized search volume was determined for the term restless legs between January 2004 and December 2012. Using cosinor analysis, seasonal effects were tested for data from the United States, Australia, Germany, the United Kingdom, and Canada. RESULTS Cosinor analysis revealed statistically significant seasonal effects on search queries in the United States (P=.005), Australia (P=.00007), Germany (P=.00009), and the United Kingdom (P=.003), though a trend was present in the search data from Canada (P=.098). Search queries peaked in summer months in both northern (June and July) and southern (January) hemispheres. Search query volume increased by 24-40% during summer relative to winter months across all evaluated countries. CONCLUSIONS Evidence from Internet search queries across a wide range of dates and geographic areas suggested a seasonality of restless legs symptomatology with a peak in summer months. Our novel finding in RLS epidemiology needs to be confirmed in additional samples, and underlying mechanisms must be elucidated.

Overnight changes in waking auditory evoked potential amplitude reflect altered sleep homeostasis in major depression

Goldstein MR, Plante DT, Hulse BK, Sarasso S, Landsness EC, Tononi G, Benca RM. Overnight changes in waking auditory evoked potential amplitude reflect altered sleep homeostasis in major depression.

Relationship between sleep disturbance and recovery in patients with borderline personality disorder.

OBJECTIVE Patients with borderline personality disorder (BPD) frequently experience sleep disturbance, however, the role of sleep quality in the course of BPD is unknown. The purpose of this study was to evaluate the cross-sectional association between sleep quality and recovery status (symptomatic remission plus good concurrent psychosocial functioning) in a well-characterized cohort of patients with BPD to examine the role of sleep disturbance in the course of the disorder. METHODS 223 patients with BPD participating in the McLean Study of Adult Development (MSAD) were administered the Pittsburgh Sleep Quality Index (PSQI) as part of the 16-year follow-up wave. Sleep quality was compared between recovered (n=105) and non-recovered (n=118) BPD participants, including adjustment for age, sex, depression, anxiety, and primary sleep disorders. RESULTS Non-recovered BPD patients had significantly worse sleep quality than recovered BPD participants as measured by the global PSQI score (adjusted means 12.01 vs. 10.73, p=0.03). In addition, non-recovered BPD participants had longer sleep onset latency (adjusted means 39.20 vs. 28.11minutes, p=0.04), as well as increased odds of using sleeping medication (adjusted OR 1.49, p=0.009) and experiencing daytime dysfunction as a result of their sleep disturbance (adjusted OR 1.48, p=0.008). CONCLUSION These results demonstrate an association between subjective sleep disturbance and recovery status among BPD patients. Further research is indicated to evaluate the mechanisms underlying sleep disturbance in BPD, and whether treatment of sleep complaints improves the symptomatic and psychosocial course of the disorder.

Altered slow wave activity in major depressive disorder with hypersomnia: a high density EEG pilot study

Hypersomnolence in major depressive disorder (MDD) plays an important role in the natural history of the disorder, but the basis of hypersomnia in MDD is poorly understood. Slow wave activity (SWA) has been associated with sleep homeostasis, as well as sleep restoration and maintenance, and may be altered in MDD. Therefore, we conducted a post-hoc study that utilized high density electroencephalography (hdEEG) to test the hypothesis that MDD subjects with hypersomnia (HYS+) would have decreased SWA relative to age- and sex-matched MDD subjects without hypersomnia (HYS-) and healthy controls (n=7 for each group). After correction for multiple comparisons using statistical non-parametric mapping, HYS+ subjects demonstrated significantly reduced parieto-occipital all-night SWA relative to HYS- subjects. Our results suggest hypersomnolence may be associated with topographic reductions in SWA in MDD. Further research using an adequately powered prospective design is indicated to confirm these findings.