Slow Wave Sleep Enhancement with Gaboxadol Reduces Daytime Sleepiness During Sleep Restriction

Walsh, James K.; Snyder, Ellen; Hall, Janine M.; Randazzo, Angela C.; Griffin, Kara; Groeger, John A.; Eisenstein, Rhody D.; Feren, Stephen D.; Dickey, Pam; Schweitzer, Paula K.

doi:10.1093/sleep/31.5.659

Cited by 52 publications

(45 citation statements)

References 47 publications

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“…The extent to which the changes in the EEG as well as the sex differences, as induced by gaboxadol treatment, reflect an intensification of the normal sleep process cannot, of course, be derived from these EEG data, but will require assessments of (for example) daytime function. 4,49,50 The exact mechanisms underlying the sex differences remain to be elucidated, but this study underlines that sex is an important variable in any clinical study evaluating sleep and SWS-enhancing agents. This study highlights that sex is one of the predictors of both individual differences of SWS at baseline and in phase-advanced sleep, as well as a predictor of the effects of a specific pharmacological manipulation with an SWS-enhancing agent.…”

Section: Discussionmentioning

confidence: 91%

EEG Power Spectra Response to a 4-h Phase Advance and Gaboxadol Treatment in 822 Men and Women

Dijk²,

Svetnik³

et al. 2011

Journal of Clinical Sleep Medicine

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study objective: To explore the effect of gaboxadol on NREM EEG in transient insomnia using power spectral analysis and evaluate the response between men and women. methods: This was a randomized, double-blind, 3-way, parallel-group transient insomnia study in 22 sleep laboratories. After a baseline night (N1), subjects underwent a 4-h phase-advance of their habitual sleep time the following night (N2). Healthy subjects aged 18-64 y were given singleblind placebo on N1 followed by double-blind treatment on N2 (gaboxadol 10 mg [n = 271], 15 mg [n = 274], or placebo [n = 277]) Results: At baseline, women showed signifi cantly greater values in low frequency activity (< 10 Hz) and in high spindle/ low beta frequency activity (14-18 Hz) compared to men. During the phase advance (placebo N2-baseline N1), there was a signifi cant increase in power within the high spindle/low beta frequency range (15-17 Hz) and a signifi cant reduction in beta activity (20-32 Hz), which was greater in women than men. Gaboxadol induced a signifi cant (dose-related) increase in low frequencies (< 8 Hz) and a signifi cant (dose-related) decrease within the alpha/spindle range (11-12 Hz). The effect was dependent upon sex, with a greater magnitude of effect observed in women than men. Conclusion: Gaboxadol shows a characteristic NREM EEG spectral profi le in a model of transient insomnia. Men and women show clear differences in NREM EEG activity at baseline, to gaboxadol treatment and to phase-shifts in habitual sleep/wake times. The exact mechanisms underlying the sex differences remain unclear, but sex is an important variable in studies evaluating sleep and gaboxadol. s C I e N t I F I C I N V e s t I G A t I o N sT he functional signifi cance of individual differences in SWS and the pharmacological enhancement of SWS is under intense investigation. [1][2][3][4] The clinical interest in a SWS-enhancing agent, one that augments delta activity, is that such agents may be able to do so in a subject group with diminished SWS/SWA (e.g., aging and males) and thereby provide some form of benefi t to the individual in terms of sleep, daytime performance, and ultimately quality of life. Sex (gender) is beginning to emerge as one of the key predictors of individual differences of SWS under normal sleep conditions, but it is not known whether sex can contribute to the individual differences observed in sleep disruption or in specifi c pharmacological manipulations of SWS. Even though gaboxadol is no longer in clinical development for insomnia, it can be used as a pharmacological research tool with a unique mechanism of action, and specifi cally one that enhances SWS. Ultimately such investigations may lead to a better understanding of both the functional signifi cance of SWS as well as the profound sex differences in the prevalence of insomnia.Gaboxadol is a novel selective extrasynaptic GABA A agonist with the α 4 δ containing receptors currently seeming the most relevant target for mediating its hypnotic activity.5 This receptor subtype occurs ...

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Section: Discussionmentioning

confidence: 91%

EEG Power Spectra Response to a 4-h Phase Advance and Gaboxadol Treatment in 822 Men and Women

Dijk²,

Svetnik³

et al. 2011

Journal of Clinical Sleep Medicine

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“…By imposing a repeating, low-frequency alternation of active and silent periods in cortical circuits, SOs may carry out the homeostatic control of synaptic weight (6). More generally, SWA is considered a reliable indicator of sleep need that increases with time awake, decreases during sleep (7), and may mediate the restorative function of slow-wave sleep (6,8). Indeed, SWA is linked to the induction of cortical plastic changes, because it increases locally after a learning task and is positively correlated with post-sleep performance improvement (32).…”

Section: Discussionmentioning

confidence: 99%

“…SOs are thought to underlie EEG SWA (0.5-4.5 Hz) (18), a reliable indicator of sleep need that is thought to mediate the restorative function of NREM sleep (6,8). We therefore asked whether the repeated induction of individual slow waves by each TMS pulse would lead to an increase in sleep SWA.…”

Section: Tms Triggering Of Slow Waves Leads To a Marked Increase Of Smentioning

confidence: 99%

“…Slow oscillations (SOs) originate locally and expand over the cortex as traveling waves that repeat several hundred times every night (3). The alternation of up-and down-states in cortical neurons is thought to be involved in memory consolidation (4,5), synaptic homeostasis (6), and the restorative function of sleep (7,8), so the ability to trigger slow waves reliably could have important applications.…”

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confidence: 99%

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Triggering sleep slow waves by transcranial magnetic stimulation

Massimini

Ferrarelli²,

Esser³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

432

293

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During much of sleep, cortical neurons undergo near-synchronous slow oscillation cycles in membrane potential, which give rise to the largest spontaneous waves observed in the normal electroencephalogram (EEG). Slow oscillations underlie characteristic features of the sleep EEG, such as slow waves and spindles. Here we show that, in sleeping subjects, slow waves and spindles can be triggered noninvasively and reliably by transcranial magnetic stimulation (TMS). With appropriate stimulation parameters, each TMS pulse at <1 Hz evokes an individual, high-amplitude slow wave that originates under the coil and spreads over the cortex. TMS triggering of slow waves reveals intrinsic bistability in thalamocortical networks during non-rapid eye movement sleep. Moreover, evoked slow waves lead to a deepening of sleep and to an increase in EEG slow-wave activity (0.5-4.5 Hz), which is thought to play a role in brain restoration and memory consolidation.consciousness ͉ electroencephalogram ͉ slow oscillation ͉ bistability ͉ perturbation

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“…Reduced SWS is seen in several diseases such as insomnia [Cervena et al, 2004], depression [Tsuno et al, 2005] and occupational burnout [Ekstedt et al, 2006]. The importance is further underscored by the close link between secretion of growth hormone and the appearance of SWS [Steiger, 2002], as well as an improved daytime functioning and increased alertness by the enhancement of gaboxadol due to SWS [Walsh et al, 2008]. An enhancement of memory functions has also been associated with SWS [Gais and Born, 2004].…”

Section: Discussionmentioning

confidence: 99%

Sleep after mobile phone exposure in subjects with mobile phone‐related symptoms

Löwden

Åkerstedt

Ingre

et al. 2010

Bioelectromagnetics

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Several studies show increases in activity for certain frequency bands (10-14 Hz) and visually scored parameters during sleep after exposure to radiofrequency electromagnetic fields. A shortened REM latency has also been reported. We investigated the effects of a double-blind radiofrequency exposure (884 MHz, GSM signaling standard including non-DTX and DTX mode, time-averaged 10 g psSAR of 1.4 W/kg) on self-evaluated sleepiness and objective EEG measures during sleep. Forty-eight subjects (mean age 28 years) underwent 3 h of controlled exposure (7:30-10:30 PM; active or sham) prior to sleep, followed by a full-night polysomnographic recording in a sleep laboratory. The results demonstrated that following exposure, time in Stages 3 and 4 sleep (SWS, slow-wave sleep) decreased by 9.5 min (12%) out of a total of 78.6 min, and time in Stage 2 sleep increased by 8.3 min (4%) out of a total of 196.3 min compared to sham. The latency to Stage 3 sleep was also prolonged by 4.8 min after exposure. Power density analysis indicated an enhanced activation in the frequency ranges 0.5-1.5 and 5.75-10.5 Hz during the first 30 min of Stage 2 sleep, with 7.5-11.75 Hz being elevated within the first hour of Stage 2 sleep, and bands 4.75-8.25 Hz elevated during the second hour of Stage 2 sleep. No pronounced power changes were observed in SWS or for the third hour of scored Stage 2 sleep. No differences were found between controls and subjects with prior complaints of mobile phone-related symptoms. The results confirm previous findings that RF exposure increased the EEG alpha range in the sleep EEG, and indicated moderate impairment of SWS. Furthermore, reported differences in sensitivity to mobile phone use were not reflected in sleep parameters.

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Slow Wave Sleep Enhancement with Gaboxadol Reduces Daytime Sleepiness During Sleep Restriction

Abstract: The results of this study are consistent with the hypothesis that enhanced SWS, in this study produced by GBX, reduces physiological sleep tendency and introspective sleepiness and fatigue which typically result from sleep restriction.

Cited by 52 publications

References 47 publications

EEG Power Spectra Response to a 4-h Phase Advance and Gaboxadol Treatment in 822 Men and Women

EEG Power Spectra Response to a 4-h Phase Advance and Gaboxadol Treatment in 822 Men and Women

Triggering sleep slow waves by transcranial magnetic stimulation

Sleep after mobile phone exposure in subjects with mobile phone‐related symptoms

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