Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study

Akeju, Oluwaseun; Hobbs, Lauren E.; Gao, Lei; Burns, Stacey; Pavone, Kara J.; Plummer, George S.; Walsh, Elisa C; Houle, Timothy T.; Kim, Seong Eun; Bianchi, Matt T.; Ellenbogen, Jeffrey M.; Brown, Emery N.

doi:10.1016/j.clinph.2017.10.005

Cited by 96 publications

(82 citation statements)

References 55 publications

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“…It is worth noting that in certain states, such as anesthesia or epilepsy 90 , cells in the thalamus may fire at the population rhythm, and sparse synchronicity in the thalamus might be a distinguishing feature of normal resting states 91 . The disruption of thalamocortical oscillations has been proposed as a pathophysiological model for several neuropsychiatric disorders 92,93 .…”

Section: Sparse Firing Of Thalamic Cells During Spindles and Its Rolementioning

confidence: 99%

mPFC Spindle Cycles Organize Sparse Thalamic Activation and Recently Active CA1 cells During non-REM Sleep

Varela

Wilson

2019

Preprint

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Sleep oscillations in neocortex and hippocampus are critical for the integration of new episodic memories into stable generalized representations in neocortex. However, the role of the thalamus in this process is poorly understood.To determine the thalamic contribution to non-REM oscillations (sharp-wave ripples, SWRs; slow/delta; spindles), we recorded units and local field potentials (LFPs) simultaneously in the limbic thalamus, mPFC, and CA1 in rats. We report that the cycles of neocortical spindles provide a key temporal window that coordinates CA1 SWRs with sparse but consistent activation of thalamic units. Thalamic units were phase-locked to delta and spindles in mPFC, and fired at consistent lags with other thalamic units within spindles, while CA1 units that were active during spatial exploration were engaged in SWRcoupled spindles after behavior. The sparse thalamic firing could promote an incremental integration of recently acquired memory traces into neocortical schemas through the interleaved activation of thalamocortical cells.

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Section: Sparse Firing Of Thalamic Cells During Spindles and Its Rolementioning

confidence: 99%

mPFC Spindle Cycles Organize Sparse Thalamic Activation and Recently Active CA1 cells During non-REM Sleep

Varela

Wilson

2019

Preprint

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“…Studies involving dexmedetomidine for sleep promotion uniformly demonstrate increased N2, [163][164][165] with inconsistent findings regarding SE and N3/SWS. 163,164,166,167 Furthermore, one study demonstrated presence of sleep spindles in patients receiving dexmedetomidine, arguing for its role in approximating "natural sleep." 165 To our knowledge, no study has demonstrated improvement in REM with dexmedetomidine.…”

Section: Dexmedetomidinementioning

confidence: 99%

Sleep in the Intensive Care Unit: Strategies for Improvement

Dorsch

Martin

Malhotra

et al. 2019

Semin Respir Crit Care Med

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Sleep in the intensive care unit (ICU) is considered to be subjectively poor, highly fragmented, and sometimes referred to as “atypical.” Although sleep is felt to be crucial for patient recovery, little is known about the association of sleep with physiologic function among critically ill patients, or those with clinically important outcomes in the ICU. Research involving ICU-based sleep disturbance is challenging due to the lack of objective, practical, reliable, and scalable methods to measure sleep and the multifactorial etiologies of its disruption. Despite these challenges, research into sleep-promoting techniques is growing and has demonstrated a variety of causes leading to ICU-related sleep loss, thereby motivating multifaceted intervention efforts. Through a focused review of (1) sleep measurement in the ICU; (2) outcomes related to poor sleep in the ICU; and (3) ICU-based sleep promotion efforts including environmental, nonpharmacological, and pharmacological interventions, this paper examines research regarding sleep in the ICU and highlights the need for future investigation into this complex and dynamic field.

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“…On entering NREM sleep, the neocortex of rats and mice cools rapidly (33,34). NREM sleep and low body temperature can also be brought together pharmacologically: a2 adrenergic agonists induce an arousable NREM sleep-like profile 5 (26,(35)(36)(37)(38), which in humans resembles stage 2/3 NREM sleep (39)(40)(41), but with the complication of sustained hypothermia (26,35). The metabotropic a2A receptor mediates both the NREM sleep-like state and the hypothermic effects of dexmedetomidine (42,43).…”

Section: Introductionmentioning

confidence: 99%

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

Ma¹,

Miracca²,

Yu³

et al. 2019

Preprint

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Sleep deprivation induces a characteristic rebound in NREM sleep accompanied by an immediate increase in the power of delta (0.5 -4 Hz) oscillations, proportional to the prior time awake. To test the idea that galanin neurons in the mouse lateral preoptic hypothalamus (LPO) regulate this sleep homeostasis, they were selectively genetically ablated. The baseline sleep architecture of LPO-DGal mice became heavily fragmented, their average core body temperature permanently increased (by about 2°C) and the diurnal variations in body temperature across the sleep-wake cycle also markedly increased. Additionally, LPO-DGal mice showed a striking spike in body temperature and increase in wakefulness at a time (ZT24) when control mice were experiencing the opposite -a decrease in body temperature and becoming maximally sleepy (start of "lights on"). After sleep deprivation sleep homeostasis was largely abolished in LPO-DGal mice: the characteristic increase in the delta power of NREM sleep following sleep deprivation was absent, suggesting that LPO galanin neurons track the time spent awake. Moreover, the amount of recovery sleep was substantially reduced over the following hours. We also found that the a2 adrenergic agonist dexmedetomidine, used for long-term sedation during intensive care, requires LPO galanin neurons to induce both the NREM-like state with increased delta power and the reduction in body temperature, characteristic features of this drug. This suggests that dexmedetomidine over-activates the natural sleep homeostasis pathway via galanin neurons. Collectively, the results emphasize that NREM sleep and the concurrent reduction in body temperature are entwined at the circuit level. 3 Significance Catching up on lost sleep (sleep homeostasis) is a common phenomenon in mammals, but there is no circuit explanation for how this occurs. We have discovered that galanin neurons in the hypothalamus are essential for sleep homeostasis as well as for the control of body temperature. This is the first time that a neuronal cell type has been identified that underlies sleep homeostasis. Moreover, we show that activation of these galanin neurons are also essential for the actions of the a2 adrenergic agonist dexmedetomidine, which induces both hypothermia together with powerful delta oscillations resembling NREM sleep. Thus, sleep homeostasis, temperature control and sedation by a2 adrenergic agonists can all be linked at the circuit level by hypothalamic galanin neurons.

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Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study

Abstract: These results suggest that α2a adrenergic agonists may be developed as a new class of sleep enhancing medications with neurocognitive sparing benefits.

Cited by 96 publications

References 55 publications

mPFC Spindle Cycles Organize Sparse Thalamic Activation and Recently Active CA1 cells During non-REM Sleep

mPFC Spindle Cycles Organize Sparse Thalamic Activation and Recently Active CA1 cells During non-REM Sleep

Sleep in the Intensive Care Unit: Strategies for Improvement

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

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