Elsevier

Sleep Medicine Reviews

Volume 61, February 2022, 101583
Sleep Medicine Reviews

Clinical Review
Sleep and anxiety: From mechanisms to interventions

https://doi.org/10.1016/j.smrv.2021.101583Get rights and content

Summary

Anxiety is the most common mental health problem worldwide. Epidemiological studies show that sleep disturbances, particularly insomnia, affect ∼50% of individuals with anxiety, and that insufficient sleep can instigate or further exacerbate it. This review outlines brain mechanisms underlying sleep and anxiety, by addressing recent human functional/structural imaging studies on brain networks underlying the anxiogenic impact of sleep loss, and the beneficial effect of sleep on these brain networks. We discuss recent developments from human molecular imaging studies that highlight the role of specific brain neurotransmitter mechanisms, such as the adenosinergic receptor system, on anxiety, arousal, and sleep. This review further discusses frontline sleep interventions aimed at enhancing sleep in individuals experiencing anxiety, such as nonbenzodiazepines/antidepressants, lifestyle and sleep interventions and cognitive behavioral therapy for insomnia. Notwithstanding therapeutic success, up to ∼30% of individuals with anxiety can be nonresponsive to frontline treatments. Thus, we address novel non-invasive brain stimulation techniques that can enhance electroencephalographic slow waves, and might help alleviate sleep and anxiety symptoms. Collectively, these findings contribute to an emerging biological framework that elucidates the interrelationship between sleep and anxiety, and highlight the prospect of slow wave sleep as a potential therapeutic target for reducing anxiety.

Introduction

Anxiety is the most common mental health disorder worldwide with a global prevalence of ∼25% [1], and is characterized by inflated and persistent feelings of fear and worry that are out of proportion to the actual threat, with impaired daily functioning [2,3]. Common anxiety disorders include generalized anxiety disorder (GAD), panic disorder (PD), specific phobias, agoraphobia, social anxiety disorder (SAD), and separation anxiety disorder [2]. Furthermore, anxiety-related disorders formerly classified anxiety disorders and no longer listed as such according to the Diagnostic and Statistical Manual (DSM-5) [2] include post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), adjustment disorder and selective mutism (more common in children) (see Table 1 for a list of anxiety/anxiety-related disorders and their main symptoms).

Individuals with anxiety/anxiety-related disorders often experience poor sleep quality, and exhibit sleep disturbances, particularly insomnia [4]. Conversely, insufficient sleep can instigate or further exacerbate anxiety [5]. Neuroimaging studies using functional magnetic resonance imaging (fMRI) indicate that total sleep loss amplifies activity within the “fear network”, which includes the limbic system [[6], [7], [8]] and the salience network involved in cognitive control (dorsal anterior cingulate cortex and anterior insula) [9]. Furthermore, the anxiogenic impact of total sleep loss relates to impaired medial prefrontal cortex activity and associated connectivity with extended limbic regions [10]. Growing molecular imaging evidence posits that specific neurotransmitter mechanisms underlying sleep-wake regulation, like the adenosinergic system, are involved in anxiety [∗[11], [12], ∗[13], [14]]. Together, these findings suggest a key contribution of sleep-arousal systems in anxiety/anxiety-related disorders (see Fig. 1 for a schematic). Current frontline treatments for anxiety/anxiety-related disorders oftentimes target sleep disturbances, particularly insomnia, by using single or combined strategies as nonbenzodiazepines and/or antidepressants [15], lifestyle interventions [16] and cognitive behavioral therapy for insomnia (CBT-I) [17,18]. Despite therapeutic success, up to a third of individuals experiencing e.g., anxiety-related disorders (OCD, PTSD) do not sufficiently respond to frontline treatments [19,20]. A promising target for improving anxiety symptoms are slow wave sleep (SWS) and slow wave activity (SWA; EEG power density in the frequency range of ∼0.5–4 Hz), which are the primary markers of sleep homeostasis. FMRI findings indicate that slow wave oscillations offer an ameliorating, anxiolytic benefit on brain networks (e.g., limbic system) following sleep [10]. Hence, there is strong interest for novel non-invasive brain stimulation (NIBS) techniques that can induce SWS/SWA [[21], ∗[22], [23]]. As individuals with anxiety/anxiety-related disorders may exhibit less SWS [24], these alternative approaches may translate to new evidence-based treatment strategies that have the potential to alleviate sleep and anxiety symptoms.

The goal of our narrative review is to address and foster an important debate on the interrelationship between sleep and anxiety, provide a comprehensive overview of recently identified brain and cortical receptor mechanisms implicated in this two-way crossroad, and address novel evidence-based sleep interventions to enhance sleep quality, thereby improving anxiety in individuals who experience this common ailment.

Section snippets

Epidemiology of sleep and anxiety

Epidemiological studies show a high prevalence of sleep complaints in individuals with anxiety in the general population [[25], [26], [27], [28]]. Sleep disturbances include a myriad of presentations, such as poor sleep quality, insufficient quantity and sleep structure alterations, which may vary across anxiety/anxiety-related disorders [24,29]. Large effects occurred for disrupted subjective sleep quality (GAD and PTSD) and reduced total sleep time (TST) (OCD), as compared to healthy

Neuroimaging of the sleep and anxiety link

Sleep disruption has been shown to worsen mood vulnerability [53,55] and to exacerbate anxiety-related symptoms [5]. While the exact mechanisms for the sleep and anxiety link are unclear, emerging evidence suggests an overlap of brain networks underlying sleep and emotional regulation. FMRI studies on individuals experiencing anxiety show increased activation of the amygdala and insula, both of which implicated in aversive stimuli responses and emotional regulation [56,57]. Furthermore, the

Neuromolecular mechanisms of sleep and anxiety

A plethora of neurotransmitter and neuromodulator systems orchestrates sleep and emotional regulation, including norepinephrine, acetylcholine, GABA, dopamine, glutamate, serotonin and adenosine, as established in animal models and/or pharmacological work. Emerging positron emission tomography (PET) studies in healthy humans or in individuals with anxiety indicate a neuromodulatory landscape that is involved in sleep as well as in the expression of anxiety symptoms.

Pharmacological interventions

Insomnia is highly prevalent in individuals experiencing anxiety [27,31,36,38]. Here we focus on pharmacological interventions for which there is evidence that they affect both sleep and anxiety.

Current nonpharmacological interventions

Common nonpharmacological interventions to improve sleep and anxiety symptoms include lifestyle interventions, manipulation of sleep and CBT-I.

Novel non-invasive strategies targeting sleep to improve anxiety

It has been established that sleep, and EEG slow waves in particular, can be modulated through non-invasive brain stimulation (NIBS) [150], including transcranial magnetic stimulation (TMS) [22], transcranial direct current stimulation (tDCS) [21] and auditory stimulation [23,151] (see Fig. 4 for current interventions and future prospects for sleep and anxiety treatment).

Conclusions

Sleep disruption is a core feature of anxiety/anxiety-related disorders, and anxiety often worsens sleep quality, which speaks to a spurring of a negative cycle involving poor sleep and anxiety. Examination of underlying factors supporting the link between sleep and anxiety suggests a shared and perhaps mutually reinforcing neurocircuitry of sleep disruption and anxiety. Molecular imaging studies confirm such shared neurocircuitry and suggest a complex web of receptor systems, including

Author contributions

S.L.C. prepared figures. S.L.C. and D.A. wrote the paper.

Practice points

  • 1.

    Individuals with sleep disturbances should be examined for anxiety, and those experiencing anxiety should be assessed for sleep disturbances;

  • 2.

    Targeting concomitant sleep disturbances can aid the therapeutic management of anxiety;

  • 3.

    Combined therapeutic strategies including cognitive behavioral therapy for insomnia, pharmacotherapy and non-invasive brain stimulation may augment overall treatment of anxiety.

Research agenda

  • 1.

Conflicts of interest

The authors do not have any conflicts of interest to disclose.

Acknowledgements

S.L.C. was supported by the Alexander von Humboldt Foundation. The funders had no role in the decision to publish or preparation of the manuscript.

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