Acceptance and Commitment Therapy, Combined with Bedtime Restriction, versus Cognitive Behavioral Therapy for Insomnia: A Randomized Controlled Pilot Trial.

INTRODUCTION: Cognitive behavioral therapy for insomnia (CBT-I) is the current first-line treatment for insomnia. However, rates of nonresponse and nonremission are high and effects on quality of life are only small to moderate, indicating a need for novel treatment developments. We propose that Acceptance and Commitment Therapy (ACT) addresses core pathophysiological pathways of insomnia. ACT therefore has the potential to improve treatment efficacy when combined with bedtime restriction, the most effective component of CBT-I. The aim of this study was to compare the efficacy of ACT for insomnia combined with bedtime restriction (ACT-I) and CBT-I in improving insomnia severity and sleep-related quality of life. METHODS: Sixty-three patients with insomnia disorder (mean age 52 years, 65% female, 35% male) were randomly assigned to receive either ACT-I or CBT-I in a group format. The primary outcomes were insomnia severity (Insomnia Severity Index) and sleep-related quality of life (Glasgow Sleep Impact Index). Outcomes were assessed before randomization (T0), directly after treatment (T1), and at 6-month follow-up (T2). RESULTS: The results indicated significant, large pre-to-post improvements in both groups, for both primary and secondary outcomes. Improvements were maintained at the 6-month follow-up. However, there was no significant group by time interactions in linear mixed models, indicating an absence of differential efficacy. On a subjective treatment satisfaction scale, patients in the ACT-I group indicated significantly greater satisfaction with their improvement of several aspects of health including their energy level and work productivity. CONCLUSIONS: The results suggest that ACT-I is feasible and effective, but not more effective than CBT-I for the improvement of insomnia severity and sleep-related quality of life. Future studies are needed to assess whether ACT-I is noninferior to CBT-I and to shed light on mechanisms of change in both treatments.

Brain stimulation techniques as novel treatment options for insomnia: A systematic review.

Despite the success of cognitive behavioural therapy for insomnia and recent advances in pharmacotherapy, many patients with insomnia do not sufficiently respond to available treatments. This systematic review aims to present the state of science regarding the use of brain stimulation approaches in treating insomnia. To this end, we searched MEDLINE, Embase and PsycINFO from inception to 24 March 2023. We evaluated studies that compared conditions of active stimulation with a control condition or group. Outcome measures included standardized insomnia questionnaires and/or polysomnography in adults with a clinical diagnosis of insomnia. Our search identified 17 controlled trials that met inclusion criteria, and assessed a total of 967 participants using repetitive transcranial magnetic stimulation, transcranial electric stimulation, transcutaneous auricular vagus nerve stimulation or forehead cooling. No trials using other techniques such as deep brain stimulation, vestibular stimulation or auditory stimulation met the inclusion criteria. While several studies report improvements of subjective and objective sleep parameters for different repetitive transcranial magnetic stimulation and transcranial electric stimulation protocols, important methodological limitations and risk of bias limit their interpretability. A forehead cooling study found no significant group differences in the primary endpoints, but better sleep initiation in the active condition. Two transcutaneous auricular vagus nerve stimulation trials found no superiority of active stimulation for most outcome measures. Although modulating sleep through brain stimulation appears feasible, gaps in the prevailing models of sleep physiology and insomnia pathophysiology remain to be filled. Optimized stimulation protocols and proof of superiority over reliable sham conditions are indispensable before brain stimulation becomes a viable treatment option for insomnia.

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice.

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here, we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21, or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.

Scientists have developed ways to remotely turn on and off populations of neurons in the brain to test the role they play in behaviour. One technique that is frequently used is chemogenetics. In this approach, specific neurons are genetically modified to contain a special 'designer receptor' which switches cells on or off when its corresponding 'designer drug' is present. Recent studies have shown that the drug most commonly used in these experiments, clozapine-N-oxide (CNO), is broken down into small amounts of clozapine, an antipsychotic drug that binds to many natural receptors in the brain and modulates sleep. Nevertheless, CNO is still widely believed to not affect animals' sleep-wake patterns which in turn could influence a range of other brain activities and behaviours. However, there have been reports of animals lacking designer receptors still displaying unusual behaviours when administered CNO. This suggests that the breakdown of CNO to clozapine may cause off-target effects which could be skewing the results of chemogenetic studies. To investigate this possibility, Traut, Mengual et al. treated laboratory mice that do not have a designer receptor with three doses of CNO, and one dose of a new designer drug called compound-21 (C21) that is not broken down to clozapine. They found that high and medium doses of CNO, but also C21 altered the sleep-wake patterns of the mice and their brain activity during sleep. These findings show that CNO and C21 both have sleep-modulating effects on the brain and suggest that these effects are not only due to the production of clozapine, but the drugs binding to off-target natural receptors. To counteract this, Traut, Mengual et al. recommend optimizing the dose of drugs given to mice, and repeating the experiment on a control group which do not have the designer receptor. This will allow researchers to determine which behavioural changes are the result of turning on or off the neuron population of interest, and which are artefacts caused by the drug itself. They also suggest testing how newly developed designer drugs impact sleep before using them in behavioural experiments. Refining chemogenetic studies in these ways may yield more reliable insights about the role specific groups of cells have in the brain.

Feasibility, efficacy, and functional relevance of automated auditory closed-loop suppression of slow-wave sleep in humans.

Slow-wave sleep (SWS) is a fundamental physiological process, and its modulation is of interest for basic science and clinical applications. However, automatised protocols for the suppression of SWS are lacking. We describe the development of a novel protocol for the automated detection (based on the whole head topography of frontal slow waves) and suppression of SWS (through closed-loop modulated randomised pulsed noise), and assessed the feasibility, efficacy and functional relevance compared to sham stimulation in 15 healthy young adults in a repeated-measure sleep laboratory study. Auditory compared to sham stimulation resulted in a highly significant reduction of SWS by 30% without affecting total sleep time. The reduction of SWS was associated with an increase in lighter non-rapid eye movement sleep and a shift of slow-wave activity towards the end of the night, indicative of a homeostatic response and functional relevance. Still, cumulative slow-wave activity across the night was significantly reduced by 23%. Undisturbed sleep led to an evening to morning reduction of wake electroencephalographic theta activity, thought to reflect synaptic downscaling during SWS, while suppression of SWS inhibited this dissipation. We provide evidence for the feasibility, efficacy, and functional relevance of a novel fully automated protocol for SWS suppression based on auditory closed-loop stimulation. Future work is needed to further test for functional relevance and potential clinical applications.

Cognitive behavioral therapy for insomnia in patients with mental disorders and comorbid insomnia: A systematic review and meta-analysis.

Almost 70% of patients with mental disorders report sleep difficulties and 30% fulfill the criteria for insomnia disorder. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia according to current treatment guidelines. Despite this circumstance, insomnia is frequently treated only pharmacologically especially in patients with mental disorders. The aim of the present meta-analysis was to quantify the effects of CBT-I in patients with mental disorders and comorbid insomnia on two outcome parameters: the severity of insomnia and mental health. The databases PubMed, CINHAL (Ebsco) und PsycINFO (Ovid) were searched for randomized controlled trials on adult patients with comorbid insomnia and any mental disorder comparing CBT-I to placebo, waitlist or treatment as usual using self-rating questionnaires as outcomes for either insomnia or mental health or both. The search resulted in 1994 records after duplicate removal of which 22 fulfilled the inclusion criteria and were included for the meta-analysis. The comorbidities were depression (eight studies, 491 patients), post-traumatic stress disorder (PTSD, four studies, 216 patients), alcohol dependency (three studies, 79 patients), bipolar disorder (one study, 58 patients), psychosis (one study, 50 patients) and mixed comorbidities within one study (five studies, 189 patients). The effect sizes for the reduction of insomnia severity post treatment were 0.5 (confidence interval, CI, 0.3-0.8) for patients with depression, 1.5 (CI 1.0-1.9) for patients with PTSD, 1.4 (CI 0.9-1.9) for patients with alcohol dependency, 1.2 (CI 0.8-1.7) for patients with psychosis/bipolar disorder, and 0.8 (CI 0.1-1.6) for patients with mixed comorbidities. Effect sizes for the reduction of insomnia severity were moderate to large at follow-up. Regarding the effects on comorbid symptom severity, effect sizes directly after treatment were 0.5 (CI 0.1-0.8) for depression, 1.3 (CI 0.6-1.9) for PTSD, 0.9 (CI 0.3-1.4) for alcohol dependency in only one study, 0.3 (CI -0.1 - 0.7, insignificant) for psychosis/bipolar, and 0.8 (CI 0.1-1.5) for mixed comorbidities. There were no significant effects on comorbid symptoms at follow-up. Together, these significant, stable medium to large effects indicate that CBT-I is an effective treatment for patients with insomnia and a comorbid mental disorder, especially depression, PTSD and alcohol dependency. CBT-I is also an effective add-on treatment with the aim of improving mental health in patients with depression, PTSD, and symptom severity in outpatients with mixed diagnoses. Thus, in patients with mental disorders and comorbid insomnia, given the many side effects of medication, CBT-I should be considered as a first-line treatment.

Phase-Synchronized Transcranial Alternating Current Stimulation-Induced Neural Oscillations Modulate Cortico-Cortical Signaling Efficacy.

Introduction: Synchronized oscillatory brain activity is considered a basis for flexible neuronal network communication. However, the causal role of inter-regional oscillatory phase relations in modulating signaling efficacy in cortical networks has not been directly demonstrated in humans so far. Aim: The current study addresses the causal role of transcranial alternating current stimulation (tACS)-induced oscillatory cross-network phase relations in modulating signaling efficacy across human cortical networks. Methods: To this end, concurrent tACS, transcranial magnetic stimulation (TMS), and electroencephalography (EEG) were employed to measure the modulation of excitability and signaling efficacy across cortical networks during externally induced neural oscillations. Theta oscillatory activity was introduced through tACS in two nodes of the human frontoparietal network: the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC). Six Hertz tACS was applied to the DLPFC and PPC simultaneously in an in-phase or antiphase manner. In addition, single-pulse TMS was administered over the DLPFC at four different phases of tACS and the propagation of TMS-evoked neuronal activity was measured with EEG. Results: We show that tACS-induced theta oscillations modulate TMS-evoked potentials (TEPs) in a phase-dependent manner, and that the induced oscillatory phase relation across the frontoparietal network affects the propagation of phase-dependent TEPs within as well as beyond the frontoparietal network. Conclusion: We show that the effect of tACS-induced phase relation across the frontoparietal network on signal transmission extends beyond the frontoparietal network. The results support a causal role of inter-nodal oscillatory phase synchrony in routing cortico-cortical information flow. Impact statement Theoretical models have proposed that phase relations of cross-network neural oscillations control communication efficacy across human cortical networks. The current study introduced concurrent transcranial alternating current stimulation-transcranial magnetic stimulation-electroencephalography (tACS-TMS-EEG) to experimentally study the theoretical framework. Dual-site in-phase or antiphase 6 Hz tACS was applied to the frontoparietal network. Synchronized tACS was shown to affect signaling within as well as beyond the targeted network. The study demonstrates how inter-regional oscillatory coherence supports the control of brain network signaling.

Shaping the slow waves of sleep: A systematic and integrative review of sleep slow wave modulation in humans using non-invasive brain stimulation.

The experimental study of electroencephalographic slow wave sleep (SWS) stretches over more than half a century and has corroborated its importance for basic physiological processes, such as brain plasticity, metabolism and immune system functioning. Alterations of SWS in aging or pathological conditions suggest that modulating SWS might constitute a window for clinically relevant interventions. This work provides a systematic and integrative review of SWS modulation through non-invasive brain stimulation in humans. A literature search using PubMed, conducted in May 2020, identified 3220 studies, of which 82 fulfilled inclusion criteria. Three approaches have been adopted to modulate the macro- and microstructure of SWS, namely auditory, transcranial electrical and transcranial magnetic stimulation. Our current knowledge about the modulatory mechanisms, the space of stimulation parameters and the physiological and behavioral effects are reported and evaluated. The integration of findings suggests that sleep slow wave modulation bears the potential to promote our understanding of the functions of SWS and to develop new treatments for conditions of disrupted SWS.

Modulating overnight memory consolidation by acoustic stimulation during slow-wave sleep: a systematic review and meta-analysis.

STUDY OBJECTIVES: The low-frequency high-amplitude oscillations of slow-wave sleep (SWS) are considered to promote the consolidation of episodic memory. Previous research suggests that sleep slow waves can be entrained and enhanced by presenting short acoustic stimuli to the up-states of endogenous waves. Several studies have investigated the effects of these increases in slow-wave activity on overnight memory consolidation, with inconsistent results. The aim of this meta-analysis was to evaluate the accumulated evidence connecting acoustic stimulation during sleep to episodic memory consolidation. METHODS: A systematic literature search was conducted in October 2020 using PubMed, Web of Science, and PsycInfo. The main study inclusion criteria were the application of acoustic slow wave enhancement in healthy participants and an assessment of pre- and post-sleep episodic memory performance. Effect sizes were pooled using a random-effects model. RESULTS: A total of 10 primary studies with 11 experiments and 177 participants were included. Results showed a combined effect size (Hedges' g) of 0.25 (p = 0.07). Subgroup models based on young adults (n = 8), phase-locked stimulation approaches (n = 8), and their combination (n = 6) showed combined effect sizes of 0.31 (p = 0.051), 0.36 (p = 0.047), and 0.44 (p = 0.01), respectively. There was no indication of publication bias or bias in individual studies. CONCLUSIONS: Acoustic enhancement of SWS tends to increase the overnight consolidation of episodic memory but effects remain small and-with the exception of subgroup models-at trend levels. Currently, the evidence is not sufficient to recommend the use of commercially available devices.

Stimulating aged brains with transcranial direct current stimulation: Opportunities and challenges.

Ageing involves significant neurophysiological changes that are both systematic while at the same time exhibiting divergent trajectories across individuals. These changes underlie cognitive impairments in elderly while also affecting the response of aged brains to interventions like transcranial direct current stimulation (tDCS). While the cognitive benefits of tDCS are more variable in elderly, older adults also respond differently to stimulation protocols compared to young adults. The age-related neurophysiological changes influencing the responsiveness to tDCS remain to be addressed in-depth. We review and discuss the premise that, in comparison to the better calibrated brain networks present in young adults, aged systems perform further away from a homoeostatic set-point. We argue that this age-related neurophysiological deviation from the homoeostatic optimum extends the leeway for tDCS to modulate the aged brain. This promotes the potency of immediate tDCS effects to induce directional plastic changes towards the homoeostatic equilibrium despite the impaired plasticity induction in elderly. We also consider how age-related neurophysiological changes pose specific challenges for tDCS that necessitate proper adaptations of stimulation protocols. Appreciating the distinctive properties of aged brains and the accompanying adjustment of stimulation parameters can increase the potency and reliability of tDCS as a treatment avenue in older adults.

Phase-Dependent Modulation of Signal Transmission in Cortical Networks through tACS-Induced Neural Oscillations.

Oscillatory neural activity is considered a basis of signal transmission in brain networks. However, the causal role of neural oscillations in regulating cortico-cortical signal transmission has so far not been directly demonstrated. To date, due to methodological limitations, studies on the online modulatory mechanisms of transcranial alternating current stimulation (tACS)-induced neural oscillations are confined to the primary motor cortex. To address the causal role of oscillatory activity in modulating cortico-cortical signal transmission, we have established a new method using concurrent tACS, transcranial magnetic stimulation (TMS) and electroencephalography (EEG). Through tACS, we introduced 6-Hz (theta) oscillatory activity in the human dorsolateral prefrontal cortex (DLPFC). During tACS, we applied single-pulse TMS over the DLPFC at different phases of tACS and assessed propagation of TMS-induced neural activity with EEG. We show that tACS-induced theta oscillations modulate the propagation of TMS-induced activity in a phase-dependent manner and that phase-dependent modulation is not simply explained by the instantaneous amplitude of tACS. The results demonstrate a phase-dependent modulatory mechanism of tACS at a cortical network level, which is consistent with a causal role of neural oscillations in regulating the efficacy of signal transmission in the brain.

Concurrent Electroencephalography Recording During Transcranial Alternating Current Stimulation (tACS).

Oscillatory brain activities are considered to reflect the basis of rhythmic changes in transmission efficacy across brain networks and are assumed to integrate cognitive neural processes. Transcranial alternating current stimulation (tACS) holds the promise to elucidate the causal link between specific frequencies of oscillatory brain activity and cognitive processes. Simultaneous electroencephalography (EEG) recording during tACS would offer an opportunity to directly explore immediate neurophysiological effects of tACS. However, it is not trivial to measure EEG signals during tACS, as tACS creates a huge artifact in EEG data. Here we explain how to set up concurrent tACS-EEG experiments. Two necessary considerations for successful EEG recording while applying tACS are highlighted. First, bridging of the tACS and EEG electrodes via leaking EEG gel immediately saturates the EEG amplifier. To avoid bridging via gel, the viscosity of the EEG gel is the most important parameter. The EEG gel must be viscous to avoid bridging, but at the same time sufficiently fluid to create contact between the tACS electrode and the scalp. Second, due to the large amplitude of the tACS artifact, it is important to consider using an EEG system with a high resolution analog-to-digital (A/D) converter. In particular, the magnitude of the tACS artifact can exceed 100 mV at the vicinity of a stimulation electrode when 1 mA tACS is applied. The resolution of the A/D converter is of importance to measure good quality EEG data from the vicinity of the stimulation site. By following these guidelines for the procedures and technical considerations, successful concurrent EEG recording during tACS will be realized.