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

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-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

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

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 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. 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: Ten 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 slow wave sleep 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 brain 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. Special Issue:SI</p

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