Network Changes during tACS Induced 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

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

Co-ordination of brain and heart oscillations during non-rapid eye movement sleep

Oscillatory activities of the brain and heart show a strong variation across wakefulness and sleep. Separate lines of research indicate that non‐rapid eye movement (NREM) sleep is characterised by electroencephalographic slow oscillations (SO), sleep spindles, and phase–amplitude coupling of these oscillations (SO–spindle coupling), as well as an increase in high‐frequency heart rate variability (HF‐HRV), reflecting enhanced parasympathetic activity. The present study aimed to investigate further the potential coordination between brain and heart oscillations during NREM sleep. Data were derived from one sleep laboratory night with polysomnographic monitoring in 45 healthy participants (22 male, 23 female; mean age 37 years). The associations between the strength (modulation index [MI]) and phase direction of SO–spindle coupling (circular measure) and HF‐HRV during NREM sleep were investigated using linear modelling. First, a significant SO–spindle coupling (MI) was observed for all participants during NREM sleep, with spindle peaks preferentially occurring during the SO upstate (phase direction). Second, linear model analyses of NREM sleep showed a significant relationship between the MI and HF‐HRV (F = 20.1, r (2) = 0.30, p < 0.001) and a tentative circular‐linear correlation between phase direction and HF‐HRV (F = 3.07, r (2) = 0.12, p = 0.056). We demonstrated a co‐ordination between SO–spindle phase–amplitude coupling and HF‐HRV during NREM sleep, presumably related to parallel central nervous and peripheral vegetative arousal systems regulation. Further investigating the fine‐graded co‐ordination of brain and heart oscillations might improve our understanding of the links between sleep and cardiovascular health

Acoustic stimulation during sleep predicts long-lasting increases in memory performance and beneficial amyloid response in older adults.

BACKGROUND Sleep and neurodegeneration are assumed to be locked in a bi-directional vicious cycle. Improving sleep could break this cycle and help to prevent neurodegeneration. We tested multi-night phase-locked acoustic stimulation (PLAS) during slow wave sleep (SWS) as a non-invasive method to improve SWS, memory performance and plasma amyloid levels. METHODS 32 healthy older adults (agemean: 68.9) completed a between-subject sham-controlled three-night intervention, preceded by a sham-PLAS baseline night. RESULTS PLAS induced increases in sleep-associated spectral-power bands as well as a 24% increase in slow wave-coupled spindles, known to support memory consolidation. There was no significant group-difference in memory performance or amyloid-beta between the intervention and control group. However, the magnitude of PLAS-induced physiological responses were associated with memory performance up to 3 months post intervention and beneficial changes in plasma amyloid. Results were exclusive to the intervention group. DISCUSSION Multi-night PLAS is associated with long-lasting benefits in memory and metabolite clearance in older adults, rendering PLAS a promising tool to build upon and develop long-term protocols for the prevention of cognitive decline

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

The hierarchy of coupled sleep oscillations reverses with aging in humans.

A well-orchestrated coupling hierarchy of slow waves and spindles during slow wave sleep supports memory consolidation. In old age, duration of slow wave sleep and number of coupling events decreases. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample (N=340, 237 female, 103 male) spanning most of the human lifespan (ages 15-83). We find that, instead of changing abruptly, spindles gradually shift from being driven by-, to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow wave frequency, and starts around midlife (∼age 40-48), with an established reversed hierarchy at age 56-83. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using phase slope index (PSI) and number of coupling events, is associated with blood plasma glial fibrillary acidic protein (GFAP) levels, a marker for astrocyte activation. Data-driven models suggest decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a back-shift of the coupling hierarchy (PSI) towards a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration.Significance StatementEvidence accumulates that sleep disturbances and cognitive decline are bi-directionally and causally linked forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human lifespan and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human lifespan

The role of brain oscillations in flexible attentional control

Our capacity to quickly adapt to changing cognitive demands fundamentally relies on the ability of our brain to quickly establish the appropriate communication among brain areas that are relevant for the task at hand. This ability to flexibly reconfigure communication in the brain underlies for instance our capacity to swiftly reorient our attention according to our goals, or to flexibly filter relevant information from ever changing distractors. Oscillatory brain activities have been considered to enable this type of flexible effective communication structure on top of the anatomical communication structure (Fries, 2005). However, amidst accumulating correlational observations supporting the connection between oscillatory neural activity and neuronal communication, there is currently still a lack of direct experimental demonstration that oscillatory activity causally modulates neural transmission. Transcranial alternating current stimulation (tACS) has held great promises in elucidating the causal role of neural oscillations in neuronal communication and in behaviour, in a non-invasive manner. However, we still know little about the actual modulatory mechanism of tACS. The goal of the present thesis was to develop a new method to measure the immediate effect of tACS on local excitability and signalling efficacy across cortical networks, with the purpose of addressing how oscillatory brain activity subserves flexible attentional control by modulating neuronal communication. To this end, the thesis comprises of the following three publications. In the first publication, we establish our experimental protocol and technical advices for simultaneous electroencephalography (EEG) recording during tACS. Concurrent EEG-tACS can offer a means to address the immediate neurophysiological effect of tACS, however the approach comes with several challenges. We show how, when improperly carried out, the artifacts introduced by tACS into the EEG data renders the data unrecoverable through any artifact removal approach. In the second publication, we establish a new method using concurrent tACS, transcranial magnetic stimulation (TMS) and EEG to address the causal role of neural oscillations in modulating transmission efficacy in cortical networks. The rationale of the concurrent tACSTMS-EEG method is that while introducing oscillatory activity with tACS, we can measure neural transmission as TMS-induced neural activity with EEG. Through tACS, we introduced theta oscillatory activity in the dorsolateral prefrontal cortex (DLPFC). For assessing resultant changes in the efficacy of neural transmission, we simultaneously apply subthreshold singlepulse TMS over the DLPFC at four different phases of tACS (90°, 180°, 270°, 360°) and measure the spread of TMS-evoked EEG potentials (TEPs). The amount of current spread is modulated by the functional status of the neural network, thereby providing a measure of changes in signalling efficacy. We demonstrate that we can successfully remove tACS artifacts from TMS-EEG data, and find that the amplitude of TEPs depends on the phase of the introduced 6 Hz activity during tACS. In the third publication, we address the causal role of inter-regional oscillatory phaserelations in modulating cortico-cortical signalling efficacy. For this purpose, we again employ our concurrent tACS-TMS-EEG method. Through tACS we introduce theta oscillatory activity in the DLPFC and the posterior parietal cortex (PPC); two nodes of the frontoparietal network. We apply 6 Hz tACS to the DLPFC and PPC simultaneously in an in-phase or anti-phase manner. We demonstrate that the tACS-induced theta oscillations modulate TEPs in a phase-dependent manner during in-phase and anti-phase tACS, and that the induced phase-relation across the human frontoparietal network affects the propagation of signal through as well as beyond the frontoparietal network, from the PPC to area V5. Our results therefore suggest that inter-nodal phase-relations of oscillatory neural activity impact neural transmission beyond the synchronizing network nodes. Our results lend support for the causal role of phase-synchronized endogenous oscillatory activity in modulating inter-regional neuronal communication. To sum up, the studies conducted as part of this thesis focus on addressing the causal role of neuronal oscillations in modulation brain network communication. The methodological groundwork carried out as part of this thesis will enable us to proceed to address how informational routing through dynamically established oscillatory coherence serves to enable flexible attentional control. The concurrent tACS-TMS-EEG also hold great promise in shedding new light on sources of variability in efficacy of tACS and could help pave the way for new clinical treatment avenues for disorders of attentional control

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