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Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18–65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4–6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782. Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4–6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103, lower 95% CI −1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. Canadian Institutes of Health Research.

•Neurofeedback (NF) training specifically enhances prefrontal theta oscillations during NF tasks and subsequent emotion regulation tasks.•NF training targeting prefrontal theta oscillations improves emotion regulation, as evidenced by reduced negative emotional ratings and decreased late positive potential amplitudes.•NF-induced enhancements in prefrontal theta power partially mediated the relationship between training efficiency and emotion regulation benefits. Prefrontal theta oscillations play a critical role in cognitive control processes that facilitate emotion regulation. However, causal evidence linking their modulation to improved emotion regulation outcomes remains limited. Using a double-blind, randomized controlled design, this study demonstrates that EEG neurofeedback (NF) targeting prefrontal theta oscillations significantly enhances emotion regulation abilities. Participants in the experimental group exhibited specific upregulation of prefrontal theta power during NF training, leading to reduced negative emotional ratings and diminished late positive potential (LPP) amplitudes. Mediation analysis further revealed that NF-induced enhancements in prefrontal theta power partially mediated the relationship between training efficiency and emotion regulation benefits. These findings underscore the theoretical significance of prefrontal theta oscillations as a core mechanism of cognitive control in emotional contexts. This study advances our understanding of the neural underpinnings of emotion regulation and highlights theta-NF as a promising, non-invasive intervention for enhancing emotional resilience.

Rapid eye movement sleep (REMS) has been linked with spatial and emotional memory consolidation. However, establishing direct causality between neural activity during REMS and memory consolidation has proven difficult because of the transient nature of REMS and significant caveats associated with REMS deprivation techniques. In mice, we optogenetically silenced medial septum γ-aminobutyric acid–releasing (MSGABA) neurons, allowing for temporally precise attenuation of the memory-associated theta rhythm during REMS without disturbing sleeping behavior. REMS-specific optogenetic silencing of MSGABA neurons selectively during a REMS critical window after learning erased subsequent novel object place recognition and impaired fear-conditioned contextual memory. Silencing MSGABA neurons for similar durations outside REMS episodes had no effect on memory. These results demonstrate that MSGABA neuronal activity specifically during REMS is required for normal memory consolidation.

Neurofeedback of self-regulated brain activity in circumscribed cortical regions is used as a novel strategy to facilitate functional restoration following stroke. Basic knowledge about its impact on motor system oscillations and functional connectivity is however scarce. Specifically, a direct comparison between different feedback modalities and their neural signatures is missing. We assessed a neurofeedback training intervention of modulating β-activity in circumscribed sensorimotor regions by kinesthetic motor imagery (MI). Right-handed healthy participants received two different feedback modalities contingent to their MI-associated brain activity in a cross-over design: (I) visual feedback with a brain–computer interface (BCI) and (II) proprioceptive feedback with a brain–robot interface (BRI) orthosis attached to the right hand. High-density electroencephalography was used to examine the reactivity of the cortical motor system during the training session of each task by studying both local oscillatory power entrainment and distributed functional connectivity. Both feedback modalities activated a distributed functional connectivity network of coherent oscillations. A significantly higher skill and lower variability of self-controlled sensorimotor β-band modulation could, however, be achieved in the BRI condition. This gain in controlling regional motor oscillations was accompanied by functional coupling of remote β-band and θ-band activity in bilateral fronto-central regions and left parieto-occipital regions, respectively. The functional coupling of coherent θ-band oscillations correlated moreover with the skill of regional β-modulation thus revealing a motor learning related network. Our findings indicate that proprioceptive feedback is more suitable than visual feedback to entrain the motor network architecture during the interplay between motor imagery and feedback processing thus resulting in better volitional control of regional brain activity. [Display omitted] •Proprioceptive input is superior to visual input to entrain the motor network during neurofeedback.•Proprioceptive feedback increases self-control of regional β-band modulation.•Proprioceptive feedback entrains motor functional connectivity in the θ- and β-band.•Large-scale functional connectivity in θ-band correlates with regional β-band control.

•Longitudinal EEG study in which 4, 7- & 11-month infants listened to nursery rhymes.•We demonstrate cortical speech tracking via delta & theta neural signals (mTRF).•Periodogram (PSD) analysis revealed stimulus related delta and theta PSD peaks.•Delta and theta driven phase amplitude coupling (PAC) was found at all ages.•Gamma frequency amplitudes displayed stronger PAC to low frequency phases than beta. The amplitude envelope of speech carries crucial low-frequency acoustic information that assists linguistic decoding at multiple time scales. Neurophysiological signals are known to track the amplitude envelope of adult-directed speech (ADS), particularly in the theta-band. Acoustic analysis of infant-directed speech (IDS) has revealed significantly greater modulation energy than ADS in an amplitude-modulation (AM) band centred on ∼2 Hz. Accordingly, cortical tracking of IDS by delta-band neural signals may be key to language acquisition. Speech also contains acoustic information within its higher-frequency bands (beta, gamma). Adult EEG and MEG studies reveal an oscillatory hierarchy, whereby low-frequency (delta, theta) neural phase dynamics temporally organize the amplitude of high-frequency signals (phase amplitude coupling, PAC). Whilst consensus is growing around the role of PAC in the matured adult brain, its role in the development of speech processing is unexplored. Here, we examined the presence and maturation of low-frequency (<12 Hz) cortical speech tracking in infants by recording EEG longitudinally from 60 participants when aged 4-, 7- and 11- months as they listened to nursery rhymes. After establishing stimulus-related neural signals in delta and theta, cortical tracking at each age was assessed in the delta, theta and alpha [control] bands using a multivariate temporal response function (mTRF) method. Delta-beta, delta-gamma, theta-beta and theta-gamma phase-amplitude coupling (PAC) was also assessed. Significant delta and theta but not alpha tracking was found. Significant PAC was present at all ages, with both delta and theta -driven coupling observed. [Display omitted]

Background Recurrent observations have indicated the presence of deficits in mismatch negativity (MMN) among schizophrenia. There is evidence suggesting a correlation between increased dopaminergic activity and reduced MMN amplitude, but there is no consensus on whether antipsychotic medications can improve MMN deficit in schizophrenia. Methods We conducted clinical assessments, cognitive function tests, and EEG data collection and analysis on 31 drug-naïve patients with schizophrenia. Comprehensive evaluation tools such as PANSS and MCCB. MMN amplitude was analyzed by event-related potential (ERP) approaches, evoked theta power was analyzed by event-related spectral perturbation (ERSP) approaches. Results Our findings indicate that antipsychotic treatment significantly improved clinical symptoms, as evidenced by reductions in PANSS positive, negative, general symptoms, and total scores (all p  < 0.001). Cognitive function improvements were observed in language learning, working memory, and overall MCCB scores ( p  < 0.05), although other cognitive domains showed no significant changes. However, no significant improvements were noted in MMN amplitude and evoke theta power after four weeks of antipsychotic treatment ( p  > 0.05). Conclusion These results suggest that while antipsychotic medications effectively alleviate clinical symptoms, their impact on MMN amplitude and evoke theta power deficit is limited in the short term. Moreover, the amelioration of cognitive impairment in individuals with schizophrenia is not readily discernible, and it cannot be discounted that the enhancement observed in language acquisition and working memory may be attributed to a learning effect. These findings underscore the complexity of the neurobiological mechanisms involved and highlight the need for further research to optimize individualized treatment strategies for schizophrenia. Trial Registration ChiCTR2000038961, October 10, 2020.

Theta oscillations support memory formation, but their exact contribution to the communication between prefrontal cortex (PFC) and the hippocampus is unknown. We tested the functional relevance of theta oscillations as a communication link between both areas for memory formation using transcranial alternating current stimulation (tACS). Healthy, young participants learned two lists of Dutch-German word pairs and retrieved them immediately and with a 30-min delay. In the encoding group (N = 30), tACS was applied during the encoding of list 1. List 2 was used to test stimulation aftereffects. In the retrieval group (N = 23), we stimulated during the delayed recall. In both groups, we applied tACS bilaterally at prefrontal and tempo-parietal sites, using either individualized theta frequency or 15 Hz (as control), according to a within-subject design. Stimulation with theta-tACS did not alter overall learning performance. An exploratory analysis revealed that immediate recall improved when word-pairs were learned after theta-tACS (list 2). Applying theta-tACS during retrieval had detrimental effects on memory. No changes in the power of the respective frequency bands were observed. Our results do not support the notion that impacting the communication between PFC and the hippocampus during a task by bilateral tACS improves memory. However, we do find evidence that direct stimulation had a trend for negatively interfering effects during immediate and delayed recall. Hints for beneficial effects on memory only occurred with aftereffects of the stimulation. Future studies need to further examine the effects during and after stimulation on memory formation.

The average power of rhythmic neural responses as captured by MEG/EEG/LFP recordings is a prevalent index of human brain function. Increasing evidence questions the utility of trial-/group averaged power estimates however, as seemingly sustained activity patterns may be brought about by time-varying transient signals in each single trial. Hence, it is crucial to accurately describe the duration and power of rhythmic and arrhythmic neural responses on the single trial-level. However, it is less clear how well this can be achieved in empirical MEG/EEG/LFP recordings. Here, we extend an existing rhythm detection algorithm (extended Better OSCillation detection: “eBOSC”; cf. Whitten et al., 2011) to systematically investigate boundary conditions for estimating neural rhythms at the single-trial level. Using simulations as well as resting and task-based EEG recordings from a micro-longitudinal assessment, we show that alpha rhythms can be successfully captured in single trials with high specificity, but that the quality of single-trial estimates varies greatly between subjects. Despite those signal-to-noise-based limitations, we highlight the utility and potential of rhythm detection with multiple proof-of-concept examples, and discuss implications for single-trial analyses of neural rhythms in electrophysiological recordings. Using an applied example of working memory retention, rhythm detection indicated load-related increases in the duration of frontal theta and posterior alpha rhythms, in addition to a frequency decrease of frontal theta rhythms that was observed exclusively through amplification of rhythmic amplitudes. [Display omitted] •Traditional narrow-band rhythm estimates conflate the power and duration of rhythmic and arrhythmic temporal episodes. We extend a state-of-the-art detection method (eBOSC) to disambiguate these episodes at the single-trial level.•eBOSC achieves high specificity in simulated and empirical data, albeit with impaired sensitivity when rhythmicity is low.•eBOSC separates sustained and transient rhythmic episodes from arrhythmic content while amplifying power estimates.•Rhythm-specificity increased sensitivity to working memory load, and indicated a frontal theta frequency shift.

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4–10 Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta’s function. To characterize human hippocampal theta, we examine the properties of theta oscillations throughout the anterior–posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observe hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displays oscillations at ~8-Hz and the precise frequency of these oscillations correlates with the speed of movement, implicating these signals in spatial navigation. We also observe slower ~3 Hz oscillations, but these signals are more prevalent in the anterior hippocampus and their frequency does not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high- and low-frequency theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes. We show that the human hippocampus exhibits two distinct theta oscillations during spatial navigation with the faster oscillation in posterior regions showing movement modulation. This result suggests a distinct feature of the human hippocampus compared to rodents, which generally show a single 8 Hz rhythm.

Self-esteem, crucial for psychological well-being, can be enhanced through targeted interventions like cognitive behavioral therapy (CBT). However, traditional CBT faces various accessibility barriers. Digital health interventions such as computerized CBT and mobile health (mHealth) applications offer potential solutions. Recent research suggests that brain oscillations, particularly theta rhythms, play a key role in memory consolidation. Combining computerized CBT with post-learning theta rhythm modulation may optimize and stabilize improvements in self-esteem and promote neuro-wellbeing. This six-month longitudinal study aimed to evaluate the synergistic effects of a computerized CBT intervention (GGSE) combined with post-training theta rhythm brain modulation on improving self-esteem in young adults with low self-esteem. Participants were randomly allocated to three groups: GGSE + theta audio–visual entrainment (AVE) with Cranio-Electro Stimulation (CES), GGSE + beta AVE + CES (active control), and GGSE only (control). The intervention lasted three weeks. Assessments of self-esteem, maladaptive beliefs, and mood were conducted at baseline, 21 days, 42 days, and six months post-baseline. Although post-treatment oscillatory entrainment did not enhance the long-term efficacy of the intervention, significant treatment effects persisted for six months across all groups. These results support the potential long-term efficacy of brief, game-like, digital CBT approaches for improving self-esteem.