Athena Stein

BackgroundTranscranial alternating current stimulation (tACS) is a promising non-pharma-cological intervention for major depressive disorder (MDD), but its effects on endogenous alpha oscillatory dynamics and their relationship to clinical improvement remain unclear.MethodsIn this double-blind, sham-controlled randomized clinical trial, 20 adults with MDD received five consecutive days of prefrontal 10 Hz tACS or sham. Resting 128-channel EEG was acquired before stimulation on Day 1 (D1), Day 5 (D5), and two-week follow-up. Changes in alpha power spectral density were quantified at the stimulation frequency (10 Hz) and at each participant’s individual alpha frequency (IAF), using prefrontal regions of interest and whole-head topographical analyses. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS-17).ResultsBetween-group comparisons revealed no significant differences in prefrontal alpha power changes at either 10 Hz or IAF during the intervention week or at follow-up, although right prefrontal 10 Hz power showed a trend-level reduction with tACS. In contrast, within the tACS group, greater reductions in prefrontal IAF power were associated with greater HDRS-17 improvement from D1 to follow-up, and early IAF power suppression during the intervention week predicted later symptom improvement. Whole-head analyses identified a posterior cluster of reduced 10 Hz power at follow-up in the tACS group relative to sham, whereas clinically relevant correlations were specific to IAF power and distributed across frontal-central and parietal electrodes. Depression scores improved over time in both groups, with greater reductions in HDRS-17 scores observed in the tACS group.ConclusionsFindings suggest that five days of 10 Hz tACS engages depression-relevant alpha mechanisms, with symptom improvement linked specifically to modulation of alpha power at IAF. Results support personalization of tACS in future trials.

Background: Transcranial alternating current stimulation (tACS) is a promising non-pharmacological intervention for major depressive disorder (MDD), but its effects on endogenous alpha oscillatory dynamics and their relationship to clinical improvement remain unclear. Methods: In this double-blind, sham-controlled randomized clinical trial, 20 adults with MDD received five consecutive days of prefrontal 10 Hz tACS or sham. Resting 128-channel EEG was acquired before stimulation on Day 1 (D1), Day 5 (D5), and two-week follow-up. Changes in alpha power spectral density were quantified at the stimulation frequency (10 Hz) and at each participant’s individual alpha frequency (IAF), using prefrontal regions of interest and whole-head topographical analyses. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS-17). Results: Between-group comparisons revealed no significant differences in prefrontal alpha power changes at either 10 Hz or IAF during the intervention week or at follow-up, although right prefrontal 10 Hz power showed a trend-level reduction with tACS. In contrast, within the tACS group, greater reductions in prefrontal IAF power were associated with greater HDRS-17 improvement from D1 to follow-up, and early IAF power suppression during the intervention week predicted later symptom improvement. Whole-head analyses identified a posterior cluster of reduced 10 Hz power at follow-up in the tACS group relative to sham, whereas clinically relevant correlations were specific to IAF power and distributed across frontal-central and parietal electrodes. Depression scores improved over time in both groups, with greater reductions in HDRS-17 scores observed in the tACS group. Conclusions: Findings suggest that five days of 10 Hz tACS engages depression-relevant alpha mechanisms, with symptom improvement linked specifically to modulation of alpha power at IAF. Results support personalization of tACS in future trials.

Background: Major depressive disorder (MDD) is characterized by altered frontal alpha oscillations. Transcranial alternating current stimulation (tACS) can normalize aberrant oscillations in MDD, yet the daily dynamics of tACS target engagement of alpha oscillations in depression remain unclear. Methods: In a double-blind randomized controlled trial ( NCT03994081 ), 20 participants with MDD received verum or sham 10 Hz tACS (40 min/day, 5 days) targeted to left and right dorsolateral prefrontal cortex (F3/F4). High-density EEG was collected pre/post-stimulation each day to quantify within-session and cumulative changes in alpha power and functional connectivity (wPLI). Results: Verum stimulation produced late-emerging, session-specific alpha power decreases compared to sham, with robust day (D)4 post-pre reductions at both IAF and 10 Hz across frontal and parietal regions (t=-2.42 to -3.82, p<0.05; parietal t=-3.82, pFDR<0.05). Whole-brain topographical analysis confirmed a distinct condition x D4 effect at left prefrontal cortex (t=2.9, pFWE<0.05, cluster permutation). Connectivity changes emerged earlier and more transiently, with D2 bilateral frontal wPLI reductions (t=-2.53, p<0.05). Cumulative analyses (change from D1) showed significant wPLI decreases on D2 and D3 (t=-2.65 and t=-2.46; p<0.05). Exploratory clinical correlations showed that the D4 IAF power decrease was associated with increased reward sensitivity (spearman rho= -0.6, p<0.05, cluster-corrected). Conclusions: Alpha-tACS produced a temporally distinct neural response: an early, transient decrease in functional connectivity on D2, which may have driven a later suppression of left prefrontal alpha power on D4, correlated with clinical and behavioral improvements. These results delineate target engagement and validation mechanisms in a multi-day tACS trial, supporting optimized dosing in future tACS interventions.

Background/Objectives: Chronic attention problems occur in approximately 25% of children after acquired brain injury (ABI). When delivered daily, transcranial direct current stimulation (tDCS) may improve attention; however, access to daily in-clinic tDCS treatment can be limited by other commitments, including concurrent therapy, school commitments, and caregiver schedules. Treatment access can be improved through home-based interventions, though these require several practical and safety considerations in a pediatric ABI population. This study evaluated the safety, feasibility, and tolerability of remotely monitored at-home tDCS during online gamified attention training in pediatric ABI. Methods: We conducted a randomized, single-blind, dose-controlled clinical trial of at home tDCS in Brisbane, Australia (10 tDCS sessions; 20 min; 1 mA or 2 mA; bilateral dorsolateral prefrontal cortex). Participants attended our clinic at baseline for clinical assessments, fitting of the personalized tDCS headband, and training in how to use tDCS at home. All sessions were remotely supervised using live videoconferencing. We assessed the feasibility and tolerability of at-home tDCS and our customized, personalized at-home tDCS headband as primary outcomes. As secondary outcomes, we evaluated changes in functional connectivity (fc) and reaction time (RT). Results: Seventy-three participants were contacted over six months (January-June 2023) and ten were enrolled (5 males; mean age: 12.10 y [SD: 2.9]), satisfying a priori recruitment timelines (CONSORT reporting). All families successfully set up tDCS and completed attention training with excellent protocol adherence. There were no serious adverse events over the 100 total sessions. Nine participants completed all stimulation sessions (1 mA: n = 5, 2 mA: n = 4). Participants in the 2 mA group reported greater tingling, itching, and discomfort (all p < 0.05). One participant in the 1 mA group was unable to complete all sessions due to tolerability challenges; however, these challenges were resolved in the second half of the intervention by gradually increasing the stimulation duration across the 10 days alongside additional coaching and support. Conclusions: Overall, daily remotely supervised at-home tDCS in patients with pediatric ABI is safe, feasible, and tolerable. Our results support larger, sham-controlled efficacy trials and provide a foundation for the development of safe and effective at-home stimulation therapeutics that may offer targeted improvement of neurocognitive symptoms in children.

Background: Approximately 1 in 4 children who sustain an acquired brain injury (ABI) have attention difficulties impacting education, employment, and community participation. These difficulties arise from dysfunction in attention-related brain networks, incentivising the use of transcranial direct current stimulation (tDCS). Objective/Hypothesis: We investigated whether a single tDCS session improved attention following childhood ABI and whether baseline structural connectivity (sc), functional connectivity (fc), attention, and/or simulated electric fields (E-field) explained variability in response. Methods: In a randomised, single-blind, within-subject, sham-controlled trial, 15 children with ABI (mean 12.7 years) and 15 healthy controls (HCs) received three single tDCS sessions (1mA dorsolateral prefrontal cortex [dlPFC], 1mA inferior frontal gyrus [IFG], sham; 20min) during gamified attention training. We examined post-intervention changes in attention according to flanker and stop signal reaction time (RT). We used multi-modal analyses (high-density electroencephalography [HD-EEG], diffusion tensor imaging, magnetic resonance imaging) to investigate inter-individual variability in tDCS response, according to associations between RT change and baseline fc, sc, attention, and E-fields. Results: Although no effect of active versus sham tDCS was found overall, participants with lower theta or higher gamma default mode network connectivity and poorer attention at baseline showed greater response to tDCS. Higher E-fields were associated with greater response. No serious adverse effects occurred. Conclusions: A s ingle tDCS session targeting dlPFC or IFG did not improve attention following pediatric ABI. We demonstrated how HD-EEG source-based connectivity may be used to personalise tDCS. Future research should explore whether personalization, and/or repeated tDCS sessions can improve attention following pediatric ABI.

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Traumatic brain injury (TBI) and stroke are the most common causes of acquired brain injury (ABI), annually affecting 69 million and 15 million people, respectively. Following ABI, the relationship between brain network disruption and common cognitive issues including attention dysfunction is heterogenous. We systematically reviewed 43 studies which reported correlations between attention and connectivity. Across all ages and stages of recovery, following TBI, greater attention was associated with greater structural efficiency within/between executive network (ECN), salience network (SN) and default mode network (DMN) and greater functional connectivity (fc) within/between ECN and DMN, indicating DMN interference. Following stroke, greater attention was associated with greater structural connectivity (sc) within ECN; or greater fc within the dorsal attention network (DAN). In childhood ABI populations, decreases in structural network segregation were associated with greater attention. Longitudinal recovery from TBI was associated with normalisation of DMN activity, and in stroke, normalisation of DMN and DAN activity. Results improve clinical understanding of attention-related connectivity changes following ABI. Recommendations for future research include increased use of EEG and fNIRS to measure connectivity at the point of care, standardized attention and connectivity outcome measures and analysis pipelines, detailed reporting of patient symptomatology, and casual analysis of attention-related connectivity using brain stimulation.