Stress priming transcranial direct current stimulation (tDCS) enhances updating of emotional content in working memory.

Transcranial direct current stimulation (tDCS) targeting the prefrontal cortex has emerged as a valuable tool in psychiatric research. Understanding the impact of affective states, such as stress at the time of stimulation, on the efficacy of prefrontal tDCS is crucial for advancing tDCS interventions. Stress-primed tDCS, wherein stress is used as a priming agent, has the potential to modulate neural plasticity and enhance cognitive functions, particularly in emotional working memory. However, prior research using stress-primed tDCS focused solely on non-emotional working memory performance, yielding mixed results. In this sham-controlled study, we addressed this gap by investigating the effects of stress-primed bifrontal tDCS (active versus sham) on both non-emotional and emotional working memory performance. The study was conducted in 146 healthy individuals who were randomly assigned to four experimental groups. The Trier Social Stress Test (TSST) or a control variant of the test was used to induce a stress versus control state. The results showed that stress priming significantly enhanced the effects of tDCS on the updating of emotional content in working memory, as evidenced by improved accuracy. Notably, no significant effects of stress priming were found for non-emotional working memory performance. These findings highlight the importance of an individual's prior affective state in shaping their response to tDCS, especially in the context of emotional working memory.

Dose-dependent response of prefrontal transcranial direct current stimulation on the heart rate variability: An electric field modeling study.

Transcranial direct current stimulation (tDCS) of the prefrontal cortex (PFC) modulates the autonomic nervous system by activating deeper brain areas via top-down pathway. However, effects on the nervous system are heterogeneous and may depend on the amount of current that penetrates. Therefore, we aimed to investigate the variable effects of tDCS on heart rate variability (HRV), a measure of the functional state of the autonomic nervous system. Using three prefrontal tDCS protocols (1.5, 3 mA and sham), we associated the simulated individual electric field (E-field) magnitude in brain regions of interest with the HRV effects. This was a randomized, double-blinded, sham-controlled and within-subject trial, in which healthy young-adult participants received tDCS sessions separated by 2 weeks. The brain regions of interest were the dorsolateral PFC (DLPFC), anterior cingulate cortex, insula and amygdala. Overall, 37 participants were investigated, corresponding to a total of 111 tDCS sessions. The findings suggested that HRV, measured by root mean squared of successive differences (RMSSD) and high-frequency HRV (HF-HRV), were significantly increased by the 3.0 mA tDCS when compared to sham and 1.5 mA. No difference was found between sham and 1.5 mA. E-field analysis showed that all brain regions of interest were associated with the HRV outcomes. However, this significance was associated with the protocol intensity, rather than inter-individual brain structural variability. To conclude, our results suggest a dose-dependent effect of tDCS for HRV. Therefore, further research is warranted to investigate the optimal current dose to modulate HRV.

Trait-dependent effects of theta burst stimulation after psychosocial stress: a sham-controlled study in healthy individuals.

OBJECTIVE: Previous studies suggest that theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS), applied to the left dorsolateral prefrontal cortex (DLPFC) might be a promising approach to modulate stress-reactive rumination and the associated psychophysiological stress response. Crucially, individuals showing higher levels of trait rumination might benefit more from prefrontal stimulation. METHODS: In this sham-controlled study, 127 healthy individuals, with varying ruminative tendencies, received a single-session of intermittent TBS (iTBS), continuous TBS (cTBS) or sham TBS (sTBS) over the left DLPFC before being confronted with a Trier Social Stress Test. RESULTS: Results showed significant TBS effects on salivary cortisol as a function of trait rumination. cTBS, as compared to sTBS and iTBS, resulted in an attenuated stress-induced cortisol response in high compared to low trait ruminators. Although independent of trait rumination levels, cTBS showed positive effects on stress-related changes in mood and, both cTBS and iTBS (versus sham) presented an enhanced heart rate recovery following the stressor. We found no evidence for (trait rumination-dependent) TBS effects on stress-reactive rumination, negative affect, subjective stress or heart rate variability. CONCLUSIONS: cTBS shows beneficial effects on certain measures of stress, especially in high trait ruminators. SIGNIFICANCE: These findings highlight the importance of accounting for individual differences when examining TBS effects.

Vagally-mediated HRV as a marker of trait rumination in healthy individuals? A large cross-sectional analysis.

The tendency to ruminate (i.e., repetitive, self-referential, negative thoughts) is a maladaptive form of emotional regulation and represents a transdiagnostic vulnerability factor for stress-related psychopathology. Vagally-mediated heart rate variability (vmHRV) provides a non-invasive, surrogate measure of vagal modulation of the heart, and higher HRV is considered an indicator of susceptibility, or ability to respond to stress. Past research has suggested a link between trait rumination and vmHRV; however, inconsistent results exist in healthy individuals. In this study, we investigated the association between the tendency to ruminate, brooding, and reflection (using the Ruminative Response Scale) with vmHRV measured at baseline in a healthy population using a large cross-sectional dataset (N = 1189, 88% female; mean age = 21.55, ranging from 17 to 48 years old), which was obtained by combining samples of healthy individuals from different studies from our laboratory. The results showed no cross-sectional correlation between vmHRV and trait rumination (confirmed by Bayesian analysis), even after controlling for important confounders such as gender, age, and depressive symptoms. Also, a non-linear relationship was rejected. In summary, based on our results in a large sample of healthy individuals, vmHRV is not a marker of trait rumination (as measured by the Ruminative Response Scale).

Investigating the variability of prefrontal tDCS effects on working memory: An individual E-field distribution study.

Transcranial direct current stimulation (tDCS) over the prefrontal cortex has the potential to enhance working memory by means of a weak direct current applied to the scalp. However, its effects are highly variable and possibly dependent on individual variability in cortical architecture and head anatomy. Unveiling sources of heterogeneity might improve fundamental and clinical application of tDCS in the field. Therefore, we investigated sources of tDCS variability of prefrontal 1.5 mA tDCS, 3 mA tDCS and sham tDCS in 40 participants (67.5% women, mean age 24.7 years) by associating simulated electric field (E-field) magnitude in brain regions of interest (dorsolateral prefrontal cortex, anterior cingulate cortex (ACC) and subgenual ACC) and working memory performance. Emotional and non-emotional 3-back paradigms were used. In the tDCS protocol analysis, effects were only significant for the 3 mA group, and only for the emotional tasks. In the individual E-field magnitude analysis, faster responses in non-emotional, but not in the emotional task, were associated with stronger E-fields in all brain regions of interest. Concluding, individual E-field distribution might explain part of the variability of prefrontal tDCS effects on working memory performance and in clinical samples. Our results suggest that tDCS effects might be more consistent or improved by applying personalizing current intensity, although this hypothesis should be confirmed by further studies.

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS)

Objective: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. Methods: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. Results: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. Conclusions: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials. Registration number: PROSPERO CRD42022296246.

Boosting affective control with bifrontal transcranial direct current stimulation (tDCS): a proof-of-concept study in healthy individuals.

Affective control refers to the ability to regulate emotions and is considered a marker of mental health. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, holds promise to enhance affective control. In this between-subjects study in healthy individuals, we investigated the effects of bifrontal tDCS on core processes and higher-level markers of affective control. As such, we assessed direct tDCS effects on emotional interference during an affective control task and indirect effects on an instructed reappraisal task afterward. Results showed that the affective control task combined with active tDCS, compared to sham, resulted in enhanced cognitive emotion regulation. Specifically, participants in the active tDCS condition showed an increased propensity to use reappraisal and were more successful in doing so. Moreover, there was reduced vagally mediated heart rate variability indicative of attenuated emotion and self-regulation, in the sham, but not in the active condition. Surprisingly, there were no effects of tDCS on emotional interference during the affective control task, with Bayesian analyses showing extreme evidence against these effects. Nevertheless, there was a positive association between the emotional interference during the affective control task and participants' reappraisal success afterward for the active, but not the sham tDCS condition. The study offers valuable insights to guide future work on combined tDCS with affective control tasks or training on the ability to regulate emotions.

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS).

OBJECTIVE: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. METHODS: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. RESULTS: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. CONCLUSION: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials.

Stimulation of the dorsolateral prefrontal cortex modulates brain cue reactivity to reward (un)availability.

Brain imaging studies have shown that stimulation of the left dorsolateral prefrontal cortex (dlPFC), which plays a pivotal role in high-order cognitive control processes, modulates brain reactivity to reward-related cues. Nevertheless, the impact of contextual factors such as reward availability (the reward that is depicted in the cue exposure task) on such modulation effect remains unclear. Here we tested whether a single session of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the left dlPFC differently impacts brain reactivity to cues signalling either availability or unavailability of a sports betting opportunity. Employing a within-subject design (verum versus sham HF-rTMS) among thirty-two frequent sports bettors, we first observed that, as compared to the sham condition, verum HF-rTMS modulated brain reactivity to game cues prior to being made (un)available for betting, through simultaneous increases (posterior insula and caudate nucleus) and decreases (occipital pole) in brain activation. Second, verum HF-rTMS led to increased ventral striatal activity towards cues available for betting but did not modulate brain response to cues unavailable for betting. Taken together, these findings demonstrate that transient stimulation of the left dlPFC led to a general modulation in brain activity in responses to cues, and that this effect is only partly dependent on cues signalling for reward (un)availability.

Combining transcranial direct current stimulation with group cognitive behavioral therapy developed to treat rumination: a clinical pilot study.

Background: As part of repetitive negative thinking (RNT), rumination is a maladaptive cognitive response style to stress or negative mood which can increase the risk of depression and may prohibit complete recovery. Cognitive behavioral therapy (CBT) and transcranial direct current stimulation (tDCS) both proved to be effective in decreasing rumination. However, the combined effects of tDCS and CBT interventions on rumination have not yet been explored. The first aim of this pilot study is to investigate whether the combination of tDCS and CBT has an accumulating positive effect on modulating state rumination. The second aim is to assess the feasibility and safety profile of the proposed combined approach. Method: Seventeen adults aged 32-60 years, suffering from RNT, were referred by their primary care professional to participate in an 8-week group intervention for RNT ("Drop It") comprising 8 sessions of CBT. Before each CBT session, patients underwent one double-blinded prefrontal active (2 mA for 20 min) or sham tDCS (anode over F3, cathode over the right supraorbital region) combined with an internal cognitive attention task focused on individual RNT, i.e., online tDCS priming. During each session, the Brief State Rumination Inventory was used to assess state rumination. Results: A mixed effects model analysis revealed no significant differences between the stimulation conditions, weekly sessions, or their interaction in terms of state rumination scores. Conclusion: Overall, the combination of online tDCS priming followed by group CBT was found to be safe and feasible. On the other hand, no significant additional effects of this combined approach on state rumination were established. Although our pilot study may have been too small to find significant clinical effects, future larger RCT studies on combined tDCS-CBT treatment protocols may reevaluate the selection of internal cognitive attention tasks and more objective neurophysiological measurements, consider the optimal timing of the combination (concurrently or sequentially), or may add additional tDCS sessions when following CBT.

Prefrontal transcranial direct current stimulation over the right prefrontal cortex reduces proactive and reactive control performance towards emotional material in healthy individuals.

The prefrontal cortex plays a crucial role in cognitive processes, both during anticipatory and reactive modes of cognitive control. Transcranial Direct Current Stimulation (tDCS) can modulate these cognitive resources. However, there is a lack of research exploring the impact of tDCS on emotional material processing in the prefrontal cortex, particularly in regard to proactive and reactive modes of cognitive control. In this study, 35 healthy volunteers underwent both real and sham tDCS applied to the right prefrontal cortex in a counterbalanced order, and then completed the Cued Emotion Control Task (CECT). Pupil dilation, a measure of cognitive resource allocation, and behavioral outcomes, such as reaction time and accuracy, were collected. The results indicate that, as compared to sham stimulation, active right-sided tDCS reduced performance and resource allocation in both proactive and reactive modes of cognitive control. These findings highlight the importance of further research on the effects of tDCS applied to the right prefrontal cortex on cognitive engagement, particularly for clinical trials utilizing the present electrode montage in combination with cognitive interventions.

The effects of left dorsolateral prefrontal transcranial direct current stimulation on episodic future thinking following acute psychosocial stress.

INTRODUCTION: Research on stress-related disorders and brain imaging suggests that (acute) stress might impact the capacity to mentally simulate specific episodic future events (EFT) through the effects of cortisol on brain regions supporting this cognitive function, such as the prefrontal cortices. This study aims to examine the mechanisms underlying this link, using transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex. METHODS: 60 healthy participants were subjected to the Montreal Imaging Stress Task (MIST), followed by either active or sham tDCS. After stimulation, the EFT task was administered. Salivary cortisol was measured throughout the protocol. RESULTS: Higher cortisol AUCi values were linked to less specific episodic future thoughts. Moreover, active tDCS enhanced EFT specificity irrespective of cortisol, especially in high trait ruminators. We did not observe an effect from active tDCS on cortisol AUCi, and equally there was no interaction effect between cortisol AUCi and stimulation condition predictive for EFT specificity. CONCLUSION: Although we did not find evidence for the effects of tDCS on the HPA-system, our data reveal a crucial link between two critical predictors of mental health for the first time, and provide a solution to help rehabilitate EFT deficits.Trial registration: Netherlands National Trial Register identifier: ntr004..

Effects of non-invasive vagus nerve stimulation on cognitive and autonomic correlates of perseverative cognition.

Perseverative cognitions can provoke psychophysiological stress in the absence of an actual stressor and are considered important transdiagnostic vulnerability factors for several (mental) health issues. These stress-related cognitive processes are reflected by both cognitive (assessed by self-reports) and autonomic inflexibility (assessed by heart rate variability; HRV), with a key role attributed to the vagus nerve. Interestingly, modulation of the afferent branches of the vagus can be achieved with transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive technique that employs a low-intensity electrical current applied to the ear. In a sample of healthy individuals, we investigated the effects of taVNS of the left concha, compared to sham (earlobe) stimulation, on the cognitive and autonomic correlates of perseverative cognition following a psychosocial stress task. Interestingly, taVNS significantly reduced cognitive rigidity, reflected by reduced subjective perseverative thinking after psychosocial stress. Although there were no direct effects on autonomic correlates of perseverative cognition, individual differences in perseverative thinking after the stressor significantly affected the effects of taVNS on HRV. Specifically, more autonomic inflexibility during the stress task (i.e., reduced HRV) was associated with increases in perseverative thinking afterward for the sham condition, but not the active taVNS condition. Additional exploratory analyses revealed no significant moderation of stimulation intensity. Overall, the study findings endorse the association between perseverative cognitions and vagus nerve functioning.

Transcranial direct current stimulation versus intermittent theta-burst stimulation for the improvement of working memory performance.

Non-invasive brain stimulation (NIBS) techniques have been increasingly used over the dorsolateral prefrontal cortex (DLPFC) to enhance working memory (WM) performance. Notwithstanding, NIBS protocols have shown either small or inconclusive cognitive effects on healthy and neuropsychiatric samples. Therefore, we assessed working memory performance and safety of transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), and both therapies combined vs placebo over the neuronavigated left DLPFC of healthy participants. Twenty-four subjects were included to randomly undergo four sessions of NIBS, once a week: tDCS alone, iTBS alone, combined protocol and placebo. The 2-back task and an adverse effect scale were applied after each NIBS session. Results revealed a significantly faster response for iTBS (b= -21.49, p= 0.04), but not for tDCS and for the interaction tDCS vs. iTBS (b= 13.67, p= 0.26 and b= 40.5, p= 0.20, respectively). No changes were observed for accuracy and no serious adverse effects were found among protocols. Although tolerable, an absence of synergistic effects for the combined protocol was seen. Nonetheless, future trials accessing different outcomes for the combined protocols, as well as studies investigating iTBS over the left DLPFC for cognition and exploring sources of variability for tDCS are encouraged.

Brain Perfusion Alterations Induced by Standalone and Combined Non-Invasive Brain Stimulation over the Dorsolateral Prefrontal Cortex.

Non-invasive brain stimulation (NIBS) interventions are promising for the treatment of psychiatric disorders. Notwithstanding, the NIBS mechanisms of action over the dorsolateral prefrontal cortex (DLPFC), a hub that modulates affective and cognitive processes, have not been completely mapped. We aimed to investigate regional cerebral blood flow (rCBF) changes over the DLPFC and the subgenual anterior cingulate cortex (sgACC) of different NIBS protocols using Single-Photon Emission Computed Tomography (SPECT). A factorial, within-subjects, double-blinded study was performed. Twenty-three healthy subjects randomly underwent four sessions of NIBS applied once a week: transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), combined tDCS + iTBS and placebo. The radiotracer 99m-Technetium-ethylene-cysteine-dimer was injected intravenously during the NIBS session, and SPECT neuroimages were acquired after the session. Results revealed that the combination of tDCS + iTBS increased right sgACC rCBF. Cathodal and anodal tDCS increased and decreased DLPFC rCBF, respectively, while iTBS showed no significant changes compared to the placebo. Our findings suggest that the combined protocol might optimize the activity in the right sgACC and encourage future trials with neuropsychiatric populations. Moreover, mechanistic studies to investigate the effects of tDCS and iTBS over the DLPFC are required.

Double the dose, double the impact? Effects of iTBS on salivary cortisol in stressed healthy volunteers.

There is a growing interest in applying double-dose repetitive transcranial Magnetic Stimulation (rTMS) as a therapeutic tool for stress-related psychiatric disorders. Such stimulation protocols may shorten the treatment duration and may result in faster symptom improvement. Currently, theta-burst stimulation (TBS) protocols have gained attention because of their significantly reduced treatment duration, compared to conventional rTMS. However, the effect of one or twice daily rTMS sessions remains unclear in relation to stress. Using a two-period cross-over design, we examined the impact of double-dosed intermittent (TBS) over the left dorsolateral prefrontal cortex on stress responses (salivary cortisol) in thirty-eight healthy participants after being stressed by a validated psychosocial stress task: the Trier Social Stress Test. After the first active iTBS session, as contrasted to sham, no differential effects on salivary output were observed. However, after the second active session, there was a significantly smaller decrease of salivary cortisol concentrations in the active iTBS condition compared to sham. Our results suggest that double-dosed iTBS after being stressed might differently affect stress recovery compared to a single session of iTBS.

The neural correlates of psychosocial stress: A systematic review and meta-analysis of spectral analysis EEG studies.

Whereas the link between psychosocial stress and health complications has long been established, the influence of psychosocial stress on brain activity is not yet completely understood. Electroencephalography (EEG) has been regularly employed to investigate the neural aspects of the psychosocial stress response, but these results have not yet been unified. Therefore, in this article, we systematically review the current EEG literature in which spectral analyses were employed to investigate the neural psychosocial stress response and interpret the results with regard to the three stress phases (anticipatory, reactive, and recovery) in which the response can be divided. Our results show that three EEG measures, alpha power, beta power and frontal alpha asymmetry (FAA), are commonly utilized and that alpha power consistently decreases, beta power shows a tendency to increase, and FAA varies inconsistently. We furthermore found that whereas changes in alpha power are independent of the stress phase, and changes in beta power show a relative stress phase independent trend, other EEG measures such as delta power, theta power, relative gamma and theta-alpha power ratio show less stress phase independent changes. Meta-analyses conducted on alpha power, beta power and FAA further revealed a significant effect size (hedge's g = 0.6; p = 0.001) for alpha power, but an insignificant effect size for beta power (hedge's g = -0.31; p = 0.29) and FAA (hedge's g = 0.01, p = 0.93). From our results, it can be concluded that psychosocial stress results in significant changes in some spectral EEG indices, but that more research is needed to further uncover the precise (temporal) mechanisms underlying these neural responses.

Non-invasive vagal nerve stimulation enhances cognitive emotion regulation.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed as a potential new tool in the treatment of major depressive disorder. Prior studies have demonstrated that taVNS enhances cognitive control and is able to modulate brain activity in key regions involved in cognitive emotion regulation, such as the anterior cingulate and medial prefrontal cortex, which is known to be impaired in depressed patients. Preclinical studies are lacking but may provide important insights into the working mechanisms of taVNS on cognitive emotion regulatory processes. In this between-subject study, 83 healthy subjects underwent a single-session of active taVNS or sham stimulation, after which cognitive reappraisal was examined using a computer-based cognitive emotion regulation task. Our results indicate that participants receiving active taVNS, compared to sham, were better at using cognitive reappraisal and rated their response to emotion-eliciting pictures as less intense. Yet, even though we found significant differences in behavioral measures of cognitive emotion regulation, no differences between groups were found in terms of physiological responses to the emotional stimuli. Overall, these findings suggest a positive effect of taVNS on the cognitive reappraisal of emotions, but future studies assessing objective measures of neural activity during cognitive emotion regulation following taVNS are warranted.

Follow-up effects of transcranial direct current stimulation (tDCS) for the major depressive episode: A systematic review and meta-analysis.

Transcranial Direct Current Stimulation (tDCS) is an effective treatment during the acute phase of a major depressive episode (MDE), although the evidence for its follow-up efficacy is mixed. A systematic review and meta-analysis were performed. MEDLINE/PubMed, Scopus (EMBASE), Web of Science, Cochrane Library and additional sources were searched from inception to April 29, 2021. Studies that followed up adults treated with tDCS during an MDE - using (interventional) and/or not using (observational) tDCS in the follow-up period were included. The primary outcome was the Hedges' g for the follow-up depression scores. Small study effects and sources of heterogeneity were explored. 427 studies were retrieved and 11 trials (13 datasets, n = 311) were included, most presenting moderate bias. Results showed a follow-up depression improvement (k = 13, g = -0.81, 95% confidence interval [CI]: -1.28; -0.34, I² = 84.0%), which was probably driven by the interventional studies (k = 7, g= -1.12, 95% CI: -1.84; -0.40, I² = 87.1%). No predictor of response was associated with the outcome. No risk of publication bias was found. Significant between-study heterogeneity may have influenced the overall results. Our findings suggest that tDCS produces effects beyond the intervention period during MDEs. Maintenance sessions are advised in future research.

Effects of combined theta burst stimulation and transcranial direct current stimulation of the dorsolateral prefrontal cortex on stress.

OBJECTIVE: Research suggests that the combination of different non-invasive brain stimulation techniques, such as intermittent theta-burst stimulation (iTBS) and transcranial direct current stimulation (tDCS), could enhance the effects of stimulation. Studies investigating the combination of tDCS and iTBS over the dorsolateral prefrontal cortex (DLPFC) are lacking. In this within-subjects study, we evaluated the additive effects of iTBS with tDCS on psychophysiological measures of stress. METHOD: Sixty-eight healthy individuals were submitted to a bifrontaltDCS + iTBS and shamtDCS + iTBS protocol targeting the DLPFC with a one-week interval. The Maastricht Acute Stress Test was used to activate the stress system after stimulation. Stress reactivity and recovery were assessed using physiological and self-report measures. RESULTS: The stressor evoked significant psychophysiological changes in both stimulation conditions. However, no evidence was found for differences between them in stress reactivity and recovery. Participants reported more pain and feelings of discomfort to the bifrontaltDCS + iTBS protocol. CONCLUSION: In this study set-up, iTBS plus tDCS was not superior to iTBS in downregulating stress in healthy subjects. SIGNIFICANCE: There is no evidence for an effect of combined tDCS-iTBS of the DLPFC on stress according to the parameters employed in our study. Future studies should explore other stimulation parameters, additive approaches and/or neurobiological markers.