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High-frequency (HF) transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is widely used in Major Depressive Episode (MDE). Optimization of its efficacy with a neuro-navigation system has been proposed based on a small randomized controlled trial (RCT) supporting a large effect. This evaluator- and patient-blind, multicenter RCT assessed the superiority in terms of efficacy of 10 HF rTMS sessions of the left DLPFC targeted with MRI based neuro-navigation versus similar sessions targeted by the standard 5 cm technique. The study was conducted between January 2013 and April 2017, at 4 hospitals centers in France where both in- and out- patients with MDE were included. Randomization was computer-generated (1:1), with allocation concealment implemented within the e-CRF. The main outcome measure was the percentage of responders 44 days (D44) after the rTMS session. Secondary outcomes were percentage of remitters, Beck Depression Inventory and psychomotor retardation assessed with Salpêtrière retardation rating scale (SRRS) for depression at D14 and D44. The results are presented along with their 95% confidence intervals. 105 patients were randomized and 92 were evaluable with respectively 45 patients in the neuronavigation group and 47 in the standard group. A treatment response was observed for 14 (31.8%) of 44 patients analyzed in the intervention group, and for 16 (35.6%) of 45 patients analyzed in the control group with no statistical difference (relative risk 0.89; 95% confidence interval, [0.50;1.61]). No difference was evidenced for secondary outcomes at D44 whether it concerns remission at D44 (relative risk, 0.82; 95% CI, 0.36 to 1.88), or BDI results (difference in means, 0,01; 95% CI, -3.06 to 3.26), or SRRS results (difference in means, 0.11; 95% CI, -2.42 to 5.02). Similar results were observed at D14. Rates of adverse events were similar in both groups with 23 (47.9%) and 1 (2.1%) of adverse events and serious adverse events in the neuro-navigation group versus 20 (40.8%) and 0 (0%) in the standard group. This study failed to reproduce previous findings supporting the use of neuro-navigation system to optimize rTMS efficacy. Limitations of this study includes a small sample size and a number of rTMS sessions that may appear substandard in 2025. NCT01677078.

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS‐EEG) to investigate evoked‐oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event‐related spectral perturbation and relative spectral power) and phase synchronization (inter‐trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS‐EEG was recorded before, during, and after noxious heat (acute pain condition) and non‐noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, β1, and β2) of TMS‐evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS‐EEG. Over M1, acute pain decreased α‐band oscillatory power locally and α‐band phase synchronization remotely in parietal–occipital clusters compared with non‐noxious warm (all p < .05). The remote (parietal–occipital) decrease in α‐band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α‐band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased β1‐band power locally compared with non‐noxious warm (p = .015). Thus, evoked‐oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal–occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and β band oscillations and may have relevance for pain therapies. We used a novel approach that combines transcranial magnetic stimulation with an electroencephalogram (known as TMS‐EEG) to study evoked‐oscillatory cortical activity during acute pain. Our main findings showed that alpha oscillations, evoked by M1 probing, were reduced during acute pain, which correlated with individual trait pain sensitivity.

Transcranial direct current stimulation (tDCS) can improve cognitive function. However, it is not clear how high-definition tDCS (HD-tDCS) regulates the cognitive function and its neural mechanism, especially in individuals with mild cognitive impairment (MCI). This study aimed to examine whether HD-tDCS can modulate cognitive function in individuals with MCI and to determine whether the potential variety is related to spontaneous brain activity changes recorded by resting-state functional magnetic resonance imaging (rs-fMRI). Forty-three individuals with MCI were randomly assigned to receive either 10 HD-tDCS sessions or 10 sham sessions to the left dorsolateral prefrontal cortex (L-DLPFC). The fractional amplitude of low-frequency fluctuation (fALFF) and the regional homogeneity (ReHo) was computed using rs-fMRI data from all participants. The results showed that the fALFF and ReHo values changed in multiple areas following HD-tDCS. Brain regions with significant decreases in fALFF values include the Insula R, Precuneus R, Thalamus L, and Parietal Sup R, while the Temporal Inf R, Fusiform L, Occipital Sup L, Calcarine R, and Angular R showed significantly increased in their fALFF values. The brain regions with significant increases in ReHo values include the Temporal Inf R, Putamen L, Frontal Mid L, Precentral R, Frontal Sup Medial L, Frontal Sup R, and Precentral L. We found that HD-tDCS can alter the intensity and synchrony of brain activity, and our results indicate that fALFF and ReHo analysis are sensitive indicators for the detection of HD-tDCS during spontaneous brain activity. Interestingly, HD-tDCS increases the ReHo values of multiple brain regions, which may be related to the underlying mechanism of its clinical effects, these may also be related to a potential compensation mechanism involving the mobilization of more regions to complete a function following a functional decline.

There is increasing awareness of interindividual variability in brain function, with potentially major implications for repetitive transcranial magnetic stimulation (rTMS) efficacy. We perform a secondary analysis using data from a double-blind randomized controlled 4-week trial of 20 Hz active versus sham rTMS to dorsolateral prefrontal cortex (DLPFC) during a working memory task in participants with schizophrenia. We hypothesized that rTMS would change local functional activity and variability in the active group compared with sham. 83 participants were randomized in the original trial, and offered neuroimaging pre- and post-treatment. Of those who successfully completed both scans (n = 57), rigorous quality control left n = 42 (active/sham: n = 19/23), who were included in this analysis. Working memory-evoked activity during an N-Back (3-Back vs 1-Back) task was contrasted. Changes in local brain activity were examined from an 8 mm ROI around the rTMS coordinates. Individual variability was examined as the mean correlational distance (MCD) in brain activity pattern from each participant to others within the same group. We observed an increase in task-evoked left DLPFC activity in the active group compared with sham (F1,36 = 5.83, False Discovery Rate (FDR))-corrected P = .04). Although whole-brain activation patterns were similar in both groups, active rTMS reduced the MCD in activation pattern compared with sham (F1,36 = 32.57, P < .0001). Reduction in MCD was associated with improvements in attention performance (F1,16 = 14.82, P = .0014, uncorrected). Active rTMS to DLPFC reduces individual variability of brain function in people with schizophrenia. Given that individual variability is typically higher in schizophrenia patients compared with controls, such reduction may \"normalize\" brain function during higher-order cognitive processing.

Transcranial direct current stimulation (tDCS) applied to the dorsolateral prefrontal cortex (DLPFC) has shown asymmetric behavioral effects, though the underlying neurophysiological mechanisms remain unclear. In this preliminary study with 34 healthy individuals, tDCS was applied to either the left or right DLPFC or a sham group. Behavioral and neurophysiological changes were examined by the Stroop test and resting‐state fMRI, respectively, which were measured before and after a 15‐min tDCS session. Seed‐to‐voxel connectivity analysis with seeds placed under the tDCS target regions (F3 and F4) showed no significant changes, but voxel‐to‐voxel whole‐brain intrinsic connectivity (IC) analysis revealed significant 3 × 2 interaction effects (stimulation site × time) in the right DLPFC (18 mm off from the F4). Post hoc analysis showed that only the right DLPFC stimulation led to an increase in IC from pre‐ to post‐stimulation. Consistent with this finding, right DLPFC stimulation improved Stroop task performance measured by increased interference score, which represents better inhibition of irrelevant information. These findings provide further insights into the hemispheric difference of tDCS effects and its underlying neurophysiological mechanisms. However, the small sample size limits the generalizability of the results and necessitates further research with a larger cohort for confirmation. Using transcranial direct current stimulation (tDCS) and fMRI, we compared the neurophysiological effects of anodal tDCS on the left vs. right dorsolateral prefrontal cortex (DLPFC). Our findings show that stimulation of the right (but not the left) DLPFC increases IC from pre‐ to post‐stimulation, demonstrating asymmetric brain connectivity.

Cognitive behavioral therapy (CBT) is an effective treatment for patients with social anxiety disorder (SAD) or major depressive disorder (MDD), yet there is variability in clinical improvement. Though prior research suggests pre-treatment engagement of brain regions supporting cognitive reappraisal (e.g. dorsolateral prefrontal cortex [dlPFC]) foretells CBT response in SAD, it remains unknown if this extends to MDD or is specific to CBT. The current study examined associations between pre-treatment neural activity during reappraisal and clinical improvement in patients with SAD or MDD following a trial of CBT or supportive therapy (ST), a common-factors comparator arm. Participants were 75 treatment-seeking patients with SAD ( = 34) or MDD ( = 41) randomized to CBT ( = 40) or ST ( = 35). Before randomization, patients completed a cognitive reappraisal task during functional magnetic resonance imaging. Additionally, patients completed clinician-administered symptom measures and a self-report cognitive reappraisal measure before treatment and every 2 weeks throughout treatment. Results indicated that pre-treatment neural activity during reappraisal differentially predicted CBT and ST response. Specifically, greater trajectories of symptom improvement throughout treatment were associated with less ventrolateral prefrontal cortex (vlPFC) activity for CBT patients, but more vlPFC activity for ST patients. Also, less baseline dlPFC activity corresponded with greater trajectories of self-reported reappraisal improvement, regardless of treatment arm. If replicated, findings suggest individual differences in brain response during reappraisal may be transdiagnostically associated with treatment-dependent improvement in symptom severity, but improvement in subjective reappraisal following psychotherapy, more broadly.

Schizophrenia has been associated with a reduced task-related modulation of cortical activity assessed through electroencephalography (EEG). However, to the best of our knowledge, no study so far has assessed the underpinnings of this decreased EEG modulation in schizophrenia. A possible substrate of these findings could be a decreased inhibitory function, a replicated finding in the field. In this pilot study, our aim was to explore the association between EEG modulation during a cognitive task and the inhibitory system function in vivo in a sample including healthy controls and patients with schizophrenia. We hypothesized that the replicated decreased task-related activity modulation during a cognitive task in schizophrenia would be related to a hypofunction of the inhibitory system. For this purpose, 27 healthy controls and 22 patients with schizophrenia (including 13 first episodes) performed a 3-condition auditory oddball task from which the spectral entropy modulation was calculated. In addition, cortical reactivity—as an index of the inhibitory function—was assessed by the administration of 75 monophasic transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex. Our results replicated the task-related cortical activity modulation deficit in schizophrenia patients. Moreover, schizophrenia patients showed higher cortical reactivity following transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex compared to healthy controls. Cortical reactivity was inversely associated with EEG modulation, supporting the idea that a hypofunction of the inhibitory system could hamper the task-related modulation of EEG activity.

Expectations modulating pain perception is a well-researched phenomenon, but less is known about the persistence of expectation effects over longer time-courses. In this preregistered study, we examined the persistence of positive (placebo) and negative (nocebo) expectation effects over one week and investigated whether neural activity on day 1 (fMRI) can predict the stability of these effects one week later ( n  = 41). We tested whether expectations were reflected in EEG oscillatory activity at the second measurement. Both positive and negative pain modulation effects persisted over the tested time-period and did not undergo extinction. Expectations of higher compared to lower pain led to larger theta-to-alpha EEG activity. Most interestingly, differential neural activity in fMRI was correlated with persistent expectations. Individual differences in the persistence of positive expectation effects were related to reduced amygdala activity and enhanced activity in the anterior insula and dorsolateral prefrontal cortex (DLPFC) during the first session. In contrast, persistence of negative expectation effects was predicted by enhanced thalamus activity. Our findings indicate relatively stable placebo and nocebo effects over longer time courses, but this persistence is based on different neural areas for positive and negative expectations.

Transcranial Direct Current Stimulation (tDCS) is a non‐invasive brain stimulation technique used to modulates cortical brain activity. However, its effects on brain metabolites within the dorsolateral prefrontal cortex (DLPFC), a crucial area targeted for brain stimulation in mental disorders, remain unclear. This study aimed to investigate whether prefrontal tDCS over the left and right DLPFC modulates levels of key metabolites, including gamma‐aminobutyric acid (GABA), glutamate (Glu), glutamine/glutamate (Glx), N‐acetylaspartate (NAA), near to the target region and to explore potential sex‐specific effects on these metabolite concentrations. A total of 41 healthy individuals (19 female, M_age = 25 years, SD = 3.15) underwent either bifrontal active (2 mA for 20 min) or sham tDCS targeting the left (anode: F3) and right (cathode: F4) DLPFC within a 3 Tesla MRI scanner. Magnetic resonance spectroscopy (MRS) was used to monitor neurometabolic changes before, during, and after 40 min of tDCS, with measurements of two 10‐min intervals during stimulation. A single voxel beneath F3 was used for metabolic quantification. Results showed a statistically significant increase in Glx levels under active tDCS compared to the sham condition, particularly during the second 10‐min window and persisting into the post‐stimulation phase. No significant changes were observed in other metabolites, but consistent sex differences were detected. Specifically, females showed lower levels of NAA and GABA under active tDCS compared to the sham condition, while no significant changes were observed in males. E‐field modeling showed no significant differences in field magnitudes between sexes, and the magnitude of the e‐fields did not correlate with changes in Glx levels between active and sham stimulation during the second interval or post‐stimulation. This study demonstrates that a single session of prefrontal tDCS significantly elevates Glx levels in the left DLPFC, with effects persisting post‐stimulation. However, the observed sex differences in the neurochemical response to tDCS were not linked to specific stimulation intervals or variations in e‐field magnitudes, highlighting the complexity of tDCS effects and the need for personalized neuromodulation strategies. Prefrontal transcranial direct current stimulation (tDCS) enhances Glx levels in the left dorsolateral prefrontal cortex, a significant finding for managing disorders characterized by glutamatergic dysregulation. Unchanged levels of GABA, Glu, and NAA and sex‐specific responses highlighting the need for further research.

•Unmedicated female major depressive disorder (MDD) patients exhibit reduced GABA+/Cr levels specifically in the left dorsolateral prefrontal cortex (DLPFC).•Lower GABA+/Cr levels across the MDD cohort correlate with greater anhedonia severity and worse executive function.•In patients with MDD, the associations between GABA+/Cr and specific functional connectivities within the triple network are disrupted. GABAergic dysfunction contributes to Major Depressive Disorder (MDD). This study examines excitatory/inhibitory (E/I) imbalance, specifically GABA deficits in the left dorsolateral prefrontal cortex (DLPFC), and their link to anhedonia and cognitive impairment in MDD. It also investigates alterations in the coupling between local E/I activity and functional connectivity (FC) within the triple network. We included 41 medication-naïve MDD patients and 33 healthy controls (HCs). Participants underwent Snaith–Hamilton Pleasure Scale (SHAPS) and cognitive assessments. GABA+/Cr, Glx, and GABA+/Glx ratios were measured in the left DLPFC using proton magnetic resonance spectroscopy (¹H-MRS). Resting-state functional magnetic resonance imaging (fMRI) data were analyzed via independent component analysis (ICA), identifying five major brain networks. Female MDD patients exhibited reduced GABA+/Cr in the left DLPFC (p = 0.021). GABA+/Cr negatively correlated with SHAPS scores (r = -0.33, p = 0.04) and Trail Making Test Part B (TMT-B) completion times (r = -0.36, p = 0.03) in MDD patients. HCs showed positive correlations between GABA+/Cr and FC within the LECN (r = 0.41, p = 0.02) and between the LECN-dDMN (r = 0.39, p = 0.03) and LECN-pSN (r = 0.46, p = 0.01); these correlations were absent in the MDD group. Female patients with MDD exhibit a specific reduction in GABA levels in the left DLPFC. Furthermore, these lower GABA levels are associated with increased anhedonia and poorer executive function. Critically, the neurochemical coupling between GABA and large-scale brain networks is also disrupted in MDD.