Adapted Beamforming: A Robust and Flexible Approach for Removing Various Types of Artifacts from TMS-EEG Data.

Electroencephalogram (EEG) recorded as response to transcranial magnetic stimulation (TMS) can be highly informative of cortical reactivity and connectivity. Reliable EEG interpretation requires artifact removal as the TMS-evoked EEG can contain high-amplitude artifacts. Several methods have been proposed to uncover clean neuronal EEG responses. In practice, determining which method to select for different types of artifacts is often difficult. Here, we used a unified data cleaning framework based on beamforming to improve the algorithm selection and adaptation to the recorded signals. Beamforming properties are well understood, so they can be used to yield customized methods for EEG cleaning based on prior knowledge of the artifacts and the data. The beamforming implementations also cover, but are not limited to, the popular TMS-EEG cleaning methods: independent component analysis (ICA), signal-space projection (SSP), signal-space-projection-source-informed-reconstruction method (SSP-SIR), the source-estimate-utilizing noise-discarding algorithm (SOUND), data-driven Wiener filter (DDWiener), and the multiple-source approach. In addition to these established methods, beamforming provides a flexible way to derive novel artifact suppression algorithms by considering the properties of the recorded data. With simulated and measured TMS-EEG data, we show how to adapt the beamforming-based cleaning to different data and artifact types, namely TMS-evoked muscle artifacts, ocular artifacts, TMS-related peripheral responses, and channel noise. Importantly, beamforming implementations are fast to execute: We demonstrate how the SOUND algorithm becomes orders of magnitudes faster via beamforming. Overall, the beamforming-based spatial filtering framework can greatly enhance the selection, adaptability, and speed of EEG artifact removal.

Evoked EEG Responses to TMS Targeting Regions Outside the Primary Motor Cortex and Their Test-Retest Reliability.

Transcranial magnetic stimulation (TMS)-evoked electroencephalography (EEG) potentials (TEPs) provide unique insights into cortical excitability and connectivity. However, confounding EEG signals from auditory and somatosensory co-stimulation complicate TEP interpretation. Our optimized sham procedure established with TMS of primary motor cortex (Gordon in JAMA 245:118708, 2021) differentiates direct cortical EEG responses to TMS from those caused by peripheral sensory inputs. Using this approach, this study aimed to investigate TEPs and their test-retest reliability when targeting regions outside the primary motor cortex, specifically the left angular gyrus, supplementary motor area, and medial prefrontal cortex. We conducted three identical TMS-EEG sessions one week apart involving 24 healthy participants. In each session, we targeted the three areas separately using a figure-of-eight TMS coil for active TMS, while a second coil away from the head produced auditory input for sham TMS. Masking noise and electric scalp stimulation were applied in both conditions to achieve matched EEG responses to peripheral sensory inputs. High test-retest reliability was observed in both conditions. However, reliability declined for the 'cleaned' TEPs, resulting from the subtraction of evoked EEG response to the sham TMS from those to the active, particularly for latencies > 100 ms following the TMS pulse. Significant EEG differences were found between active and sham TMS at latencies < 90 ms for all targeted areas, exhibiting distinct spatiotemporal characteristics specific to each target. In conclusion, our optimized sham procedure effectively reveals EEG responses to direct cortical activation by TMS in brain areas outside primary motor cortex. Moreover, we demonstrate the impact of peripheral sensory inputs on test-retest reliability of TMS-EEG responses.

Reflecting the causes of variability of EEG responses elicited by cerebellar TMS.

Recently, Fong et al. published EEG responses in cerebral cortex elicited by cerebellar TMS (cbTMS) (Fong et al., 2023), which differ from our recently identified cbTMS-EEG responses (Gassmann et al., 2022). Fong et al. argued that this discrepancy is due to coil placement unsuitable for eliciting cerebellar brain inhibition (CBI) in our study. However, we reliably elicited CBI in our subjects. Consequently, this leads to a compelling discussion on possible reasons for the observed discrepancies in cbTMS-evoked EEG responses. Reliably measuring cbTMS-evoked EEG responses could become an important neurophysiological tool to test effective cerebellum-to-cortex connectivity.

Untangling TMS-EEG responses caused by TMS versus sensory input using optimized sham control and GABAergic challenge.

The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) elegantly probes the excitability and connectivity of the human brain. However, TMS-EEG signals inevitably also contain sensory-evoked responses caused by TMS-associated auditory and somatosensory inputs, constituting a substantial confounding factor. Here we applied our recently established optimized SHAM protocol (Gordon et al., Neuroimage 2021:118708) to disentangle TMS-EEG responses caused by TMS vs. sensory input. One unresolved question is whether these responses superimpose without relevant interaction, a requirement for their disaggregation by the optimized SHAM approach. We applied in 20 healthy subjects a pharmacological intervention using a single oral dose of 20 mg of diazepam, a positive modulator of GABAA receptors. Diazepam decreased the amplitudes of the P60 and P150 components specifically in the ACTIVE TMS and/or the ACTIVE TMS minus SHAM conditions but not in the SHAM condition, pointing to a response caused by TMS. In contrast, diazepam suppressed the amplitude of the N100 component indiscriminately in the ACTIVE TMS and SHAM conditions but not in the ACTIVE TMS minus SHAM condition, pointing to a response caused by sensory input. Moreover, diazepam suppressed the beta-band response observed in the motor cortex specifically after ACTIVE TMS and ACTIVE TMS minus SHAM. These findings demonstrate a lack of interaction of TMS-EEG responses caused by TMS vs. sensory input and validate optimized SHAM-controlled TMS-EEG as an appropriate approach to untangle these TMS-EEG responses. This knowledge will enable the proficient use of TMS-EEG to probe the physiology of the human cortex. KEY POINTS: Optimized SHAM disentangles TMS-EEG responses caused by TMS vs. sensory input. Diazepam differentially modulates TMS-EEG responses caused by TMS vs. sensory input. Diazepam modulation of P60 and P150 indicate TMS-EEG responses caused by TMS. Diazepam modulation of N100 indicate a TMS-EEG response caused by sensory input.

Assessing effective connectivity of the cerebellum with cerebral cortex using TMS-EEG.

BACKGROUND AND OBJECTIVES: The cerebellum provides important input to the cerebral cortex but its assessment is difficult. Cerebellar brain inhibition tested by paired-coil transcranial magnetic stimulation (TMS) is limited to the motor cortex. Here we sought to measure responses to cerebellar TMS (cbTMS) throughout the cerebral cortex using electroencephalography (EEG). METHODS: Single-pulse TMS was applied with an induced upward current to the right cerebellar hemisphere in 46 healthy volunteers while recording EEG. Multiple control conditions, including TMS of right occipital cortex, cbTMS with induced downward current, and a sham condition modified specifically for cbTMS were tested to provide evidence for the specificity of the EEG responses evoked by cbTMS with an upward induced current. RESULTS: Distinct EEG response components could be specifically attributed to cbTMS, namely a left-hemispheric prefrontal positive deflection 25 ms after cbTMS, and a subsequent left-hemispheric parietal negative deflection peaking at 45 ms. In the time-frequency-response analysis, cbTMS induced a left-hemispheric prefrontal power increase in the high-beta frequency band. These responses were not seen in the control and sham conditions. CONCLUSIONS: The EEG responses observed in this highly controlled experimental design may cautiously be attributed to reflect specific signatures of the activation of the cerebello-dentato-thalamo-cortical pathway by cbTMS. Therefore, these responses may provide biomarkers for assessing the integrity of this pathway, a proposition that will need further testing in clinical populations.

µ-rhythm phase from somatosensory but not motor cortex correlates with corticospinal excitability in EEG-triggered TMS.

BACKGROUND: Sensorimotor µ-rhythm phase is correlated with corticospinal excitability. Transcranial magnetic stimulation (TMS) of motor cortex results in larger motor evoked potentials (MEPs) during the negative peak of the EEG oscillation as extracted with a surface Laplacian. However, the anatomical source of the relevant oscillation is not clear and demonstration of the relationship is sensitive to the choice of EEG montage. OBJECTIVE/HYPOTHESIS: Here, we compared two EEG montages preferentially sensitive to oscillations originating from the crown of precentral gyrus (dorsal premotor cortex) vs. postcentral gyrus (secondary somatosensory cortex). We hypothesized that the EEG signal from precentral gyrus would correlate more strongly with MEP amplitude, given that the corticospinal neurons are located in the anterior wall of the sulcus and the corticospinal tract has input from premotor cortex. NEW METHOD: Real-time EEG-triggered TMS of motor cortex was applied in 6 different conditions in randomly interleaved order, 3 phase conditions (positive peak, negative peak, random phase of the ongoing µ-oscillation), and each phase condition for 2 different EEG montages corresponding to oscillations preferentially originating in precentral gyrus (premotor cortex) vs. postcentral gyrus (somatosensory cortex), extracted using FCC3h vs. C3 centered EEG montages. RESULTS: The negative vs. positive peak of sensorimotor µ-rhythm as extracted from the C3 montage (postcentral gyrus, somatosensory cortex) correlated with states of high vs. low corticospinal excitability (p < 0.001), replicating previous findings. However, no significant correlation was found for sensorimotor µ-rhythm as extracted from the neighboring FCC3 montage (precentral gyrus, premotor cortex). This implies that EEG-signals from the somatosensory cortex are better predictors of corticospinal excitability than EEG-signals from the motor areas. CONCLUSIONS: The extraction of a brain oscillation whose phase corresponds to corticospinal excitability is highly sensitive to the selected EEG montage and the location of the EEG sensors on the scalp. Here, the cortical source of EEG oscillations predicting response amplitude does not correspond to the cortical target of the stimulation, indicating that even in this simple case, a specific neuronal pathway from somatosensory cortex to primary motor cortex is involved.

Expression Profiling in Ovarian Cancer Reveals Coordinated Regulation of BRCA1/2 and Homologous Recombination Genes.

Predictive biomarkers are crucial in clarifying the best strategy to use poly(ADP-ribose) polymerase inhibitors (PARPi) for the greatest benefit to ovarian cancer patients. PARPi are specifically lethal to cancer cells that cannot repair DNA damage by homologous recombination (HR), and HR deficiency is frequently associated with BRCA1/2 mutations. Genetic tests for BRCA1/2 mutations are currently used in the clinic, but results can be inconclusive due to the high prevalence of rare DNA sequence variants of unknown significance. Most tests also fail to detect epigenetic modifications and mutations located deep within introns that may alter the mRNA. The aim of this study was to investigate whether quantitation of BRCA1/2 mRNAs in ovarian cancer can provide information beyond the DNA tests. Using the nCounter assay from NanoString Technologies, we analyzed RNA isolated from 38 ovarian cancer specimens and 11 normal fallopian tube samples. We found that BRCA1/2 expression was highly variable among tumors. We further observed that tumors with lower levels of BRCA1/2 mRNA showed downregulated expression of 12 additional HR genes. Analysis of 299 ovarian cancer samples from The Cancer Genome Atlas (TCGA) confirmed the coordinated expression of BRCA1/2 and HR genes. To facilitate the routine analysis of BRCA1/2 mRNA in the clinical setting, we developed a targeted droplet digital PCR approach that can be used with FFPE samples. In conclusion, this study underscores the potential clinical benefit of measuring mRNA levels in tumors when BRCA1/2 DNA tests are negative or inconclusive.

Prefrontal theta phase-dependent rTMS-induced plasticity of cortical and behavioral responses in human cortex.

BACKGROUND: Prefrontal theta oscillations are involved in neuronal information transfer and retention. Phases along the theta cycle represent varied excitability states, whereby high-excitability states correspond to high-frequency neuronal activity and heightened capacity for plasticity induction, as demonstrated in animal studies. Human studies corroborate this model and suggest a core role of prefrontal theta activity in working memory (WM). OBJECTIVE/HYPOTHESIS: We aimed at modulating prefrontal neuronal excitability and WM performance in healthy humans, using real-time EEG analysis for triggering repetitive transcranial magnetic stimulation (rTMS) theta-phase synchronized to the left dorsomedial prefrontal cortex. METHODS: 16 subjects underwent 3 different rTMS interventions on separate days, with pulses triggered according to the individual's real-time EEG activity: 400 rTMS gamma-frequency (100 Hz) triplet bursts applied during either the negative peak of the prefrontal theta oscillation, the positive peak, or at random phase. Changes in cortical excitability were assessed with EEG responses following single-pulse TMS, and behavioral effects by using a WM task. RESULTS: Negative-peak rTMS increased single-pulse TMS-induced prefrontal theta power and theta-gamma phase-amplitude coupling, and decreased WM response time. In contrast, positive-peak rTMS decreased prefrontal theta power, while no changes were observed after random-phase rTMS. CONCLUSION: Findings point to the feasibility of EEG-TMS technology in a theta-gamma phase-amplitude coupling mode for effectively modifying WM networks in human prefrontal cortex, with potential for therapeutic applications.

Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder in Older Adults: Systematic Review and Meta-analysis.

BACKGROUND: Major depressive disorder (MDD) in older adults is a serious public health concern. Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological intervention approved for MDD treatment in adults, but its value in older adults remains unknown. This study aims to systematically review and meta-analyze evidence of rTMS efficacy in MDD treatment among older adults. METHODS: We systematically reviewed the literature for randomized controlled trials (RCTs) and open-label studies assessing rTMS for the treatment of MDD in patients older than 50 years, published until June 2020. Random-effects meta-analyses using standardized mean differences (SMDs) were conducted to assess change in depression severity score (primary outcome), while odds ratios (ORs) were used to assess secondary categorical outcomes (response and remission). Additionally, univariate meta-regression analyses were performed to identify potential predictors of change in depression severity scores. RESULTS: Fourteen RCTs were included in meta-analyses and 26 studies (10 RCTs and 16 open-label studies) in meta-regression. Active rTMS was significantly superior to sham treatment for reduction of severity (SMD = 0.36; 95% CI = 0.13-0.60), as well as response (OR = 3.26; 95% CI = 2.11-5.04) and remission (OR = 4.63; 95% CI = 2.24-9.55). Studies were of moderate to high quality, with funnel plots and Egger's regression test not suggestive of publication bias. In meta-regressions, higher mean age and number of sessions were significantly associated with greater improvement. CONCLUSIONS: Our results support that rTMS is an effective, safe, and well-tolerated treatment for MDD in older adults and that it should be considered in the treatment of this vulnerable population.

Recording brain responses to TMS of primary motor cortex by EEG - utility of an optimized sham procedure.

INTRODUCTION: Electroencephalography (EEG) is increasingly used to investigate brain responses to transcranial magnetic stimulation (TMS). A relevant issue is that TMS is associated with considerable auditory and somatosensory stimulation, causing peripherally evoked potentials (PEPs) in the EEG, which contaminate the direct cortical responses to TMS (TEPs). All previous attempts to control for PEPs suffer from significant limitations. OBJECTIVE/HYPOTHESIS: To design an optimized sham procedure to control all sensory input generated by subthreshold real TMS targeting the hand area of the primary motor cortex (M1), enabling reliable separation of TEPs from PEPs. METHODS: In 23 healthy (16 female) subjects, we recorded EEG activity evoked by an optimized sham TMS condition which masks and matches auditory and somatosensory co-stimulation during the real TMS condition: auditory control was achieved by noise masking and by using a second TMS coil that was placed on top of the real TMS coil and produced a calibrated sound pressure level. Somatosensory control was obtained by electric stimulation (ES) of the scalp with intensities sufficient to saturate somatosensory input. ES was applied in both the sham and real TMS conditions. Perception of auditory and somatosensory inputs in the sham and real TMS conditions were compared by psychophysical testing. Transcranially evoked EEG signal changes were identified by subtraction of EEG activity in the sham condition from EEG activity in the real TMS condition. RESULTS: Perception of auditory and somatosensory inputs in the sham vs. real TMS conditions was comparable. Both sham and real TMS evoked a series of similar EEG signal deflections and induced broadband power increase in oscillatory activity. Notably, the present procedure revealed EEG potentials and a transient increase in beta band power at the site of stimulation that were only present in the real TMS condition. DISCUSSION: The results validate the effectiveness of our optimized sham approach. Despite the presence of typical responses attributable to sensory input, the procedure provided evidence for direct cortical activation by subthreshold TMS of M1. The findings are relevant for future TMS-EEG experiments that aim at measuring regional brain target engagement controlled by an optimized sham procedure.

Prefrontal Theta-Phase Synchronized Brain Stimulation With Real-Time EEG-Triggered TMS.

BACKGROUND: Theta-band neuronal oscillations in the prefrontal cortex are associated with several cognitive functions. Oscillatory phase is an important correlate of excitability and phase synchrony mediates information transfer between neuronal populations oscillating at that frequency. The ability to extract and exploit the prefrontal theta rhythm in real time in humans would facilitate insight into neurophysiological mechanisms of cognitive processes involving the prefrontal cortex, and development of brain-state-dependent stimulation for therapeutic applications. OBJECTIVES: We investigate individual source-space beamforming-based estimation of the prefrontal theta oscillation as a method to target specific phases of the ongoing theta oscillations in the human dorsomedial prefrontal cortex (DMPFC) with real-time EEG-triggered transcranial magnetic stimulation (TMS). Different spatial filters for extracting the prefrontal theta oscillation from EEG signals are compared and additional signal quality criteria are assessed to take into account the dynamics of this cortical oscillation. METHODS: Twenty two healthy participants were recruited for anatomical MRI scans and EEG recordings with 18 composing the final analysis. We calculated individual spatial filters based on EEG beamforming in source space. The extracted EEG signal was then used to simulate real-time phase-detection and quantify the accuracy as compared to post-hoc phase estimates. Different spatial filters and triggering parameters were compared. Finally, we validated the feasibility of this approach by actual real-time triggering of TMS pulses at different phases of the prefrontal theta oscillation. RESULTS: Higher phase-detection accuracy was achieved using individualized source-based spatial filters, as compared to an average or standard Laplacian filter, and also by detecting and avoiding periods of low theta amplitude and periods containing a phase reset. Using optimized parameters, prefrontal theta-phase synchronized TMS of DMPFC was achieved with an accuracy of ±55°. CONCLUSION: This study demonstrates the feasibility of triggering TMS pulses during different phases of the ongoing prefrontal theta oscillation in real time. This method is relevant for brain state-dependent stimulation in human studies of cognition. It will also enable new personalized therapeutic repetitive TMS protocols for more effective treatment of neuropsychiatric disorders.

TMS-EEG signatures of glutamatergic neurotransmission in human cortex.

Neuronal activity in the brain reflects an excitation-inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders. Here, we tested the effects of a single oral dose of two anti-glutamatergic drugs (dextromethorphan, an NMDA receptor antagonist; perampanel, an AMPA receptor antagonist) and an L-type voltage-gated calcium channel blocker (nimodipine) on transcranial magnetic stimulation (TMS)-evoked electroencephalographic (EEG) potentials (TEPs) and TMS-induced oscillations (TIOs) in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled crossover design. Single-pulse TMS was delivered to the hand area of left primary motor cortex. Dextromethorphan increased the amplitude of the N45 TEP, while it had no effect on TIOs. Perampanel reduced the amplitude of the P60 TEP in the non-stimulated hemisphere, and increased TIOs in the beta-frequency band in the stimulated sensorimotor cortex, and in the alpha-frequency band in midline parietal channels. Nimodipine and placebo had no effect on TEPs and TIOs. The TEP results extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA receptor-mediated glutamatergic excitation. In contrast, AMPA receptor-mediated glutamatergic neurotransmission contributes to propagated activity reflected in the P60 potential and midline parietal induced oscillations. This pharmacological characterization of TMS-EEG responses will be informative for interpreting TMS-EEG abnormalities in neuropsychiatric disorders with pathological excitation-inhibition balance.

Targeting mRNA processing as an anticancer strategy.

Discoveries in the past decade have highlighted the potential of mRNA as a therapeutic target for cancer. Specifically, RNA sequencing revealed that, in addition to gene mutations, alterations in mRNA can contribute to the initiation and progression of cancer. Indeed, precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3' ends by cleavage and polyadenylation, is frequently altered in tumours. These alterations result in numerous cancer-specific mRNAs that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumour-suppressor genes. Abnormally spliced and polyadenylated mRNAs are also associated with resistance to cancer treatment and, unexpectedly, certain cancers are highly sensitive to the pharmacological inhibition of splicing. This Review summarizes recent progress in our understanding of how splicing and polyadenylation are altered in cancer and highlights how this knowledge has been translated for drug discovery, resulting in the production of small molecules and oligonucleotides that modulate the spliceosome and are in clinical trials for the treatment of cancer.

Efficacy and Safety of Transcranial Direct Current Stimulation for Treating Negative Symptoms in Schizophrenia: A Randomized Clinical Trial.

Importance: Negative symptoms represent a substantial burden in schizophrenia. Although preliminary studies have suggested that transcranial direct current stimulation (tDCS) is effective for some clusters of symptoms, the clinical benefits for negative symptoms are unclear. Objective: To determine the efficacy and safety of tDCS vs sham as an add-on treatment for patients with schizophrenia and predominant negative symptoms. Design, Setting, and Participants: The double-blind Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) randomized clinical trial was conducted from September 2014 to March 2018 in 2 outpatient clinics in the state of São Paulo, Brazil. Patients with schizophrenia with stable negative and positive symptoms and a minimum score of 20 points in the negative symptoms subscale of the Positive and Negative Syndrome Scale (PANSS) were included. Interventions: Ten sessions of tDCS performed twice a day for 5 days or a sham procedure. The anode and the cathode were positioned over the left prefrontal cortex and the left temporoparietal junction, respectively. Main Outcomes and Measures: Change in the PANSS negative symptoms subscale score at week 6 was the primary outcome. Patients were followed-up for an additional 6 weeks. Results: Of the 100 included patients, 20 (20.0%) were female, and the mean (SD) age was 35.3 (9.3) years. A total of 95 patients (95.0%) finished the trial. In the intention-to-treat analysis, patients receiving active tDCS showed a significantly greater improvement in PANSS score compared with those receiving the sham procedure (difference, 2.65; 95% CI, 1.51-3.79; number needed to treat, 3.18; 95% CI, 2.12-6.99; P < .001). Response rates for negative symptoms (20% improvement or greater) were also higher in the active group (20 of 50 [40%]) vs the sham group (2 of 50 [4%]) (P < .001). These effects persisted at follow-up. Transcranial direct current stimulation was well tolerated, and adverse effects did not differ between groups, except for burning sensation over the scalp in the active group (43.8%) vs the sham group (14.3%) (P = .003). Conclusions and Relevance: Transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia. Trial Registration: ClinicalTrials.gov identifier: NCT02535676.

Brain oscillation-synchronized stimulation of the left dorsolateral prefrontal cortex in depression using real-time EEG-triggered TMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD), but response rates are low and effect sizes small. Synchronizing TMS pulses with instantaneous brain oscillations can reduce variability and increase efficacy of TMS-induced plasticity. OBJECTIVE: To study whether brain oscillation-synchronized rTMS is feasible, safe and has neuromodulatory effects when targeting the DLPFC of patients with MDD. METHODS: Using real-time EEG-triggered TMS we conducted a pseudo-randomized controlled single-session crossover trial of brain oscillation-synchronized rTMS of left DLPFC in 17 adult patients with antidepressant-resistant MDD. Stimulation conditions in separate sessions were: (1) rTMS triggered at the negative EEG peak of instantaneous alpha oscillations (alpha-synchronized rTMS), (2) a variation of intermittent theta-burst stimulation (modified iTBS), and (3) a random alpha phase control condition. RESULTS: Triggering TMS at the negative peak of instantaneous alpha oscillations by real-time analysis of the electrode F5 EEG signal was successful in 15 subjects. Two subjects reported mild transient discomfort at the site of stimulation during stimulation; no serious adverse events were reported. Alpha-synchronized rTMS, but not modified iTBS or the random alpha phase control condition, reduced resting-state alpha activity in left DLPFC and increased TMS-induced beta oscillations over frontocentral channels. CONCLUSIONS: Alpha-synchronized rTMS of left DLPFC is feasible, safe and has specific single-session neuromodulatory effects in patients with antidepressant-resistant MDD. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of brain oscillation-synchronized rTMS in MDD.

Brain State-dependent Brain Stimulation with Real-time Electroencephalography-Triggered Transcranial Magnetic Stimulation.

The effect of a stimulus to the brain depends not only on the parameters of the stimulus but also on the dynamics of brain activity at the time of the stimulation. The combination of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) in a real-time brain state-dependent stimulation system allows the study of relations of dynamics of brain activity, cortical excitability, and plasticity induction. Here, we demonstrate a newly developed method to synchronize the timing of brain stimulation with the phase of ongoing EEG oscillations using a real-time data analysis system. This real-time EEG-triggered TMS of the human motor cortex, when TMS is synchronized with the surface EEG negative peak of the sensorimotor µ-alpha (8-14 Hz) rhythm, has shown differential corticospinal excitability and plasticity effects. The utilization of this method suggests that real-time information about the instantaneous brain state can be used for efficacious plasticity induction. Additionally, this approach enables personalized EEG-synchronized brain stimulation which may lead to the development of more effective therapeutic brain stimulation protocols.

Schizophrenia TreAtment with electRic Transcranial Stimulation (STARTS): design, rationale and objectives of a randomized, double-blinded, sham-controlled trial.

INTRODUCTION: Schizophrenia is a severe mental disorder. While some antipsychotic medications have demonstrated efficacy in treating positive symptoms, there is no widely recognized treatment for negative symptoms, which can cause significant distress and impairment for patients with schizophrenia. Here we describe the rationale and design of the STARTS study (Schizophrenia TreAtment with electRic Transcranial Stimulation), a clinical trial aimed to test the efficacy of a non-pharmacological treatment known as transcranial direct current stimulation (tDCS) for treating the negative symptoms of schizophrenia. METHODS: The STARTS study is designed as a randomized, sham-controlled, double-blinded trial evaluating tDCS for the treatment of the negative symptoms of schizophrenia. One-hundred patients will be enrolled and submitted to 10 tDCS sessions over the left dorsolateral prefrontal cortex (anodal stimulation) and left temporoparietal junction (cathodal stimulation) over 5 consecutive days. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in the Positive and Negative Syndrome Scale (PANSS) negative subscale score over time and across groups. Biological markers, including blood neurotrophins and interleukins, genetic polymorphisms, and motor cortical excitability, will also be assessed. RESULTS: The clinical results will provide insights about tDCS as a treatment for the negative symptoms of schizophrenia, and the biomarker investigation will contribute towards an improved understanding of the tDCS mechanisms of action. CONCLUSION: Our results could introduce a novel therapeutic technique for the negative symptoms of schizophrenia. Clinical trial registration: ClinicalTrials.gov, NCT02535676 .

Schizophrenia TreAtment with electRic Transcranial Stimulation (STARTS): design, rationale and objectives of a randomized, double-blinded, sham-controlled trial / Tratamento da esquizofrenia com estimulação transcraniana por corrente contínua (ETCC): fundamentação teórica e objetivos de um ensaio clínico randomizado, duplo-cego, controlado por simulação

Abstract Introduction Schizophrenia is a severe mental disorder. While some antipsychotic medications have demonstrated efficacy in treating positive symptoms, there is no widely recognized treatment for negative symptoms, which can cause significant distress and impairment for patients with schizophrenia. Here we describe the rationale and design of the STARTS study (Schizophrenia TreAtment with electRic Transcranial Stimulation), a clinical trial aimed to test the efficacy of a non-pharmacological treatment known as transcranial direct current stimulation (tDCS) for treating the negative symptoms of schizophrenia Methods The STARTS study is designed as a randomized, sham-controlled, double-blinded trial evaluating tDCS for the treatment of the negative symptoms of schizophrenia. One-hundred patients will be enrolled and submitted to 10 tDCS sessions over the left dorsolateral prefrontal cortex (anodal stimulation) and left temporoparietal junction (cathodal stimulation) over 5 consecutive days. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in the Positive and Negative Syndrome Scale (PANSS) negative subscale score over time and across groups. Biological markers, including blood neurotrophins and interleukins, genetic polymorphisms, and motor cortical excitability, will also be assessed. Results The clinical results will provide insights about tDCS as a treatment for the negative symptoms of schizophrenia, and the biomarker investigation will contribute towards an improved understanding of the tDCS mechanisms of action. Conclusion Our results could introduce a novel therapeutic technique for the negative symptoms of schizophrenia. Clinical trial registration: ClinicalTrials.gov, NCT02535676 .

Resumo Introdução A esquizofrenia é um transtorno mental grave. Embora alguns medicamentos antipsicóticos tenham demonstrado eficácia no tratamento de sintomas positivos, não há tratamento amplamente reconhecido para sintomas negativos, o que pode causar sofrimento e prejuízo significativos para pacientes com esquizofrenia. Aqui descrevemos a fundamentação teórica e o design do estudo STARTS (Schizophrenia TreAtment with electRic Transcranial Stimulation), um ensaio clínico destinado a testar a eficácia de um tratamento não farmacológico conhecido como estimulação transcraniana por corrente contínua (ETCC) para tratar os sintomas negativos da esquizofrenia. Métodos O estudo STARTS foi concebido como um ensaio clínico randomizado, controlado por simulação, duplo-cego, avaliando a ETCC para o tratamento dos sintomas negativos da esquizofrenia. Cem pacientes serão incluídos e submetidos a 10 sessões de ETCC sobre o córtex pré-frontal dorsolateral esquerdo (estimulação anódica) e a junção temporoparietal esquerda (estimulação catodal) durante 5 dias consecutivos. Os participantes serão avaliados através de testes clínicos e neuropsicológicos antes e após a intervenção. O desfecho primário é a mudança na pontuação da subescala negativa da Escala da Síndrome Positiva e Negativa (Positive and Negative Syndrome Scale [PANSS]) ao longo do tempo e entre os grupos. Marcadores biológicos, incluindo neurotrofinas e interleucinas do sangue, polimorfismos genéticos e excitabilidade cortical motora, também serão avaliados. Resultados Os resultados clínicos fornecerão informações sobre a ETCC como um tratamento para os sintomas negativos da esquizofrenia, e a investigação dos biomarcadores contribuirá para uma melhor compreensão dos mecanismos de ação da ETCC. Conclusão Nossos resultados podem trazer uma nova técnica terapêutica para o tratamento dos sintomas negativos da esquizofrenia. Registro do ensaio clínico: ClinicalTrials.gov, NCT02535676.