Background and objective: Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective treatment for major depressive disorder (MDD); however, this treatment currently lacks reliable biomarkers of treatment response. TMS-evoked potentials (TEPs), measured using TMS-electroencephalography (TMS-EEG), have been suggested as potential biomarker candidates, with the N100 peak being one of the most promising. This study investigated the association between baseline N100 amplitude and 1 Hz right dorsolateral prefrontal cortex (RDLPFC) accelerated rTMS (arTMS) treatment in MDD. Methods: Baseline TMS-EEG sessions were performed for 23 MDD patients. All patients then underwent 40 sessions of 1 Hz R-DLPFC (F4) arTMS over 5 days and a follow-up TMS-EEG session one week after the end of theses arTMS sessions. Results: Baseline N100 amplitude at F4 showed a strong positive association (p p < .001) with treatment outcome. The association between the change in N100 amplitude (baseline to follow-up) and treatment outcome did not remain significant after Bonferroni correction (p p = .06, corrected; p = .03, uncorrected). Furthermore, treatment responders had a significantly larger mean baseline F4 TEP amplitude during the N100 time frame compared to non-responders (p p < .001). Topographically, after Bonferroni correction, F4 is the only electrode at which its baseline N100 amplitude showed a significant positive association (p < .001) with treatment outcome. Limitations: Lack of control group and auditory masking. Conclusion: Baseline N100 amplitude showed a strong association with treatment outcome and thus demonstrated great potential to be utilized as a cost-effective and widely adoptable biomarker of rTMS treatment in MDD.

Background: Dysfunctional sensory gating in anxiety disorders, indexed by the failure to inhibit the P50 event-related potential (ERP) to repeated stimuli, has been linked to deficits in the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Aims/Methods: This study, conducted in 30 healthy volunteers, examined the acute effects of GABA(A) (lorazepam: 1 mg) and GABA(B) receptor (baclofen: 10 mg) agonists on P50 measures of auditory sensory gating within a paired-stimulus (S1-S2) paradigm and assessed changes in gating in relation to self-ratings of anxiety. Results: Compared to placebo, lorazepam reduced ERP indices of sensory gating by attenuating response to S1. Although not directly impacting P50 inhibition, baclofen-induced changes in gating (relative to placebo) were negatively correlated with trait but not state anxiety. Conclusions: These preliminary findings support the involvement of GABA in sensory gating and tentatively suggest a role for GABA(B) receptor signaling in anxiety-associated gating dysregulation.

Background and objective: High frequency (HF) left dorsolateral prefrontal cortex (L-DLPFC) rTMS has been reported to induce mild, transient bradycardia in patients with major depressive disorder (MDD), measured using electrocardiography (ECG). Low frequency (LF) rTMS has distinct advantages compared to HF rTMS and our previous investigation of a similar design suggested that heart rate (HR) may have biomarker potential for LF rTMS in MDD patients. Our previous study supported the utilization of HR biomarkers for LF-rTMS in MDD and thus this exploratory replication study aims to further investigate, in a different cohort and with a different coil, the effect of 1Hz right hemisphere (R)-DLPFC rTMS on the HR of MDD patients, as well as the potential of using HR as a simple, scalable biomarker to predict rTMS treatment response. Methods: 24 participants underwent 30 sessions of accelerated 1Hz R-DLPFC rTMS within 7 days after the baseline ECG session, followed by 20-25 once-a-day sessions 7 days after. The Beck Depression Inventory-II score was used as the primary outcome measure. Results: HR significantly decreased during the first 3 min of the rTMS period. Resting HR, HR during rTMS, and the degree of HR reduction were not significantly associated with treatment outcome. Conclusion: The results of the current study remain in concordance in trend with that of our previous study despite the use of a less accurate rTMS coil. Therefore, this study further supports the biomarker potential of HR for LF-rTMS in MDD patients.

Auditory cortical plasticity deficits in schizophrenia are evidenced with electroencephalographic (EEG)-derived biomarkers, including the 40-Hz auditory steady-state response (ASSR). Aiming to understand the underlying oscillatory mechanisms contributing to the 40-Hz ASSR, we examined its response to transcranial alternating current stimulation (tACS) applied bilaterally to the temporal lobe of 23 healthy participants. Although not responding to gamma tACS, the 40-Hz ASSR was modulated by theta tACS (vs sham tACS), with reductions in gamma power and phase locking being accompanied by increases in theta-gamma phase–amplitude cross-frequency coupling. Results reveal that oscillatory changes induced by frequency-tuned tACS may be one approach for targeting and modulating auditory plasticity in normal and diseased brains.

Background and objectiveRepetitive transcranial magnetic stimulation (rTMS) is an effective and safe treatment for major depressive disorder (MDD). rTMS is in need of a reliable biomarker of treatment response. High frequency (HF) dorsolateral prefrontal cortex (DLPFC) rTMS has been reported to induce significant changes in the cardiac activity of MDD patients. Low frequency DLPFC rTMS has many advantages over HF-DLPFC rTMS and thus this study aims to further investigate the effect of low frequency 1 Hz right hemisphere (R)-DLPFC rTMS on the cardiac activity of MDD patients, as well as the potential of using electrocardiogram (ECG) parameters as biomarkers of treatment outcome.MethodsBaseline ECG sessions were performed for 19 MDD patients. All patients then underwent 40 sessions of accelerated 1 Hz R-DLPFC rTMS one week after the baseline session.ResultsHeart rate (HR) significantly decreased from the resting period to the first and third minute of the 1 Hz R-DLPFC rTMS period. Resting HR was found to have a significant negative association with treatment outcome. Prior to Bonferroni correction, HR during stimulation and the degree of rTMS-induced HR reduction were significantly negatively associated with treatment outcome. No significant changes were observed for the heart rate variability (HRV) parameters.LimitationsSample size (n = 19); the use of electroencephalography equipment for ECG; lack of respiration monitoring; relatively short recording duration for HRV parameters.ConclusionThis novel study provides further preliminary evidence that ECG may be utilized as a biomarker of rTMS treatment response in MDD.Trial registrationClinicalTrials.gov Identifier: NCT04376697.

In schizophrenia, a disorder associated with N-methyl-D-aspartate receptor (NMDAR) hypofunction, auditory cortical plasticity deficits have been indexed by the synchronized electroencephalographic (EEG) auditory steady-state gamma-band (40-Hz) response (ASSR) and the early auditory evoked gamma-band response (aeGBR), both considered to be target engagement biomarkers for NMDAR function, and potentially amenable to treatment by NMDAR modulators. As transcranial direct current stimulation (tDCS) is likely dependent on NMDAR neurotransmission, this preliminary study, conducted in 30 healthy volunteers, assessed the off-line effects of prefrontal anodal tDCS and sham (placebo) treatment on 40-Hz ASSR and aeGBR. Anodal tDCS failed to alter aeGBR but increased both 40-Hz ASSR power, as measured by event-related spectral perturbations (ERSP), and phase locking, as measured by inter-trial phase consistency (ITPC). Inter-individual differences in tDCS-induced increases in ERSP were negatively related to baseline ERSPs. These findings provide tentative support for further study of tDCS as a potential NMDAR neuromodulatory intervention for synchronized auditory gamma response deficits.

Although effective in major depressive disorder (MDD), repetitive transcranial magnetic stimulation (rTMS) is costly and complex, limiting accessibility. To address this, we tested the feasibility of novel rTMS techniques with cost-saving opportunities, such as an open-room setting, large non-focal parabolic coils, and custom-built coil arms. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved device. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. Repeated measures ANOVA showed significant changes of BDI-II scores over time. Even though our protocol will require further improvements, some of the concepts we introduced here could help guide the design of future trials aiming at increasing accessibility to rTMS.

•There are no validated and scalable biomarkers for response prediction in MDD.•Heart rate variability (HRV) has shown promise in some antidepressant studies.•We tested the role of HRV for outcome prediction to accelerated 1 Hz rTMS in MDD.•A linear mixed effects model did not show association between HRV and outcomes.•Other approaches using cardiac biomarkers might prove useful.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention for major depressive disorder (MDD). Completing a full treatment course, however, is costly and time-consuming. Biomarkers of clinical outcome such as baseline resting-state brain activity measured with electroencephalography (EEG) may spare people futile treatment and conserve limited clinical resources. Additionally, investigating changes in EEG power post-treatment could provide insights into the working mechanism of rTMS. Methods: 39 MDD patients received 6 daily sessions of accelerated low-frequency (LF) rTMS over the right dorsolateral prefrontal cortex (DLPFC) for 5 days followed by a tapering course of 25 once-daily sessions. Resting-state EEG and heart rate (HR) measures were acquired immediately before and after a single rTMS session at 3 different timepoints: baseline, one week after the final accelerated session, and upon completion of the tapering course. The primary clinical outcome measure was the Beck Depression Inventory II (BDI-II). Results: High relative baseline theta power in prefrontal areas and high baseline HR were associated with poorer clinical outcome. HR decreased acutely at the beginning of the patients’ first rTMS session but this effect was not associated with treatment outcome. Limitations: The main limitations were small sample size and a lack of sham and healthy control group. Conclusion: Our results suggest that high relative theta power at baseline may be a marker of poorer response to right-sided LF rTMS. If validated, this easily applicable measure could inform rTMS protocol choice for the individual, thereby potentially speeding up patient recovery and saving clinical resources.

BACKGROUNDRepetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retaining similar effectiveness would thus increase the practicality and scalability of the technique, and therefore its accessibility.OBJECTIVEWe assessed the feasibility of a novel 5 day accelerated 1 Hz rTMS protocol. We hypothesized that this novel rTMS protocol would be safe and well-tolerated while shortening the overall treatment course.METHODSWe conducted a prospective, single-arm, open-label feasibility study. Thirty (30) participants received a one-week (5 days) accelerated (8 sessions per day, 40 sessions total) course of 1 Hz rTMS (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex (R-DLPFC) using a figure-of-eight coil at 120% of the resting motor threshold (rMT). Depression severity was assessed on the Beck Depression Inventory-II (BDI-II) and 17-item Hamilton Rating Scale for Depression (HRSD-17).RESULTSResponse and remission rates 1 week after treatment were 33.3% and 13.3% respectively and increased to 43.3% and 30.0% at 4 weeks after treatment. No serious adverse events occurred. All participants reported manageable pain levels.CONCLUSION1 Hz rTMS administered 8 times daily for 5 days is safe and well-tolerated. Efficacy at the end of the course was similar to a standard daily course of 1 Hz rTMS, and there appears to be an additional delayed effect. Further validation in a randomized trial is required.ClinicalTrials.gov Identifier:NCT04376697

Widespread adoption of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD) has been impeded by high complexity and operational costs, decreasing accessibility.

ABSTRACTBACKGROUNDRepetitive transcranial magnetic stimulation (rTMS) is effective in major depressive disorder (MDD). However, technical complexity and operational costs might have been barriers for its wide use and implementation in some jurisdictions, thereby decreasing accessibility.OBJECTIVEOur main goal was to test the feasibility of a novel rTMS protocol optimized for practicality, scalability and cost-effectiveness. We hypothesized that our novel rTMS protocol would be simple to implement and well-tolerated, but less costly and allow for more treatment capacity.METHODSTreatment was administered in an open-room setting, allowing a single technician to attend to multiple patients. Large non-focal parabolic coils held by custom-built arms allowed simple yet efficient and accurate placement. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved devices. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression.RESULTSForty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course.CONCLUSIONIf rTMS could be delivered for lower cost at higher volume, while preserving efficacy, safety and tolerability, it could warrant further investigation of this treatment as a first-line intervention in MDD.TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT04376697

Objective The effects of GABA modulating drugs and nicotine, the prototypical nicotinic cholinergic agonist, on attention have been investigated using subcomponents of the P300 event-related potentials (ERP), which index involuntary (P3a) and voluntary attention (P3b). However, investigations into how such pharmacologic effects interact with genetic features in the GABA system remain unclear. This study examined the moderating effects of a single nucleotide polymorphism (rs7557793) in the glutamic acid decarboxylase 67 (GAD1) gene, which is implicated in the conversion of glutamate to GABA, on P300-indices of auditory attentional processing; the influence of nicotine administration was also assessed. Methods The effects of GAD1 genotype (TT/CC/CT) were examined on the P3a/b in response to an auditory selective attention task in healthy, nonsmoking male volunteers (N = 126; 18-40 years). Participants responded to rare target stimuli (P3b-eliciting) and ignored frequent nontarget stimuli as well as rare distractor stimuli (P3a-eliciting). In a subsample (N = 59), P3a/b profiles to acute nicotine (vs. placebo) administration were examined as a function of GAD1 genotype. As a secondary aim, earlier sensory processes were assessed with N200 ERP subcomponents elicited by novel (N2a) and target (N2b) auditory stimuli. Results GAD1 allelic variation moderated early sensory processes, enhancing N2a amplitudes in CT versus TT carriers. Further, TT homozygotes exhibited larger P3b amplitudes than CC homozygotes in the placebo versus nicotine condition. Regardless of genotype, nicotine versus placebo moderated the N200 ERP. Conclusion These findings expand our knowledge regarding the attentional effects of GAD1 genetic variants in relation to nicotine.

Schizophrenia is associated with disturbed auditory perceptions including auditory verbal hallucinations (AVH), which have been related to aberrant phase-locking of gamma-band steady state responses and have responded to treatment with transcranial direct current stimulation (tDCS). The objective of this study was to examine the effects of a single session of tDCS on auditory cortex responsiveness by assessing EEG power and phase measures of the 40-HZ auditory steady-state response (ASSR). In a randomized, crossover, sham-controlled design, 20 min of 2 mA anodal tDCS over the left prefrontal cortex in 30 healthy participants significantly increased 40-HZ ASSR spectral power and phase locking compared with sham tDCS. Increases in gamma power with anodal stimulation correlated with sham evoked gamma power, indicating a baseline-dependant relationship in which individuals with smaller baseline gamma power exhibit greater power increases with tDCS. This data suggests that altered gamma circuitry may be one mechanism underlying AVH responsiveness to tDCS in schizophrenia patients.

Schizophrenia (SZ) is a psychiatric disorder characterized by cognitive dysfunction within the realm of attentional processing. Reduced P3a and P3b event-related potentials (ERPs), indexing involuntary and voluntary attentional processing respectively, have been consistently observed in SZ patients who also express prominent cholinergic deficiencies. The involvement of the brain's cholinergic system in attention has been examined for several decades; however, further inquiry is required to further comprehend how abnormalities in this system affect neighbouring neurotransmitter systems and contribute to neurocognitive deficits. The objective of this pilot study was to examine the moderating role of the CHRNA4 (rs1044396), CHRNA7 (rs3087454), and SLC5A7 (rs1013940) genes on ERP indices of attentional processing in healthy volunteers (N=99; Caucasians and non-Caucasians) stratified by genotype and assessed using the auditory P300 "oddball" paradigm. Results indicated significantly greater P3a and P3b-indexed attentional processing for CT (vs. CC) CHRNA4 carriers and greater P3b for AA (vs. CC) CHRNA7 carriers. SLC5A7 allelic variants did not show significant differences in P3a and P3b processing. These findings expand our knowledge on the moderating effect of cholinergic genes on attention and could help inform targeted drug developments aimed at restoring attention deficits in SZ patients.