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Background: Investigating approaches for determining a functionally meaningful dorsolateral prefrontal cortex (DLPFC) stimulation site is imperative for optimising repetitive transcranial magnetic stimulation (rTMS) response rates for treatment-resistant depression. One proposed approach is neuro-cardiac-guided rTMS (NCG-TMS) in which high frequency rTMS is applied to the DLPFC to determine the site of greatest heart rate deceleration. This site is thought to index a frontal-vagal autonomic pathway that intersects a key pathway believed to underlie rTMS response., Objective: We aimed to independently replicate previous findings of high-frequency NCG-TMS and extend it to evaluate the use of low-frequency rTMS for NCG-TMS., Methods: Twenty healthy participants (13 female; aged 38.6 ± 13.9) underwent NCG-TMS on frontal, fronto-central (active) and central (control) sites. For high-frequency NCG-TMS, three 5 s trains of 10 Hz were provided at each left hemisphere site. For low-frequency NCG-TMS, 60 s trains of 1 Hz were applied to left and right hemispheres and heart rate and heart rate variability outcome measures were analysed., Results: For high-frequency NCG-TMS, heart rate deceleration was observed at the left frontal compared with the central site. For low-frequency NCG-TMS, accelerated heart rate was found at the right frontal compared with central sites. No other site differences were observed., Conclusion: Opposite patterns of heart rate activity were found for high- and low-frequency NCG-TMS. The high-frequency NCG-TMS data replicate previous findings and support further investigations on the clinical utility of NCG-TMS for optimising rTMS site localisation. Further work assessing the value of low-frequency NCG-TMS for rTMS site localisation is warranted., Competing Interests: Declaration of competing interest PBF has received equipment for research from MagVenture A/S, Medtronic Ltd, Neuronetics and Brainsway Ltd and funding for research from Neuronetics. He is on scientific advisory boards for Bionomics Ltd and LivaNova and is a founder of TMS Clinics Australia. MA reports options from Brain Resource (Sydney, Australia), is unpaid research director of the Brainclinics Foundation, a minority shareholder in neuroCare group (Munich, Germany); TAI and MA are co-inventor on a patent application covering NCG-TMS, but do not own the patent nor receive any royalties related to this patent; Research Institute Brainclinics received research funding from Brain Resource (Sydney, Australia) and neuroCare group (Munich, Germany); equipment support from Deymed, neuroConn and MagVenture, however data analyses and writing of this manuscript were unconstrained. We have no other conflicts of interest to declare., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Heart rate in MDD is often dysregulated, expressed in overall higher heart rates (HR) and lower heart rate variability (HRV). Interestingly, HR decelerations have been reported after stimulation of the DLPFC using rTMS, suggesting connectivity between the DLPFC and the heart. Recently, a new form of rTMS called theta burst stimulation (TBS) has been developed. One form of TBS, intermittent TBS (iTBS), delivers 600 pulses in just 3 min., Objective: To determine whether iTBS aimed at the DLPFC also affects HR, blood pressure and HRV, and whether these cardiac responses at baseline are associated with treatment response., Methods: ECG and blood pressure were recorded during both sham and active iTBS in 15 MDD patients, over 30 sessions., Results: We found a significantly larger HR deceleration for active iTBS, compared to sham, within the first minute of stimulation. Also, a trend towards an association between HR deceleration and treatment response was found, explaining 26% of the variance. Furthermore, several measures of heart rate variability were significantly higher during iTBS stimulation over sessions, compared to sham. Both systolic and diastolic blood pressure, were lower during active iTBS., Conclusion: Active iTBS applied to the DLPFC is able to transsynaptically modulate the autonomic nervous system, in particular the parasympathetic branch, similar to what has been found for conventional rTMS methods. Furthermore, data suggest that the larger the autonomic changes induced at baseline, the better the clinical response after 30 sessions of iTBS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Major Depressive Disorder (MDD) is a psychiatric disorder characterized by high comorbidity with cardiovascular disease. Furthermore, a combination of high heart rate (HR) and low heart rate variability (HRV) has been frequently reported in depressed patients. The present review proposes a frontal-vagal (brain-heart) network that overlaps with functional nodes of the depression network. Moreover, we summarize neuromodulation studies that have targeted key nodes in this depression network, with subsequent impact on heart rate (HR) or heart-rate-variability (HRV), such as the dorsolateral prefrontal cortex (DLPFC), subgenual anterior cingulate cortex (sgACC), and the vagus nerve (VN). Based on the interplay of this frontal-vagal network, we emphasize the importance of including HR and HRV measurements in human depression studies, in particular those that conduct neuromodulation, in order to obtain a better understanding of the pathways that are affected, and we explore the possibilities of using this frontal-vagal interplay as a method for target engagement in neuromodulation treatments. This frontal-vagal network theory opens-up the possibility for individualizing neuromodulation treatments such as rTMS. A recent development called Neuro-Cardiac-Guided TMS (NCG-TMS), was developed based on this theory, and an individual-participant meta-analysis is presented. Four studies provide consistent and replicable support for NCG-TMS as a target engagement method, with consistent HR deceleration during frontal TMS and HR acceleration during motor strip TMS., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique increasingly used to modulate neural activity in the living brain. In order to establish the neurophysiological, cognitive or clinical effects of tDCS, most studies compare the effects of active tDCS to those observed with a sham tDCS intervention. In most cases, sham tDCS consists in delivering an active stimulation for a few seconds to mimic the sensations observed with active tDCS and keep participants blind to the intervention. However, to date, sham-controlled tDCS studies yield inconsistent results, which might arise in part from sham inconsistencies. Indeed, a multiplicity of sham stimulation protocols is being used in the tDCS research field and might have different biological effects beyond the intended transient sensations. Here, we seek to enlighten the scientific community to this possible confounding factor in order to increase reproducibility of neurophysiological, cognitive and clinical tDCS studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation (rTMS) is considered an efficacious non-invasive neuromodulation treatment for major depressive disorder (MDD). However, little is known about the clinical outcome of combined rTMS and psychotherapy (rTMS + PT). Through common neurobiological brain mechanisms, rTMS + PT may exert enhanced antidepressant effects compared to the respective monotherapies., Objective: The current naturalistic study aimed to evaluate feasibility and clinical outcome of rTMS + PT in a large group of MDD patients. The second aim was to identify clinical predictors of response and remission., Methods: A total of 196 patients with MDD were treated with at least 10 sessions of simultaneous rTMS and PT. rTMS was applied over the DLPFC, either 10 Hz left or 1 Hz right. Psychotherapy was based on principles of cognitive behavioral therapy (CBT). Symptoms were measured using the BDI each fifth session until end of treatment and at 6-month follow-up. Comparisons were made between responders and non-responders, as well as between the 10 Hz and 1 Hz protocol. Additionally, baseline variables and early BDI change were evaluated as predictors of response/remission., Major Findings and Conclusions: 1) Combining rTMS and PT resulted in a 66% response and a 56% remission rate at the end of treatment with 60% sustained remission at follow-up. Compared to previous findings in RCTs, these rates are relatively high; 2) No differences were found between the 10 Hz and 1 Hz TMS regarding clinical outcome; 3) Clinical baseline variables were not predictive of treatment outcomes; 4) Early symptom improvement (at session 10) was highly predictive of response, and may therefore be used to guide rTMS + PT continuation; 5) Based on the current findings in a large naturalistic study, future studies employing a more standardized method are warranted to draw solid conclusions on the unique effect of rTMS + PT., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The application of rTMS in Depression has been very well investigated over the last few years. However, little is known about predictors of non-response associated with rTMS treatment., Objective: This study examined neurophysiological parameters (EEG and ERP) in 90 depressed patients treated with rTMS and psychotherapy and sought to identify predictors of non-response., Methods: This study is a multi-site open-label study assessing pre-treatment EEG and ERP measures associated with non-response to rTMS treatment., Results: Non-responders were characterized by 1) Increased fronto-central theta EEG power, 2) a slower anterior individual alpha peak frequency, 3) a larger P300 amplitude, and 4) decreased pre-frontal delta and beta cordance. A discriminant analysis yielded a significant model, and subsequent ROC curve demonstrated an area under the curve of 0.814., Conclusions: Several EEG variables demonstrated clear differences between R and NR such as the anterior iAPF, fronto-central Theta and pre-frontal cordance in the Delta and Beta band (representative of increased relative pre-frontal perfusion). The increased P300 amplitude as a predictor for non-response requires further study, since this was the opposite as hypothesized and there were no correlations of this measure with clinical improvement for the whole sample. Combining these biomarkers in a discriminant analysis resulted in a reliable identification of non-responders with low false positive rates. Future studies should prospectively replicate these findings and also further investigate appropriate treatments for the sub-groups of non-responders identified in this study, given that most of these biomarkers have also been found in antidepressant medication studies., (Copyright © 2012 Elsevier Inc. All rights reserved.)