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Neuro-Cardiac-Guided Transcranial Magnetic Stimulation (NCG-TMS) was studied for its potential to specifically target the frontal-vagal network. Previous research demonstrated that prefrontal stimulation led to significant heartrate slowing. We aimed to replicate these results in a larger sample and extend the findings to investigate dose-response relationships, reproducibility and stimulation frequency (10 Hz and intermittent theta burst (iTBS)). Data of forty-five healthy controls were analyzed, of which 28 received 10 Hz TMS (NCG-TMS) and 27 iTBS (NCG-iTBS; 10 received both protocols) at different stimulation sites according to the 10-20-EEG system. NCG-TMS yielded a relative heartrate deceleration at the F3/4 coil position replicating earlier studies. Both internal consistency and dose-response relationships were found. For NCG-iTBS adverse events were reported and topography for frontal-vagal activation was more lateralised relative to NCG-TMS. These results indicate that we were able to transsynaptically stimulate the frontal-vagal network and that excitability thresholds for the prefrontal cortex may differ relative to motor cortex., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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: Few studies focused on the relationship between psychological measures, major depressive disorder (MDD) and repetitive transcranial magnetic stimulation (rTMS) response. This study investigated several psychological measures as potential predictors for rTMS treatment response. Additionally, this study employed two approaches to evaluate the robustness of our findings by implementing immediate replication and full-sample exploration with strict p-thresholding., Methods: This study is an open-label, multi-site study with a total of 196 MDD patients. The sample was subdivided in a Discovery (60% of total sample, n = 119) and Replication sample (40% of total sample, n = 77). Patients were treated with right low frequency (1 Hz) or left high frequency (10 Hz) rTMS at the dorsolateral prefrontal cortex. Clinical variables [Beck Depression Inventory (BDI), Neuroticism, Extraversion, Openness Five-Factor Inventory, and Depression, Anxiety, and Stress Scale, and BDI subscales] were obtained at baseline, post-treatment, and at follow-up. Predictors were analyzed in terms of statistical association, robustness (independent replication), as well as for their clinical relevance [positive predictive value (PPV) and negative predictive value (NPV)]., Results: Univariate analyses revealed that non-responders had higher baseline anhedonia scores. Anhedonia scores at baseline correlated negatively with total BDI percentage change over time. This finding was replicated. However, anhedonia scores showed to be marginally predictive of rTMS response, and neither PPV nor NPV reached the levels of clinical relevance., Conclusions: This study suggests that non-responders to rTMS treatment have higher baseline anhedonia scores. However, anhedonia was only marginally predictive of rTMS response. Since all other psychological measures did not show predictive value, it is concluded that psychological measures cannot be used as clinically relevant predictors to rTMS response in MDD.

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.)

Low heart rate variability (HRV) has strongly been associated with an increased risk for cardiovascular disease. With cardiovascular disease being the number one cause of global deaths, factors that influence its development are relevant to understand. Season of birth has been suggested as one of the factors influencing the development of HRV. The current study was set up to replicate the finding that men born in winter have higher HRV later in life compared to those born in other seasons. To this end, we studied a sample of 1,871 healthy participants from the Brain Resource International Database during rest and during task. Furthermore, sex and age differences and associations with personality traits and psychiatric symptoms were explored. We replicated the earlier finding that men born in winter have a lower ratio of low frequency (LF) power to high frequency (HF) power during rest compared to summer and fall, and, although less pronounced, higher HF compared to summer. A difference between summer and winter for LF/HF in men was internally replicated using data recorded during task. Additionally, for both sexes, LF/HF ratio increased with age, and LF and HF both decreased. In general, LF/HF was lower in women, but heart rate was higher. In men, low HRV was associated with depression and the personality trait openness. In conclusion, results from a large multicenter data set covering the entire lifespan demonstrate that HRV changes with age in both sexes and confirm that season of birth influences HRV later in life in men., (© 2019 Research Institute Brainclinics. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.)

Cannabis produces a broad range of acute, dose-dependent psychotropic effects. Only a limited number of neuroimaging studies have mapped these effects by examining the impact of cannabis on resting state brain neurophysiology. Moreover, how genetic variation influences the acute effects of cannabis on resting state brain function is unknown. Here we investigated the acute effects of ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on resting state brain neurophysiology, and their modulation by catechol-methyl-transferase (COMT) Val158Met genotype. Thirty-nine healthy volunteers participated in a pharmacological MRI study, where we applied Arterial Spin Labelling (ASL) to measure perfusion and functional MRI to assess resting state connectivity. THC increased perfusion in bilateral insula, medial superior frontal cortex, and left middle orbital frontal gyrus. This latter brain area showed significantly decreased connectivity with the precuneus after THC administration. THC effects on perfusion in the left insula were significantly related to subjective changes in perception and relaxation. These findings indicate that THC enhances metabolism and thus neural activity in the salience network. Furthermore, results suggest that recruitment of brain areas within this network is involved in the acute effects of THC. Resting state perfusion was modulated by COMT genotype, indicated by a significant interaction effect between drug and genotype on perfusion in the executive network, with increased perfusion after THC in Val/Met heterozygotes only. This finding suggests that prefrontal dopamine levels are involved in the susceptibility to acute effects of cannabis., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Antidepressant medication is the most common treatment for major depressive disorder (MDD), however, the precise working mechanism underlying these treatments remains unclear. Recent neuromodulation treatments demonstrate that direct stimulation of the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and subgenual anterior cingulate (sgACC) relate to clinical improvement, suggesting connectivity alterations of the DLPFC-DMPFC-sgACC network to mediate antidepressant response. The international Study to Predict Optimized Treatment in Depression (iSPOT-D) is an international multicentre study that collected EEG data for 1008 MDD patients, randomized to 3 different antidepressant medications (N=447 MDD with complete pre- and post-treatment data and N=336 non-MDD). Treatment response was defined by a decline of >50% on the Hamilton Rating Score for Depression (HRSD 17 ). We investigated whether connectivity in alpha and theta frequencies of the DLPFC-DMPFC-sgACC network changed from pre- to post-treatment between: (i) patients and controls, and (ii) responders (R) and non-responders (NR). Women exhibited higher alpha and theta connectivity compared to males, both pre- and post-treatment. Furthermore, theta, but not alpha, hypo-connectivity was found for MDD patients. A decreased alpha connectivity after treatment was found only for male responders, while non-responders and females exhibited no changes in alpha connectivity. Decreasing alpha connectivity could potentially serve as a treatment emergent biomarker, in males only. Furthermore, it could be useful to a priori stratify by gender for future MDD studies., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Despite extensive study over the past decades, available treatments for schizophrenia are only modestly effective and cause serious metabolic and neurological side effects. Therefore, there is an urgent need for novel therapeutic targets for the treatment of schizophrenia. A highly promising new pharmacological target in the context of schizophrenia is the endocannabinoid system. Modulation of this system by the main psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), induces acute psychotic effects and cognitive impairment. However, the non-psychotropic, plant-derived cannabinoid agent cannabidiol (CBD) may have antipsychotic properties, and thus may be a promising new agent in the treatment of schizophrenia. Here we review studies that investigated the antipsychotic properties of CBD in human subjects. Results show the ability of CBD to counteract psychotic symptoms and cognitive impairment associated with cannabis use as well as with acute THC administration. In addition, CBD may lower the risk for developing psychosis that is related to cannabis use. These effects are possibly mediated by opposite effects of CBD and THC on brain activity patterns in key regions implicated in the pathophysiology of schizophrenia, such as the striatum, hippocampus and prefrontal cortex. The first small-scale clinical studies with CBD treatment of patients with psychotic symptoms further confirm the potential of CBD as an effective, safe and well-tolerated antipsychotic compound, although large randomised clinical trials will be needed before this novel therapy can be introduced into clinical practice., (Copyright © 2015 Elsevier B.V. All rights reserved.)