A frontal-vagal network theory for Major Depressive Disorder: Implications for optimizing neuromodulation techniques
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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.
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ANS function is purportedly modulated by the core-ICNs and one of the most robust ANS disturbances found in IDs is cardiac dysautonomia in the form of reduced HRV.
“ANS function is purportedly modulated by the core-ICNs and one of the most robust ANS disturbances found in IDs is cardiac dysautonomia in the form of reduced HRV [52, 96, 103, 280, 282–293].”
From Infraslow closed-loop brain training for anxiety and depression (ISAD): a protocol for a randomized, double-blind, sham-controlled pilot trial in adult females with internalizing disorders (2022) · cites this paper as [283]
The section “Major Depressive Disorder (MDD) and the autonomic nervous system” (page unavailable) reports lower HRV in depressed patients than in healthy controls. The General discussion (page unavailable) describes a frontal-vagal network linking brain regions to autonomic cardiac control. The paper does not establish the claim for IDs broadly or identify the proposed modulators as core-ICNs. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA frontal-vagal brain network - including the medulla of brainstem, hypothalamus, amygdala, insula, as well as dorsolateral prefrontal, anterior cingulate and orbitofrontal cortex - has been proposed to link cardiovascular diseases, metabolic diseases and MDD, because of its influence on the cardiovascular system, mood, appetite and sleep.
“A frontal-vagal brain network – including the medulla of brainstem, hypothalamus, amygdala, insula, as well as dorsolateral prefrontal, anterior cingulate and orbitofrontal cortex – has been proposed to link cardiovascular diseases, metabolic diseases and MDD, because of its influence on the cardiovascular system, mood, appetite and sleep265.”
From Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management (2023) · cites this paper as [265]
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Theta-tACS modulates brain-heart interplay to enhance sleep in insomnia disorder
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- Authors
- Iseger, T. A., van Bueren, N. E. R., Kenemans, J. L., Gevirtz, R., & Arns, M.
- Affiliations
- Utrecht University (NL)
- Alliant University (US)
- Corresponding author
- Arns, Martijn
- Venue
- Brain Stimulation
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 13
- Issue
- 1
- Pages
- 1-9
- ISSN
- 1876-4754 (ISSN-L)
- 1935-861X
- OpenAlex
- W2979927084
- Cited by
- 142
- References
- 98
- Citations by year
- 2026: 17 · 2025: 26 · 2024: 17 · 2023: 18 · 2022: 18 · 2021: 31 · 2020: 15
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain stimulation (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Topics
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive disorder, heart rate variability, heart rate, vagus nerve, neuromodulation, repetitive transcranial magnetic stimulation, dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, heart-brain interaction, cardiovascular comorbidity
- MeSH terms
- Depressive Disorder, Major, Major Depressive Disorder, Gyrus Cinguli, Heart Rate, Humans, Motor Cortex, Vagus Nerve, Prefrontal Cortex, Transcranial Magnetic Stimulation
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