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A frontal-vagal network theory for Major Depressive Disorder: Implications for optimizing neuromodulation techniques
Open accessAbstract
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 [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]
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“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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Heart Rate Variability: Standards of Measurement, Physiological Interpretation, and Clinical Use
Electrophysiology, T. F. O. T. E. S. O. C. T. N. A. (1996) · Circulation · doi:10.1161/01.cir.93.5.1043 · Cited by 17,159
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“Higher HRV is also related to an adaptive and increased top-down and bottom up modulation of cognitive emotional processing and to effective processing of negative stimuli [29].”
Deep Brain Stimulation for Treatment-Resistant Depression
Mayberg, H. S., Lozano, A. M., Voon, V., McNeely, H. E., Seminowicz, D., Hamani, C., Schwalb, J. M., & Kennedy, S. H. (2005) · Neuron · doi:10.1016/j.neuron.2005.02.014 · Cited by 4,059
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A model of neurovisceral integration in emotion regulation and dysregulation
Thayer, J. F., & Lane, R. D. (2000) · Journal of Affective Disorders · doi:10.1016/s0165-0327(00)00338-4 · Cited by 3,092
Heart rate variability: A review
Rajendra Acharya, U., Paul Joseph, K., Kannathal, N., Lim, C. M., & Suri, J. S. (2006) · Medical & Biological Engineering & Computing · doi:10.1007/s11517-006-0119-0 · Cited by 2,820
The Epidemiology of Depression Across Cultures
Kessler, R. C., & Bromet, E. J. (2013) · Annual Review of Public Health · doi:10.1146/annurev-publhealth-031912-114409 · Cited by 2,657
Shaffer, F., McCraty, R., & Zerr, C. L. (2014) · Frontiers in Psychology · doi:10.3389/fpsyg.2014.01040 · Cited by 1,866
The Relationship of Depression to Cardiovascular Disease: Epidemiology, Biology, and Treatment
Musselman, D. L., Evans, D. L., & Nemeroff, C. B. (1998) · Archives of General Psychiatry · doi:10.1001/archpsyc.55.7.580 · Cited by 1,532
Kemp, A. H., Quintana, D. S., Gray, M. A., Felmingham, K. L., Brown, K., & Gatt, J. M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.12.012 · Cited by 1,286
Research works printed but not linked: 1
- T.A. Iseger, F. Padberg, J.L. Kenemans, H. van Dijk & M. Arns. Neuro-cardiac-guided TMS: a validation study (under review at NeuroImage).
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Farmer, A. D., Strzelczyk, A., Finisguerra, A., Gourine, A. V., Gharabaghi, A., Hasan, A., Burger, A. M., Jaramillo, A. M., Mertens, A., Majid, A., et al. (2021) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2020.568051 · Cited by 375
Berk, M., Köhler‐Forsberg, O., Turner, M., Penninx, B. W. J. H., Wrobel, A., Firth, J., Loughman, A., Reavley, N. J., McGrath, J. J., Momen, N. C., et al. (2023) · World Psychiatry · doi:10.1002/wps.21110 · Cited by 336
Fitzgerald, P. B. (2021) · Brain Stimulation · doi:10.1016/j.brs.2021.04.018 · Cited by 126
Cash, R. F. H., & Zalesky, A. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.11.013 · Cited by 128
Sack, A. T., Paneva, J., Küthe, T. T., Dijkstra, E., Zwienenberg, L., Arns, M., & Schuhmann, T. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.09.011 · Cited by 126
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Metadata
- 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 (medical) › 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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