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The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex
Open accessAbstract
A primary aim in the neuroscientific study of depression is to identify the brain areas involved in the pathogenesis of symptoms. In this review, we describe evidence from studies employing various experimental approaches in humans (functional imaging, lesion method, and brain stimulation) that converge to implicate the ventromedial and dorsolateral sectors of prefrontal cortex as critical neural substrates for depression, albeit with distinct functional contributions. The putative roles of ventromedial and dorsolateral prefrontal cortex in depression are discussed in light of the results.
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“Consistent with the original FDA label, rTMS for MDD most commonly targets the left hemisphere DLPFC, a key node in the functional pathophysiology thought to underlie depressive symptoms (21).”
From Adaptive trial for the treatment of depressive symptoms associated with concussion using accelerated intermittent theta burst stimulation (ADEPT): rationale, design and methods (2025) · cites this paper as [21]
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“Furthermore, damage to the ventromedial prefrontal cortex has been associated with emotional deficits including diminished guilt (Koenigs & Grafman, 2009)”
From A novel resting-state functional magnetic resonance imaging signature of resilience to recurrent depression (2017) · cites this paper as Koenigs & Grafman, 2009
In the citing paper
“Substantial evidence indicates that mPFC dysfunction plays a critical role in the pathology of major depressive disorder (MDD) 203.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [203]
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“One recent review of brain function in depression [71] concluded that depression is typified by hypoactivation in dorsolateral PFC (including dorsal ACC), as well as hyperactivation in ventromedial PFC (including subgenual ACC).”
From Arrested development? Reconsidering dual-systems models of brain function in adolescence and disorders (2012) · cites this paper as [71]
In the citing paper
“Research efforts aimed at understanding the neural circuits underlying depression have been mainly devoted to the prefrontal cortex, hippocampus, and mesolimbic structures [12, 55, 56].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [12]
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Citations
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“[43-45] L dlPFC -- -- ----R dlPFC -- -- -----”
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“One of the functions of DLPFC is to perform top-down regulation for appropriate behavioral response [114], [115] and cognitive regulation of negative emotions [116]–[121].”
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“Its abnormal activation has been associated with psychiatric disorders and cognitive impairment (Koenigs & Grafman, 2009; Zhang et al., 2022).”
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Liang, R., Fang, T., Wang, L., Ren, J., Meng, L., Zhao, M., Zheng, C., Fan, Q., Chen, Y., Yang, J., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03538-6 · Cited by 1
“Dysregulation of synaptic transmission in the PFC is closely associated with social de fi cits, emotional disorders, and memory loss in neuropsychiatric conditions such as autism [66], schizophrenia [67 – 69], depression [70, 71], and Alzheimer ’ s disease [72, 73].”
Sutherland, B. D., Hill-Bowen, L. D., Trucco, E. M., Laird, A. R., & Sutherland, M. T. (2025) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2025.101634 · Cited by 3
“As primary CEN nodes, lPFC activity often positively correlates with cognitive performance (Hu et al., 2013) and is also involved with affective processes (Koenigs and Grafman, 2009); for example, emotion regulation through reappraisal (Golkar et al., 2012).”
Xu, L., He, J., Yang, L., Du, D., Yang, F., Feng, L., Jin, Y., Li, C., & Yang, J. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-07393-z · Cited by 2
“…activity and ameliorate hypo-activation of the prefrontal cogni-tive-control network, thereby enhancing verbal learning and executive function [62, 63], and low-frequency stimulation over the right DLPFC to down-regulate hyper-active amygdala–anterior-cingulate circuitry, reduce anxiety and…”
Wu, J., Luo, Z.-C., Xiong, N., Gan, C., & Chen, W. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.124052 · Cited by 1
Factors Associated with Posttraumatic Stress Disorder in Patients with Major Depressive Disorder
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Cortical Thickness Associated with the Degree of Anemia in Children with Sickle Cell Disease
Vishnubhotla, R. V., Class, J. A., Porter, T. A., Goubeaux, D. L., LaMotte, J. E., Jacob, S. A., & Radhakrishnan, R. (2025) · American Journal of Neuroradiology · doi:10.3174/ajnr.a9114 · Cited by 1
Memory in Psychiatric Disorders: A Review
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“Neuroimaging reveals hypoacti-vation of the DLPFC during STM tasks [104,105].”
Sousa-Ho, R. L., Demchenko, I., Baltazar, V. A., Tailor, I., Dunkley, B. T., Schweizer, T. A., Kennedy, S. H., Boutet, A., Lozano, A. M., Fatt, C. C., et al. (2026) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111616 · Cited by 1
Guo, Y., Gao, X., Liu, J., Shen, Q., Jia, X., Zhang, H., Wu, Y., Li, W., Gao, H., Zhou, C., et al. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.121277 · Cited by 1
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“Lesions or hypoactivity in this region are linked to reduced self-awareness and insight, diminished feelings of guilt or remorse, and heightened impulsivity (Koenigs and Grafman 2009; Mayberg 1997).”
Kim, J.-Y., & Park, S.-J. (2026) · Sensors · doi:10.3390/s26030985 · Cited by 1
Zhou, J., Liao, A., Ma, X., Yang, Z., Li, C., Hé, Y., & Chen, X. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.121353 · Cited by 1
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“Notably, individuals with social anxiety disorder (SAD) show elevated activity in the insular cortex under social stress conditions, while activity in the ventral striatum is reduced (Koenigs and Grafman, 2009).”
Feng, X., Wang, Q., & Wu, X. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1749844 · Cited by 1
Zeiler, K., Jämterud, S. M., León, F., Andersson, A., Thornberg, U. B., Blystad, I., Divanoglou, A., Eklund, A., Engblom, D., & Levi, R. (2026) · Phenomenology and the Cognitive Sciences · doi:10.1007/s11097-026-10151-5 · Cited by 1
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Dorsolateral Prefrontal Cortex Circuitry at the Intersection of Cognition and Disease
Datta, D., Arnsten, A. F. T., Rizzo, S. J. S., Silva, A. C., Joyce, M. K. P., Tripathy, S. J., Roberts, A., & Lewis, D. A. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2026.07.012 · Cited by 2
Brain Imaging Correlates of Anhedonia
Preda, A. (2014) · Springer eBooks · doi:10.1007/978-94-017-8591-4_14 · Cited by 1
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Singh, R. B., Torshin, V. I., Bawareed, O., Verma, N., Fabian, M., Wichansawakun, S., Chládeková, A., Kartikey, K., & Wichansawakun, S. (2019) · Biomedical Journal of Scientific & Technical Research · doi:10.26717/bjstr.2019.14.002484
“Neuroscientists have reported that the amygdala, hippocampus, prefrontal cortex, striatum, nucleus accumbens, and the cerebellum are some of the many structures of the brain that are smaller in size among patients with depression, as compared with those of typical, healthy individuals, which may be due to inflammation…”
Background
Metadata
- Authors
- Koenigs, M., & Grafman, J.
- Affiliations
- University of Wisconsin–Madison (US)
- National Institutes of Health (US)
- Corresponding author
- Koenigs, Michael
- Venue
- Behavioural Brain Research
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 201
- Issue
- 2
- Pages
- 239-243
- ISSN
- 0166-4328 (ISSN-L)
- PMC
- PMC2680780
- OpenAlex
- W2156809536
- Cited by
- 956
- References
- 39
- Citations by year
- 2026: 43 · 2025: 54 · 2024: 60 · 2023: 60 · 2022: 83 · 2021: 88 · 2020: 64 · 2019: 80 · 2018: 77 · 2017: 52 · 2016: 70 · 2015: 55 · 2014: 38 · 2013: 41 · 2012: 38
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Behavioural Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (Z01NS002792)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- depression, ventromedial prefrontal cortex, dorsolateral prefrontal cortex, prefrontal cortex, functional neuroanatomy, brain lesions, transcranial magnetic stimulation, functional imaging
- MeSH terms
- Brain Mapping, Depression, Depressive Disorder, Humans, Prefrontal Cortex, Transcranial Magnetic Stimulation
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