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The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex
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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
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“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]
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“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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“The dlPFC is also involved in working memory processing (96, 97), decision making and cognitive control (98, 99), executive functions (100), as well as conflict resolution (101).”
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“…frontal area, richly connected to lateral prefrontal areas and the amygdala, provides access to object recognition to the amygdala, which is responsible for fear‐relevant information processing and its activation of fear or threat response both in animals and in humans (Koenigs & Grafman, 2009).”
BackgroundKorean red ginseng alleviate depressive disorder by improving astrocyte gap junction function
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“in almost all activities and decreased appetite in depression [19], supporting the idea that DLPFC plays a crucial role in the symptomatology of MDD [20].”
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“Working memory depends on the stability and functionality of the DLPFC, but schizophrenic patients perform poorly on working memory tasks due to this decreased activation [10–13] In addition, the amount of gray matter volume in the DLPFC has been found to be reduced in SCH and MDD patients compared to C subjects [14–1…”
BackgroundTranscranial Magnetic Stimulation for the Treatment of Pediatric Neurological Disorders
Malone, L. A., & Sun, L. R. (2019) · Current Treatment Options in Neurology · doi:10.1007/s11940-019-0600-3 · Cited by 22
“The rationale for the use of rTMS in this setting derives from prior imaging studies demonstrating that the left dorsolateral prefrontal cortex (DLPFC) is less active in patients with depression compared with healthy controls [15], and applica-”
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“Low-frequency rTMS over the right DLPFC has been proposed to potentially reduce hyperactivity in this region and alleviate associated negative cognitive and affective symptoms in major depressive disorder, such as impaired executive functioning, rumination, and persistent negative mood (8, 12, 13).”
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Pretreatment Brain Connectome Fingerprint Predicts Treatment Response in Major Depressive Disorder
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Exo- and Endo-cannabinoids in Depressive and Suicidal Behaviors
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“Lesions in the vmPFC can cause a loss of self-awareness and insight, with a marked reduction in feelings of shame, guilt, embarrassment, and regret (117).”
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“A large number of functional imaging, lesion, and brain stimulation studies have indicated that the PFC is essential for depression (5).”
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“A total of 26 proteins were identified that may have roles in the pathogenesis of MDD. Based on the MOTIF database (http://www.genome.jp/tools/motif/) and previous studies (16), a biological function classification on the differentially expressed proteins in the PFC was established.”
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“…in emotional regulation (Etkin et al., 2011; H€ansel and von K€anel, 2008; Motzkin et al., 2015), depressive symptoms (H€ansel and von K€anel, 2008; Koenigs and Grafman, 2009), stress and coping (H€ansel and von K€anel, 2008; Maier and Watkins, 2010; Sinha et al., 2016), the placebo effect…”
Behavioral consequences of co-administration of MTEP and the COX-2 inhibitor NS398 in mice. Part 1
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Dysfunction in primate dorsolateral prefrontal area 46 affects motivation and anxiety
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“Moreover, their results may be more related to the association between depressive symptoms and vmPFC (Koenigs and Grafman 2009; Koenigs et al.”
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“Furthermore, there is a wealth of evidence implicating dysregulation of serotonergic activity in this region with depression (Koenigs and Grafman 2009; Albert et al. 2014).”
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“Indeed, dlPFC has primarily been associated with ‘cognitive’ or ‘executive’ functions, whereas vmPFC is largely ascribed ‘emotional’ or ‘affective’ functions [9].”
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Self-citationImpaired white matter microstructure associated with severe depressive symptoms in patients with PD
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Razza, L. B., Smet, S. D., Hoornweder, S. V., Witte, S. D., Luethi, M. S., Baeken, C., Brunoni, A. R., & Vanderhasselt, M. (2023) · Cortex · doi:10.1016/j.cortex.2023.10.025 · Cited by 18
Neuroanatomical correlates of individual differences in social anxiety in a non-clinical population
Tian, X. S., Hou, X., Wang, K., Wei, D., & Qiu, J. (2015) · Social Neuroscience · doi:10.1080/17470919.2015.1091037 · Cited by 18
“However, distinct subregions of the PFC have different functions (Koenigs & Grafman, 2009; Kringelbach & Rolls, 2004; Zald, 2007).”
BackgroundA Brain Centred View of Psychiatric Comorbidity in Tinnitus: From Otology to Hodology
Salviati, M., Bersani, F. S., Valeriani, G., Minichino, A., Panico, R., Romano, G. F., Mazzei, F., Testugini, V., ALTISSIMI, G., & Cianfrone, G. (2014) · Neural Plasticity · doi:10.1155/2014/817852 · Cited by 17
“Results from a large body of functional and structural brain imaging studies provide convergent evidence that DLPFC plays critical roles in mood regulation and DLPCF hypoactivity is nowadays considered a critical neural substrate for depression [128].”
BackgroundOh, J., Kim, E., & Nam, T. (2018) · Marine Drugs · doi:10.3390/md16020044 · Cited by 19
Xia, W., Zhou, R., Zhao, G., Wang, F., Mao, R., Peng, D., Yang, T., Wang, Z., Chen, J., & Fang, Y. (2018) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s169583 · Cited by 18
“The role of the DLPFC and its connections in the pathogenesis of depression have been described by several previous studies.(65,66) DLPFC is also known to be involved in attention, executive functions, and internally guided behavior during goal-oriented and working memory tasks.”
Lehto, L. J., Filip, P., Laakso, H., Sierra, A., Slopsema, J. P., Johnson, M. D., Eberly, L. E., Low, W. C., Gröhn, O. H. J., Tanila, H., et al. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00899 · Cited by 18
Qiu, W., Duarte‐Guterman, P., Eid, R. S., Go, K. A., Lamers, Y., & Galea, L. A. M. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108174 · Cited by 18
Prefrontal-limbic Change in Dopamine Turnover by Acupuncture in Maternally Separated Rat Pups
Kwon, S., Kim, D., Park, H., Yoo, D., Park, H., Hahm, D., Lee, H., & Kim, S.-T. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0830-1 · Cited by 18
Evans, C., Banissy, M. J., & Charlton, R. A. (2018) · Clinical Neurophysiology · doi:10.1016/j.clinph.2018.03.012 · Cited by 17
“The left DLPFC is often targeted for active tES as it may be hypoactive in MDD (Grimm et al., 2008; Koenigs and Grafman, 2009).”
BackgroundRudroff, T. (2024) · Experimental Brain Research · doi:10.1007/s00221-024-06882-z · Cited by 18
“The DLPFC is involved in executive functions, attention, and working memory (Koenigs and Grafman 2009).”
Neuromodulation and neural networks in psychiatric disorders: current status and emerging prospects
Michalopoulou, P. G., Meshreky, K. M., Hommerich, Z., & Shergill, S. S. (2025) · Psychological Medicine · doi:10.1017/s003329172510158x · Cited by 18
“…which may be related to the biased focus on unpleasant memories in MDD (Young et al., 2023). fMRI studies have shown DLPFC underactivation and VMPFC overactivation in depression (Koenigs & Grafman, 2009), while recovery is linked with ‘normalization’ of this pattern (Brody et al., 2001).”
Chen, Y., Liu, C., Xin, F., Zou, H., Huang, Y., Wang, J., Dai, J., Zou, Z., Ferraro, S., Kendrick, K. M., et al. (2023) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110716 · Cited by 18
The neurobiology of brain recovery from traumatic stress: A longitudinal DTI study
Meng, L., Chen, Y., Xu, X. Y., Chen, T., Lui, S., Huang, X., Sweeney, J. A., Li, K., & Gong, Q. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.08.075 · Cited by 19
“, 2007), in particular in moderating the intensity of responses to negative emotion (Koenigs and Grafman, 2009; Phan et al., 2005).”
BackgroundBi, K., Chattun, M. R., Liu, X., Wang, Q., Tian, S., Zhang, S., Lü, Q., & Yao, Z. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.05.078 · Cited by 17
Focal application of accelerated iTBS results in global changes in graph measures
Klooster, D., Franklin, S. L., Besseling, R. M. H., Jansen, J. F. A., Caeyenberghs, K., Duprat, R., Aldenkamp, A. P., de Louw, A. J. A., Boon, P., & Baeken, C. (2018) · Human Brain Mapping · doi:10.1002/hbm.24384 · Cited by 18
Gao, J., Chen, M., Xiao, D., Li, Y., Zhu, S., Li, Y., Dai, X., Lu, F., Wang, Z., Cai, S., et al. (2022) · Cerebral Cortex · doi:10.1093/cercor/bhac217 · Cited by 17
Natural Psychoplastogens As Antidepressant Agents
Benko, J., & Vranková, S. (2020) · Molecules · doi:10.3390/molecules25051172 · Cited by 17
Hakamata, Y., Iwase, M., Kato, T., Senda, K., & Inada, T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0075526 · Cited by 16
“Moreover, the sgACC/vmPFC has been implicated in the integration of sensory information into self-relevant representations that result in self-insight [44–46].”
The Complexity of Suicide: Review of Recent Neuroscientific Evidence
Ching, E. (2016) · Cited by 16
Chitnis, T., Vandercappellen, J., King, M., & Brichetto, G. (2022) · Neurology and Therapy · doi:10.1007/s40120-022-00368-2 · Cited by 19
“Further analyses showed that, compared with the healthy controls and those with MS but no MDD, PlwMS with MDD had an increased shortest distance between the right hippocampus/right amygdala and a series of frontal and prefrontal cortical regions, including the dorsolateral PFC [235], which is thought to play a key rol…”
Kouba, B. R., Torrá, A. C. N. C., Camargo, A., & Rodrigues, A. L. S. (2022) · Metabolic Brain Disease · doi:10.1007/s11011-022-01115-0 · Cited by 16
Amerio, A., Baccino, C., Breda, G. S., Cortesi, D., Spiezio, V., Magnani, L., Berardis, D. D., Conio, B., Costanza, A., Paola, G. D., et al. (2023) · Psychiatry Research · doi:10.1016/j.psychres.2023.115491 · Cited by 16
Zhao, J., Zhang, M., Zhang, H., Wang, Y., Chen, B., & Shao, J. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110843 · Cited by 15
“Functional imaging studies suggested that hyperactivity was found in PFC during both the progression and the recovery phases in depression (Koenigs and Grafman, 2009; Mayberg et al., 2000).”
BackgroundAlteration of spontaneous neuronal activity in young adults with non-clinical depressive symptoms
Wei, X., Shen, H., Ren, J., Liu, W., Yang, R., Liu, J., Wu, H., Xu, X., Lai, L., Hu, J., et al. (2015) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2015.04.008 · Cited by 16
“, 2007), the DLPFC is thought to have a role of “cognitive” or “executive” function during emotional regulation (Koenigs and Grafman, 2009).”
BackgroundGawrysiak, M. J., Carvalho, J. P., Rogers, B. P., Nicholas, C. R. N., Dougherty, J. H., & Hopko, D. R. (2012) · Case Reports in Psychiatry · doi:10.1155/2012/152916 · Cited by 16
“These changes may plausibly reflect decreased depressive rumination, increased utilization of cognitive resources, or increased capacity to experience reward during more pleasurable experiences as such phenomena have been associated with dlPFC and moPFC activity [36, 64–66].”
BackgroundRational design of transcranial alternating current stimulation
Kurmann, R., Gast, H., Schindler, K. A., & Frӧhlich, F. (2018) · Clinical and Translational Neuroscience · doi:10.1177/2514183x18793515 · Cited by 16
Ano, Y., Kita, M., Kobayashi, K., Koikeda, T., & Kawashima, R. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10030480 · Cited by 16
“Moreover, DLPFC dysfunction has been associated with schizophrenia [33], depression [34], stress [35], and Alzheimer’s disease [36], as well as reduced CBF in the DLPFC, especially in the left DLPFC.”
BackgroundBhattacharyya, P. K., Anand, A., Lin, J. Y., & Altinay, M. I. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.665347 · Cited by 16
Pathak, Y. J., Kopell, B. H., Szabó, A., Rainey, C. J., Harsch, H. H., & Butson, C. R. (2012) · Brain stimulation · doi:10.1016/j.brs.2012.07.001 · Cited by 16
“In MDD, the DLPFC tends to be hypometabolic while the ventro-medial prefrontal cortex (VMPFC), including subgenual cingulate (Cg25) is hypermetabolic.”
InfluentialSalavati, B., Daskalakis, Z. J., Zomorrodi, R., Blumberger, D. M., Chen, R. E., Pollock, B. G., & Rajji, T. K. (2018) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2018.00155 · Cited by 16
“Further, abnormalities in the DLPFC structure and function are observed in various brain disorders including Alzheimer’s disease (Kaufman et al., 2010), depression (Koenigs and Grafman, 2009) and schizophrenia (Callicott et al., 2000).”
BackgroundGirls' internalizing symptoms and white matter tracts in Cortico-Limbic circuitry
Ali, O. M., Vandermeer, M. R. J., Sheikh, H. I., Joanisse, M. F., & Hayden, E. P. (2018) · NeuroImage Clinical · doi:10.1016/j.nicl.2018.101650 · Cited by 18
“Activity of the cingulate and PFC is associated with affective and behavioral responding, as well as reward anticipation and modulation of autonomic nervous system functioning, which, in turn, underlies neurovegetative processes, such as arousal, sleep, and appetite known to go awry in internalizing psychopathology (K…”
Guo, Y., Zhang, L., Zhang, J., Lv, S.-X., Du, C., Wang, T., Wang, H., Xie, W., & Liu, J. (2020) · Neuropsychobiology · doi:10.1159/000508680 · Cited by 16
Schecklmann, M., Nejati, V., Poeppl, T. B., Peytard, J., Rupprecht, R., Wetter, T. C., Langguth, B., & Kreuzer, P. M. (2020) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2020.10.011 · Cited by 16
Wang, T., Liu, X., Wu, X., Fan, Y., Lv, Y., & Chen, B. (2023) · Clinical Neurophysiology · doi:10.1016/j.clinph.2023.11.019 · Cited by 15
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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