Cited by 956Neural and Behavioral Psychology StudiesTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

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The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex

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Koenigs, Michael, Grafman, Jordan·2009·Behavioural Brain Research

DOI 10.1016/j.bbr.2009.03.004PMC PMC2680780

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Abstract

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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Background
Antidepressant-like effects of cinnamamide derivative M2 via D2 receptors in the mouse medial prefrontal cortex
Che, Y.-X., Jin, X., Xiao, R.-H., Ming, Z., Ma, X., Guo, F., & Li, Y. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00854-7 · Cited by 6
“M2 increased excitatory synaptic transmission in the prelimbic mPFC The mPFC plays a critical role in the pathophysiology of depression [25].”
Background
Neuropsychiatric disorders and genetic aspects of bowel or bladder dysfunction
Franco, I. (2015) · Wiley eBooks · doi:10.1002/9781118814789.ch7 · Cited by 6
Functional connectivity changes with rapid remission from moderate-to-severe major depressive disorderPreprint
Xiao, X., Bentzley, B. S., Cole, E. J., Tischler, C., Stimpson, K. H., Duvio, D., Bishop, J. H., DeSouza, D. D., Schatzberg, A. F., Keller, C. J., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/672154 · Cited by 7
“This hypothesis has been reinforced by observations that antidepressant treatments lead to reductions in sgACC activity (Dougherty et al., 2003; Drevets et al., 2008; Goldapple et al., 2004; Koenigs and Grafman, 2009; Mayberg et al., 2005, 2000; Mottaghy et al., 2002; Nobler et al., 2001) .”
Background
EEG biomarkers for a precision-medicine approach to noninvasive brain stimulation for major depressive disorder
Romero-Marín, R., Cappon, D., Sánchez, J. S., Bartrés‐Faz, D., Pascual‐Leone, Á., & Cattaneo, G. (2025) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2025.112121 · Cited by 5
Brain entropy as a biomarker of major depression in adolescents and young adults: insights from multimodal resting-state functional magnetic resonance imaging
Lu, R., Li, J., Li, Y., Zeng, X., Guo, Y., Li, D., Cui, Y., Liang, X., Zhang, H., Wang, J., et al. (2026) · Psychoradiology · doi:10.1093/psyrad/kkag009 · Cited by 5
Epigenetic and Neuronal Activity Markers Suggest the Recruitment of the Prefrontal Cortex and Hippocampus in the Three-Hit Model of Depression in Male PACAP Heterozygous Mice
Gaszner, T., Farkas, J. I., Kun, D., Ujvari, B., Füredi, N., Kovács, L. Á., Hashimoto, H., Reglődi, D., Kormos, V., & Gaszner, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911739 · Cited by 7
“The question of how this brain area contributes to the pathogenesis of depression has been investigated for a long time [32,33], including through functional imaging [34], studies on individuals who suffered damage of the PFC [35], and reports on cases treated by deep brain stimulation [36,37].”
Background
Tetrabenazine, a vesicular monoamine transporter 2 inhibitor, inhibits vesicular storage capacity and release of monoamine transmitters in mouse brain tissue
Tod, P., Varga, A., Román, V., Lendvai, B., Palkovacs, R., Sperlágh, B., & Vizi, E. S. (2024) · British Journal of Pharmacology · doi:10.1111/bph.17348 · Cited by 5
“These two regions of the brain play critical roles in depression (Koenigs & Grafman, 2009) and parkinsonism, which are side effects observed in clinical studies of VMAT-2 inhibitors (Caroff et al., 2018; Margolis, 2014).”
What can the psychoneuroimmunology of yoga teach us about depression's psychopathology?
Chiarpenello, C., & Brodmann, K. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100877 · Cited by 5
“Depressed individuals have dorsolateral PFC hypoactivity, ventromedial PFC and amygdala hyperactivity (Pizzagalli and Roberts, 2021; Koenigs and Grafman, 2009; Fales et al., 2009).”
Background
Prefrontal Internal Event‐Driven Analysis of Dynamical Electroencephalographic Biomarkers in Depression During Emotional Auditory Task
Zhao, Q., Cui, K., Jiang, H., Wu, Z., Zhang, L., Zhao, M., & Hu, B. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70382 · Cited by 5
“This enhanced activation during positive stimuli may be explained by the previously re-ported pleasure deficit in depressed subjects [62, 63].”
Optimization of multiple coils immersed in a conducting liquid for half-hemisphere or whole-brain deep transcranial magnetic stimulation: A simulation study
Sousa, S. C. P., Almeida, J., Miranda, P. C., Salvador, R., Silvestre, J., Simões, H., & Crespo, P. (2014) · Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) · doi:10.1109/embc.2014.6943647 · Cited by 5
Stress adaptation in older adults with and without cognitive impairment: an fMRI pattern-based similarity analysis
Wang, X., Heffner, K. L., Anthony, M., & Lin, F. V. (2019) · Aging · doi:10.18632/aging.102204 · Cited by 5
“Specifically, perceived self-efficacy in control and mastery over stressors is related to the dorsal pathway of PFC, while perceived helplessness is related to the ventral pathway of PFC [40, 41].”
Background
Fractional anisotropy measurements of the left dorsolateral prefrontal cortex for therapeutic response assessment after repetitive transcranial magnetic stimulation (rTMS) in relapsing remitting multiple sclerosis patients suffering from depression
Hassan, T. A., Elkholy, S. F., Shehata, H., Shalaby, N., Elmazny, A. N., Sadek, M. N., Mahmoud, B. E., & Elsherbiny, M. M. (2021) · The Egyptian Journal of Radiology and Nuclear Medicine · doi:10.1186/s43055-020-00404-x · Cited by 5
“Besides, accumulating evidence also implicates it as an important neural substrate for depression and being the most accessible area for stimulation compared to other regions linked to depression pathophysiology [4].”
Background
Inhibitory control mediates the interaction between serotonin transporter gene (5-HTTLPR) and peer victimization on adolescent depressive symptoms
Lin, X., Cao, Y., Ji, L., & Zhang, W. (2021) · Scientific Reports · doi:10.1038/s41598-021-94267-5 · Cited by 6
Individual large-scale functional network mapping for major depressive disorder with electroconvulsive therapy
Sun, H., Cui, H., Sun, Q., Li, Y., Bai, T., Wang, K., Zhang, J., Tian, Y., & Wang, J. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.05.141 · Cited by 5
Association of inflammatory cytokines with magnetic resonance imaging features of the brain in patients with depression
Zhou, L., Li, Q., Liu, S., Wang, L., Yu, M., Lü, X., Yang, L., Lei, W., & Chen, G. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.111131 · Cited by 5
“The SFG is an important component of the dorsolateral prefrontal cortex (DLPFC), which is closely related to cognitive and executive functions (Koenigs and Grafman, 2009).”
Abnormal regional brain activity in patients with first-episode medication-naïve depressive disorder: A longitudinal fNIRS study
Wang, H., Wang, W., Diao, Y., Deng, L., Xie, Y., Duan, D., Li, J., Liu, X., Shao, Q., Wang, X., et al. (2024) · Psychiatry Research · doi:10.1016/j.psychres.2024.116288 · Cited by 5
Divergent effects of irradiation on brain cortical morphology in patients with nasopharyngeal carcinoma: one-year follow-up study using structural magnetic resonance imaging
Lv, X., Guo, Z., Tang, L., Li, Z., Lin, X., Li, J., Han, L., Qiu, Y., & Mai, H. (2021) · Quantitative Imaging in Medicine and Surgery · doi:10.21037/qims-20-662 · Cited by 5
“The rostral middle frontal gyrus is critical for higher-order executive functions that are associated with stress perception and appraisal (53,54).”
Background
Differential neural structures, intrinsic functional connectivity, and episodic memory in subjective cognitive decline and healthy controls
Nellessen, N. D., Onur, O. A., Richter, N., Jacobs, H. I. L., Dillen, K. N. H., von Reutern, B., Langen, K., Fink, G. R., & Kukolja, J. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.04.016 · Cited by 6
Default Model Network Mechanism in Current and Remitted Depression
Dai, Q., Yin, X., Huang, J., Li, H., Wang, J., & Feng, Z. (2018) · Neuropsychiatry · doi:10.4172/neuropsychiatry.1000333 · Cited by 5
Shared facial emotion processing functional network findings in medication-naïve major depressive disorder and healthy individuals: detection by sICA
Li, J., Edmiston, E. K., Tang, Y., Fan, G., Xu, K., Wang, F., & Xu, J. (2018) · BMC Psychiatry · doi:10.1186/s12888-018-1631-0 · Cited by 5
Resting-state functional connectivity in prefrontal cortex investigated by functional near-infrared spectroscopy: A longitudinal and cross-sectional study
Wu, S., Gao, L., Chen, C., Li, J., & He, S. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.06.034 · Cited by 6
Depressive Symptoms Differentially Predict Neurocognition in Latinx and non-Hispanic White People Living with HIV
Morris, E., Byrd, D., Summers, A., Tureson, K., Guzman, V. A., Crook, C., & Mindt, M. R. (2020) · Journal of the International Neuropsychological Society · doi:10.1017/s1355617720000855 · Cited by 4
“Prior research supports the finding that depressive symptoms are associated with impaired processing speed and executive function (Koenigs & Grafman, 2009; Lam et al., 2014; McDermott & Ebmeier, 2009; Rubin & Maki, 2019; Shenal et al., 2003), and this study suggests that there may be some domain…”
Background
Neurocircuits commonly involved in psychiatric disorders and their stimulation and lesion therapies
Heilbronner, S. R., Safadi, Z., & Haber, S. N. (2015) · Wiley eBooks · doi:10.1002/9781118801086.ch3 · Cited by 4
Structural and functional abnormalities in the medial prefrontal cortex were associated with pain and depressive symptoms in patients with adhesive capsulitis
Li, J., Zhao, R., Wang, C., Song, J., Guo, X., Ge, Y., & Chu, X. (2024) · PAIN Reports · doi:10.1097/pr9.0000000000001139 · Cited by 4
“10,14,16,21,22,30 Moreover, studies focused on the molecular mechanisms associated with chronic pain, and depression-induced neural plasticity changes have also identified the shared molecular changes in both pain and depression.”
Background
Investigating glymphatic function and bed nucleus of the stria terminalis-based functional connectivity in Parkinson’s disease with and without depression
Dai, X., Zhang, Y., Fu, C., Gao, Z., Hou, X., Yan, Z., Zheng, C., Gao, L., & Liu, B. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00985-2 · Cited by 3
“Dysfunction in the basal forebrain that regulates the HPA axis, such as the hippocampus, amygdala, and medial prefrontal cortex (MPFC) 43,44 , has implications for the etiology of stress-related conditions, including post-traumatic stress disorder (PTSD) and depression, which often manifest as…”
ΔFosB protein and its role in the nucleus accumbens – an important factor in addiction, stress and response to natural rewards and psychoactive drugs
Frankowska, A., Dudek, D., & Siwek, M. (2016) · Neuropsychiatria i Neuropsychologia · doi:10.5114/nan.2016.62250 · Cited by 4
Meta-analysis of resting-state fMRI in cervical spondylosis patients using AES-SDM
Zhang, Q., & Ding, H. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1439939 · Cited by 4
Cross‐Validation of Paranoid and Depressive Scales: Results From Functional MRI Group Independent Component Analysis
Stoyanov, D., Paunova, R., Najar, D., Zlateva, G., Kandilarova, S., Khorev, V. S., & Kurkin, S. (2024) · Mental Illness · doi:10.1155/2024/7739939 · Cited by 4
Effects of focal brain damage on political behaviour across different political ideologies
Siddiqi, S., Balters, S., Zamboni, G., Cohen‐Zimerman, S., & Grafman, J. H. (2025) · Brain · doi:10.1093/brain/awaf101 · Cited by 4
Self-citation
Changes in prefrontal hemodynamics and mood states during screen use: a functional near-infrared spectroscopy study
Fehring, D. J., Gaillard, A., Mazzoli, E., Rossell, S. L., Dempsey, P. C., Wheeler, M. J., Owen, N. G., Dunstan, D. W., & Hallgren, M. Å. (2025) · Scientific Reports · doi:10.1038/s41598-025-09360-w · Cited by 5
“We focused on activity in the dlPFC as this brain region plays a key role in emotional control (modulation of affective processing), working memory, goal-driven attention, planning, and problem-solving 38 .”
Incorporation of massage into psychotherapy: An integrative and conjoint approach
Posadzki, P., & Bhurke, S. (2011) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-011-0633-2 · Cited by 4
GABABR1 in DRN mediated GABA to regulate 5-HT expression in multiple brain regions in male rats with high and low aggressive behavior
Liu, X., Wang, H., Wang, X., Ning, Y.-X., & Gao, J. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105180 · Cited by 4
“The dorsolateral region is mainly involved in cognitive and executive functions, while the ventromedial region is mainly associated with positive or negative emotions (Koenigs and Grafman, 2009; Rahm et al., 2013; Turriziani et al., 2012).”
Use of music for mood regulation in adolescents with intellectual disabilities: a case control study
Lundqvist, L., & Korošec, K. (2021) · International Journal of Developmental Disabilities · doi:10.1080/20473869.2021.2001728 · Cited by 4
“Based on the findings that hypoactivity in this area is associated with depression (Koenigs and Grafman 2009), they concluded that the use of Discharge and Diversion might be a poor strategy for males since it correlated with lower activation levels of mPFC.”
Background
The relationship between pre-treatment heart rate variability and response to low-frequency accelerated repetitive transcranial magnetic stimulation in major depression
Miron, J., Sheen, J., Panzarella, T., Hyde, M., Mansouri, F., Fox, L., Voetterl, H., Jodoin, V. D., Lespérance, P., Longpré-Poirier, C., et al. (2021) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2021.100270 · Cited by 4
Ketamine alleviating depressive-like behaviors is associated with regulation of nNOS–CAPON–Dexras1 complex in chronic unpredictable mild stress rats
Shen, Y., Lv, F., Min, S., Hao, X., & Yu, J. Q. (2022) · Translational Neuroscience · doi:10.1515/tnsci-2022-0245 · Cited by 4
“A large number of functional ima - ging, lesion, and brain stimulation studies have indicated that the PFC is essential for depression [ 33 ] .”
Bittersweet memories and somatic marker hypothesis: adaptive control in emotional recall facilitates long-term decision-making in the Iowa Gambling Task
Singh, V. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1214271 · Cited by 6
“…2002), negative aﬀect engages greater cognitive control (Ochsner and Gross, 2005) the negative–positive aﬀect implicates the subregion of ventromedial and dorsolateral prefrontal cortex in depression, a disorder characteristic of negative aﬀect (Northoﬀ et al., 2000; Koenigs and Grafman, 2009).”
Background
Major Depressive Disorder as a Driver of Dual Systems Model Development During Adolescence and Emerging Adulthood Among Justice-Involved Youth: Is Salience Age-Graded?
Wojciechowski, T. W., & Krupa, J. M. (2024) · International Journal of Offender Therapy and Comparative Criminology · doi:10.1177/0306624x241236717 · Cited by 5
Concussion risk and suicide prevention: balancing the risks and benefits of youth sport
Clacy, A., Hermens, D. F., Broadhouse, K. M., & Lagopoulos, J. (2019) · The Medical Journal of Australia · doi:10.5694/mja2.50319 · Cited by 4
The Neurobiology of Autism
Gillberg, C., Allely, C. S., Bourgeron, T., Coleman, M., Fernell, E., Hadjikhani, N. K., & Sarovic, D. (2019) · Cambridge University Press eBooks · doi:10.1017/9781108297769.007 · Cited by 5
Epigenetics of Major Depressive Disorder
Wang, K. Z., Dada, O. O., Bani‐Fatemi, A., Tasmim, S., Monda, M., Graff, A., & Luca, V. D. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-58131-8.00002-1 · Cited by 4
All the Self We Need
Gerrans, P. (2015) · doi:10.15502/9783958570078 · Cited by 4
Resting-state fMRI graph theory analysis for predicting selective serotonin reuptake inhibitors treatment response in adolescent major depressive disorder
Mo, X., Li, X., Liu, M., Hu, L., Li, Q., Wang, J., Deng, H., Lv, F., Zhou, X., Mao, Y. J., et al. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1675719 · Cited by 3
Brain-Behavior Associations: From Discovery to Clinical Application
Iannone, S., Samardzija, A., Simon, A. J., Parra, F., & Constable, R. T. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2026.02.020 · Cited by 5

Authors: Koenigs, M., & Grafman, J.
Affiliations: University of Wisconsin–Madison (US)
National Institutes of Health (US)
Corresponding author: Koenigs, Michael
ORCID: Koenigs, Michael
Grafman, Jordan
Venue: Behavioural Brain Research
Publisher: Elsevier BV
Published: 2009-08
Volume: 201
Issue: 2
Pages: 239-243
ISSN: 0166-4328 (ISSN-L)
DOI: 10.1016/j.bbr.2009.03.004
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex

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