The DOI matches its Crossref record; 65 of the 67 references it cites were found in a registry or an index.
Direct Electrical Stimulation of Lateral Orbitofrontal Cortex Acutely Improves Mood in Individuals with Symptoms of Depression
Open accessAbstract
Mood disorders cause significant morbidity and mortality, and existing therapies fail 20%-30% of patients. Deep brain stimulation (DBS) is an emerging treatment for refractory mood disorders, but its success depends critically on target selection. DBS focused on known targets within mood-related frontostriatal and limbic circuits has been variably efficacious. Here, we examine the effects of stimulation in orbitofrontal cortex (OFC), a key hub for mood-related circuitry that has not been well characterized as a stimulation target. We studied 25 subjects with epilepsy who were implanted with intracranial electrodes for seizure localization. Baseline depression traits ranged from mild to severe. We serially assayed mood state over several days using a validated questionnaire. Continuous electrocorticography enabled investigation of neurophysiological correlates of mood-state changes. We used implanted electrodes to stimulate OFC and other brain regions while collecting verbal mood reports and questionnaire scores. We found that unilateral stimulation of the lateral OFC produced acute, dose-dependent mood-state improvement in subjects with moderate-to-severe baseline depression. Stimulation suppressed low-frequency power in OFC, mirroring neurophysiological features that were associated with positive mood states during natural mood fluctuation. Stimulation potentiated single-pulse-evoked responses in OFC and modulated activity within distributed structures implicated in mood regulation. Behavioral responses to stimulation did not include hypomania and indicated an acute restoration to non-depressed mood state. Together, these findings indicate that lateral OFC stimulation broadly modulates mood-related circuitry to improve mood state in depressed patients, revealing lateral OFC as a promising new target for therapeutic brain stimulation in mood disorders.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In general agreement with these findings, recent work by Rao et al. (2018) showed that iES of the lateral OFC caused improvements in mood in patients with moderate to severe trait depression, whereas iES of medial OFC had no significant effect.”
From Does the Prefrontal Cortex Play an Essential Role in Consciousness? Insights from Intracranial Electrical Stimulation of the Human Brain (2021) · cites this paper as Rao et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Stimulation of the ACC produced analogous improvements in mood, although with less consistency than stimulation of OFC.”
From Does the Prefrontal Cortex Play an Essential Role in Consciousness? Insights from Intracranial Electrical Stimulation of the Human Brain (2021) · cites this paper as Rao et al., 2018
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“This study provided further confirmation that stimulation of specific PFC subregions can result in high-level changes in conscious experience, such as alterations of mood.”
From Does the Prefrontal Cortex Play an Essential Role in Consciousness? Insights from Intracranial Electrical Stimulation of the Human Brain (2021) · cites this paper as Rao et al., 2018
In the citing paper
“many of the sites were in the middle part of the OFC, areas 13 and 11, which are categorized as medial OFC, the area activated by rewards (Rolls, 2019c).”
From The orbitofrontal cortex: reward, emotion and depression (2020) · cites this paper as Rao et al., 2018
In the citing paper
“Electrical stimulation of the human OFC can also produce reward and raise mood (Rao et al., 2018)”
From The orbitofrontal cortex: reward, emotion and depression (2020) · cites this paper as Rao et al., 2018
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The PHQ-9: Validity of a brief depression severity measure
Kroenke, K., Spitzer, R. L., & Williams, J. B. W. (2001) · Journal of General Internal Medicine · doi:10.1046/j.1525-1497.2001.016009606.x · Cited by 44,910
Delorme, A., & Makeig, S. (2004) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2003.10.009 · Cited by 24,371
Fischl, B. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.01.021 · Cited by 9,526
Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients
Beck, A. T., Steer, R. A., Ball, R., & Ranieri, W. F. (1996) · Journal of Personality Assessment · doi:10.1207/s15327752jpa6703_13 · Cited by 5,965
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
Greicius, M. D., Flores, B. H., Menon, V., Glover, G. H., Solvason, H. B., Kenna, H., Reiss, A. L., & Schatzberg, A. F. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.09.020 · Cited by 2,214
The human orbitofrontal cortex: linking reward to hedonic experience
Kringelbach, M. L. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1747 · Cited by 2,180
Resting-state connectivity biomarkers define neurophysiological subtypes of depression
Drysdale, A. T., Grosenick, L., Downar, J., Dunlop, K., Mansouri, F., Meng, Y., Fetcho, R. N., Zebley, B., Oathes, D. J., Etkin, A., et al. (2017) · Nature Medicine · doi:10.1038/nm.4246 · Cited by 2,170
KRINGELBACH, M. (2004) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2004.03.006 · Cited by 1,977
A functional anatomical study of unipolar depression
Drevets, W., Videen, T., Price, J., Preskorn, S., Carmichael, S., & Raichle, M. (1992) · The Journal of Neuroscience · doi:10.1523/jneurosci.12-09-03628.1992 · Cited by 1,266
Multimodal image coregistration and partitioning--a unified framework.
Ashburner, J., & Friston, K. (1997) · NeuroImage · doi:10.1006/nimg.1997.0290 · Cited by 1,051
Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression
Lozano, A. M., Mayberg, H. S., Giacobbe, P., Hamani, C., Craddock, R. C., & Kennedy, S. H. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.05.034 · Cited by 1,024
Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Treatment-Resistant Depression
Malone, D. A., Dougherty, D. D., Rezai, A. R., Carpenter, L. L., Friehs, G. M., Eskandar, E. N., Rauch, S. L., Rasmussen, S. A., Machado, A. G., Kubu, C. S., et al. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.08.029 · Cited by 897
The orbitofrontal cortex and beyond: From affect to decision-making
Rolls, E. T., & Fabian Grabenhorst, B. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2008.09.001 · Cited by 851
Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Unipolar and Bipolar Depression
Holtzheimer, P. E. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.1456 · Cited by 608
Holtzheimer, P. E., Husain, M. M., Lisanby, S. H., Taylor, S. F., Whitworth, L. A., McClintock, S., Slavin, K. V., Berman, J., McKhann, G. M., Patil, P. G., et al. (2017) · The Lancet Psychiatry · doi:10.1016/s2215-0366(17)30371-1 · Cited by 577
Rapid effects of deep brain stimulation for treatment-resistant major depression
Schlaepfer, T. E., Bewernick, B. H., Kayser, S., Mädler, B., & Coenen, V. A. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.01.034 · Cited by 563
Dougherty, D. D., Rezai, A. R., Carpenter, L. L., Howland, R. H., Bhati, M. T., O’Reardon, J. P., Eskandar, E. N., Baltuch, G. H., Machado, A. D., Kondziolka, D., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.11.023 · Cited by 558
What the orbitofrontal cortex does not do
Stalnaker, T. A., Cooch, N. K., & Schoenbaum, G. (2015) · Nature Neuroscience · doi:10.1038/nn.3982 · Cited by 531
Riva-Posse, P., Choi, K. S., Holtzheimer, P. E., McIntyre, C. C., Gross, R. E., Chaturvedi, A., Crowell, A. L., Garlow, S. J., Rajendra, J. K., & Mayberg, H. S. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.03.029 · Cited by 460
Riva-Posse, P., Choi, K. S., Holtzheimer, P. E., Crowell, A. L., Garlow, S. J., Rajendra, J. K., McIntyre, C. C., Gross, R. E., & Mayberg, H. S. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.59 · Cited by 441
Orbitofrontal cortex function and structure in depression
DREVETS, W. C. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1401.029 · Cited by 417
Rudebeck, P. H., & Murray, E. A. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.049 · Cited by 405
Bewernick, B. H., Kayser, S., Sturm, V., & Schlaepfer, T. E. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.44 · Cited by 371
Decoding subjective decisions from orbitofrontal cortex
Rich, E. L., & Wallis, J. D. (2016) · Nature Neuroscience · doi:10.1038/nn.4320 · Cited by 368
Bergfeld, I. O., Mantione, M., Hoogendoorn, M. L. C., Ruhé, H. G., Notten, P., van Laarhoven, J., Visser, I., Figee, M., de Kwaasteniet, B. P., Horst, F., et al. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2016.0152 · Cited by 336
The search for imaging biomarkers in psychiatric disorders
Abi-Dargham, A., & Horga, G. (2016) · Nature Medicine · doi:10.1038/nm.4190 · Cited by 311
Williams, L. M. (2016) · Depression and Anxiety · doi:10.1002/da.22556 · Cited by 302
Phasic and sustained fear in humans elicits distinct patterns of brain activity
Alvarez, R. P., Chen, G., Bodurka, J., Kaplan, R., & Grillon, C. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2010.11.057 · Cited by 299
Fettes, P., Schulze, L., & Downar, J. (2017) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2017.00025 · Cited by 299
Cheng, W., Rolls, E. T., Qiu, J., Liu, W., Tang, Y., Huang, C.-C., Wang, X., Zhang, J., Lin, W., Zheng, L., et al. (2016) · Brain · doi:10.1093/brain/aww255 · Cited by 294
Golkar, A., Lonsdorf, T. B., Olsson, A., Lindstrom, K. M., Berrebi, J., Fransson, P., Schalling, M., Ingvar, M., & Öhman, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048107 · Cited by 235
Brain metabolic changes associated with symptom factor improvement in major depressive disorder
Brody, A. L., Saxena, S., Mandelkern, M. A., Fairbanks, L. A., Ho, M. L., & Baxter, L. R. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01117-9 · Cited by 212
Choi, K. S., Riva‐Posse, P., Gross, R. E., & Mayberg, H. S. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.2564 · Cited by 136
Lateral orbitofrontal cortex anticipates choices and integrates prior with current information
Nogueira, R., Abolafia, J. M., Drugowitsch, J., Balaguer‐Ballester, E., Sanchez-Vives, M. V., & Moreno‐Bote, R. (2017) · Nature Communications · doi:10.1038/ncomms14823 · Cited by 128
Guillory, S. A., & Bujarski, K. A. (2014) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsu002 · Cited by 127
Orbitofrontal neurons infer the value and identity of predicted outcomes
Stalnaker, T. A., Cooch, N. K., McDannald, M. A., Liu, T., Wied, H. M., & Schoenbaum, G. M. (2014) · Nature Communications · doi:10.1038/ncomms4926 · Cited by 124
Single-pulse electrical stimulation identifies epileptogenic frontal cortex in the human brain
Valentı́n, A., Alarcón, G., García-Seoane, J. J., Lacruz, M. E., Nayak, S. D., Honavar, M., Selway, R., Binnie, C. D., & Polkey, C. E. (2005) · Neurology · doi:10.1212/01.wnl.0000171340.73078.c1 · Cited by 124
Dissecting the Anticipation of Aversion Reveals Dissociable Neural Networks
Grupe, D. W., Oathes, D. J., & Nitschke, J. B. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs175 · Cited by 119
Emotional impairment after right orbitofrontal lesion in a patient without cognitive deficits
Angrilli, A., Palomba, D., Cantagallo, A., Maietti, A., & Stegagno, L. (1999) · Neuroreport · doi:10.1097/00001756-199906030-00021 · Cited by 117
Feffer, K., Fettes, P., Giacobbe, P., Daskalakis, Z. J., Blumberger, D. M., & Downar, J. (2018) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.11.011 · Cited by 116
Deep brain stimulation for treatment-refractory obsessive compulsive disorder: a systematic review
Kohl, S., Schönherr, D. M., Luigjes, J., Denys, D. A. J. P., Mueller, U. J., Lenartz, D., Visser-Vandewalle, V. E. R. M., & Kuhn, J. (2014) · BMC Psychiatry · doi:10.1186/s12888-014-0214-y · Cited by 110
Rudebeck, P. H., & Murray, E. A. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06267.x · Cited by 108
Mazzola, L., Mauguı̀ere, F., & Isnard, J. (2017) · Journal of Clinical Neurophysiology · doi:10.1097/wnp.0000000000000382 · Cited by 106
Crowell, A. L., Garlow, S. J., Riva-Posse, P., & Mayberg, H. S. (2015) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2015.00041 · Cited by 105
Immediate Mood Scaler: Tracking Symptoms of Depression and Anxiety Using a Novel Mobile Mood Scale
Nahum, M., Vleet, T. V., Sohal, V. S., Mirzabekov, J. J., Rao, V. R., Wallace, D. L., Lee, M. B., Dawes, H. E., Stark‐Inbar, A., Jordan, J. T., et al. (2017) · JMIR mhealth and uhealth · doi:10.2196/mhealth.6544 · Cited by 97
Induction and Quantification of Excitability Changes in Human Cortical Networks
Keller, C. J., Huang, Y., Herrero, J. L., Fini, M. E., Du, V. X., Lado, F. A., Honey, C. J., & Mehta, A. D. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1088-17.2018 · Cited by 89
Nofzinger, E. A., Buysse, D. J., Germain, A., Price, J. C., MELTZER, C. C., Miewald, J. M., & Kupfer, D. J. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.4.387 · Cited by 66
Anatomy and white matter connections of the orbitofrontal gyrus
Burks, J. D., Conner, A. K., Bonney, P. A., Glenn, C. A., Baker, C. M., Boettcher, L. B., Briggs, R. G., OʼDonoghue, D. L., Wu, D. H., & Sughrue, M. E. (2017) · Journal of neurosurgery · doi:10.3171/2017.3.jns162070 · Cited by 66
The neural dynamics of reward value and risk coding in the human orbitofrontal cortex
Li, Y., Vanni-Mercier, G., Isnard, J., Mauguìere, F., & Dreher, J. (2016) · Brain · doi:10.1093/brain/awv409 · Cited by 65
Guinjoan, S. M., Mayberg, H. S., Costanzo, E. Y., Fahrer, R. D., Tenca, E., Antico, J. C., Cerquetti, D., Smyth, E., Leiguarda, R. C., & Nemeroff, C. B. (2010) · Journal of Neuropsychiatry · doi:10.1176/jnp.2010.22.3.265 · Cited by 57
(2003) · Cited by 55
Anterior Cingulate Pathways May Affect Emotions Through Orbitofrontal Cortex
García‐Cabezas, M. Á., & Barbas, H. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw284 · Cited by 55
Gálvez, J. F., Keser, Z., Mwangi, B., Ghouse, A. A., Fenoy, A. J., Schulz, P. E., Sanches, M., Quevedo, J., Selvaraj, S., Gajwani, P., et al. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.12.003 · Cited by 53
Changes in subjective experience elicited by direct stimulation of the human orbitofrontal cortex
Fox, K. C. R., Yih, J., Raccah, O., Pendekanti, S., Limbach, L. E., Maydan, D. D., & Parvizi, J. (2018) · Neurology · doi:10.1212/wnl.0000000000006358 · Cited by 49
Veniero, D., Maioli, C., & Miniussi, C. (2010) · Journal of Neurophysiology · doi:10.1152/jn.00172.2010 · Cited by 41
Gao, Q. C., Zou, K., He, Z., Sun, X., & Chen, H. (2016) · Scientific Reports · doi:10.1038/srep21861 · Cited by 41
Kuniishi, H., Ichisaka, S., Matsuda, S., Futora, E., Harada, R., & Hata, Y. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00250 · Cited by 34
State of the Art: Novel Applications for Cortical Stimulation
Ridder, D. D., Perera, S., & Vanneste, S. (2017) · Neuromodulation Technology at the Neural Interface · doi:10.1111/ner.12593 · Cited by 32
Fettes, P., Peters, S., Giacobbe, P., Blumberger, D. M., & Downar, J. (2017) · Brain Stimulation · doi:10.1016/j.brs.2016.11.008 · Cited by 31
Jung, J., Bayle, D. J., Jerbi, K., Vidal, J. R., Hénaff, M., Ossandón, T., Bertrand, O., Mauguı̀ere, F., & Lachaux, J.-P. (2010) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2010.09.014 · Cited by 30
Intracranial stimulation study of lateralization of affect
Smith, J. R., Lee, G. P., Fountas, K. N., King, D. W., & Jenkins, P. D. (2006) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2005.12.014 · Cited by 27
Cooch, N. K., Stalnaker, T. A., Wied, H. M., Bali-Chaudhary, S., McDannald, M. A., Liu, T., & Schoenbaum, G. M. (2015) · Nature Communications · doi:10.1038/ncomms8195 · Cited by 22
Scangos, K. W., & Shahlaie, K. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.12.003 · Cited by 8
Acute and Reproducible Mood Improvement Due to Nucleus Accumbens Deep Brain Stimulation
Giordana, B., Benoît, M., Darmon, N., Yelnik, J., Millet, B., & Fontaine, D. (2015) · Brain stimulation · doi:10.1016/j.brs.2015.05.004 · Cited by 4
Cited by
Sorted by citations
Closed-loop neuromodulation in an individual with treatment-resistant depression
Scangos, K. W., Khambhati, A. N., Daly, P. M., Makhoul, G. S., Sugrue, L. P., Zamanian, H., Liu, T. X., Rao, V. R., Sellers, K. K., Dawes, H. E., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01480-w · Cited by 535
The orbitofrontal cortex: reward, emotion and depression
Rolls, E. T., Cheng, W., & Feng, J. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa196 · Cited by 474
McTeague, L. M., Rosenberg, B. M., Lopez, J. W., Carreon, D. M., Huemer, J., Jiang, Y., Chick, C. F., Eickhoff, S. B., & Etkin, A. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.18111271 · Cited by 388
Using brain imaging to improve spatial targeting of transcranial magnetic stimulation for depression
Cash, R. F. H., Weigand, A., Zalesky, A., Siddiqi, S. H., Downar, J., Fitzgerald, P. B., & Fox, M. D. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.05.033 · Cited by 366
Brain–machine interfaces from motor to mood
Shanechi, M. M. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0488-y · Cited by 263
Self-citation
Metadata
- Authors
- Rao, V. R., Sellers, K. K., Wallace, D. L., Lee, M. B., Bijanzadeh, M., Sani, O. G., Yang, Y., Shanechi, M. M., Dawes, H. E., & Chang, E. F.
- Affiliations
- University of California, San Francisco (US)
- University of Southern California (US)
- Corresponding author
- Chang, Edward F.
- ORCID
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 28
- Issue
- 24
- Pages
- 3893-3902.e4
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2903033387
- Cited by
- 181
- References
- 67
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 23 · 2023: 20 · 2022: 18 · 2021: 26 · 2020: 35 · 2019: 22
- FWCI
- 13.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Defense Advanced Research Projects Agency (W911NF-14-2-0043)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Keywords
- lateral orbitofrontal cortex, direct electrical stimulation, depression, mood regulation, deep brain stimulation targets, mood states, epilepsy patients, intracranial electrodes, electrocorticography, low-frequency power, hypomania
- MeSH terms
- Adult, Affect, Depression, Electric Stimulation, Electrodes, Implanted, Epilepsy, Female, Humans, Male, Middle Aged, Deep Brain Stimulation, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
