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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.
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“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
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“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
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The PHQ-9: Validity of a brief depression severity measure
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Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients
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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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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
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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
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