Deep Brain Stimulation for Depression Informed by Intracranial Recordings
Open accessAbstract
The success of deep brain stimulation (DBS) for treating Parkinson's disease has led to its application to several other disorders, including treatment-resistant depression. Results with DBS for treatment-resistant depression have been heterogeneous, with inconsistencies largely driven by incomplete understanding of the brain networks regulating mood, especially on an individual basis. We report results from the first subject treated with DBS for treatment-resistant depression using an approach that incorporates intracranial recordings to personalize understanding of network behavior and its response to stimulation. These recordings enabled calculation of individually optimized DBS stimulation parameters using a novel inverse solution approach. In the ensuing double-blind, randomized phase incorporating these bespoke parameter sets, DBS led to remission of symptoms and dramatic improvement in quality of life. Results from this initial case demonstrate the feasibility of this personalized platform, which may be used to improve surgical neuromodulation for a vast array of neurologic and psychiatric disorders.
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A case study of combined VC/VS and SCC DBS reported remission until 75 weeks of follow-up and differential response profiles.
“A case study of combined VC/VS and SCC DBS reports remission until 75 weeks follow-up of combined stimulation and differential response-profiles.”
From Deep brain stimulation for depression. (2022) · cites this paper as [77]
SCC stimulation reduced mental noise and produced calmness and attention, while VC/VS stimulation produced energy and motivation.
“SCC stimulation reduced “mental noise” and produced calmness and attention and VC/VS stimulation produced energy and motivation [77].”
From Deep brain stimulation for depression. (2022) · cites this paper as [77]
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“Symptom severity also shifts as connectivity patterns within the left and right prefrontal cortices become imbalanced.”
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“32 Research on other therapy options, such as vagus nerve stimulation (VNS) 33,34 and deep brain stimulation (DBS), 35–37 have continued to accumulate, offering further insight to these treatment options for psychiatric disorders.”
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“Adaptive DBS and the related biomarkers might better discriminate those states 66 and enable programming to drive the brain to a specific physiologic state 12,67 or to activate ‘detect and treat’ systems that directly respond to symptom flares 18 .”
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“Another case study developed an effective dual-target strategy for depression that stimulated the subcallosal cingulate (SCC) and the VC/VS at the same time and demonstrated that SCC stimulation lessened negative emotions and VC/VS stimulation evinced an increase in positive mood [93].”
Application of advanced biosensors in nervous system diseases
Meng, Z., Zhang, Y., Lu, Y., Yuan, F., Wang, J., Chen, J., Liu, J., Wang, G., & Zang, G. (2024) · Interdisciplinary medicine · doi:10.1002/inmd.20240024 · Cited by 17 · see citing works
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Electrode Development for Epilepsy Diagnosis and Treatment
Paulk, A. C., Salami, P., Zelmann, R., & Cash, S. S. (2023) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2023.09.003 · Cited by 17 · see citing works
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Remore, L. G., Tolossa, M., Wei, W., Karnib, M., Tsolaki, E. C., Rifi, Z., & Bari, A. (2023) · Neuromodulation Technology at the Neural Interface · doi:10.1016/j.neurom.2023.03.011 · Cited by 12 · see citing works
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Risk and aversion coding in human habenula high gamma activity
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“While a previous inactivation study in rats demonstrated a role for LHb in risk aversion, the probabilities of receiving rewards given different choices were learned through experience.(43) In contrast, here the stimuli presented during the decision phase had no direct association with reward or”
Holographic visualization for stereotactic neurosurgery research
Noecker, A. M., Mlakar, J., Petersen, M. S., Griswold, M. A., & McIntyre, C. C. (2023) · Brain stimulation · doi:10.1016/j.brs.2023.02.001 · Cited by 12 · see citing works
“More recently, HoloSNS was employed in prospective patient-specific stereotactic neurosurgical planning as part of an experimental clinical trial that used a combination of deep brain stimulation (DBS) and stereo-electroencephalography (SEEG) electrodes to study depression [6].”
MethodSelf-citationWang, D. X., Ng, N., Seger, S. E., Ekstrom, A. D., Kriegel, J., & Lega, B. C. (2023) · Cerebral Cortex · doi:10.1093/cercor/bhad105 · Cited by 11 · see citing works
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NeuroDots: From Single-Target to Brain-Network Modulation: Why and What Is Needed?
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“Moreover, Sheth et al. have demonstrated that personalized DBS stimulation parameters, informed by intracranial electrophysiology, can enhance the neuromodulation of TRD [47].”
BackgroundThe BRAIN Initiative: a pioneering program on the precipice
Miller, C. T., Chen, X., Donaldson, Z. R., Marlin, B. J., Tsao, D. Y., Williams, Z. M., Zelikowsky, M., Zeng, H., & Hong, W. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01811-3 · Cited by 11 · see citing works
Neuromodulation of the anterior thalamus: Current approaches and opportunities for the future
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“As a result, current methods for targeted perturbations are labor-intensive, time-consuming, potentially harmful, and often unable to generalize beyond the limited task set they are optimized for [9].”
BackgroundOutcome of stereo-electroencephalography with single-unit recording in drug-refractory epilepsy
Nagahama, Y., Dewar, S. R., Behnke, E., Eliashiv, D. S., Stern, J. M., Kalender, G., Fields, T. A., Wilson, C. L., Staba, R. J., Engel, J., et al. (2023) · Journal of neurosurgery · doi:10.3171/2023.4.jns222633 · Cited by 11 · see citing works
Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov
Mishra, A., Begley, S. L., Shah, H. A., Santhumayor, B. A., Ramdhani, R., Fenoy, A. J., & Schulder, M. (2024) · World Neurosurgery X · doi:10.1016/j.wnsx.2024.100378 · Cited by 8 · see citing works
“30,31 More recent studies have shown promise by utilizing a network-based approach that implement stereoelectroencephalography (SEEG) electrodes or DBS leads with chronic local field potential-sensing capabilities to identify and map the dysfunctional network prior to implementing DBS, 32 – 36 but increased understand…”
BackgroundInfluentialPetersen, M. S., & McIntyre, C. C. (2023) · Brain Connectivity · doi:10.1089/brain.2022.0068 · Cited by 8 · see citing works
Self-citationAibar‐Durán, J. Á., Corripio, I., Roldán, A., Nevado, R. S., Aracil‐Bolaños, I., García‐Cornet, J., Alonso-Solís, A., Grasa, E., Schmidt, C. D. Q., Muñoz, F., et al. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.05.056 · Cited by 9 · see citing works
Prefrontal network engagement by deep brain stimulation in limbic hubs
Allawala, A. B., Bijanki, K. R., Oswalt, D. N., Mathura, R. K., Adkinson, J. A., Pirtle, V., Shofty, B., Robinson, M. E., Harrison, M. T., Mathew, S. J., et al. (2024) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2023.1291315 · Cited by 8 · see citing works
“While a rigorous pipeline for optimal surgical targeting was implemented (Sheth et al., 2021), one possible reason for inconsistent results within and across participants is that small variations in targeting may result in modifications in the electrophysiological effects observed.”
BackgroundSelf-citationHadar, P., Zelmann, R., Salami, P., Cash, S. S., & Paulk, A. C. (2024) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2024.1439541 · Cited by 7 · see citing works
“…bands (Provenza et al., 2019, 2021; Basu et al., 2021; Scangos et al., 2021a), voltage responses to identify connected sites (Miocinovic et al., 2018; Sheth et al., 2021; Scangos et al., 2021c, 2021a), and combinations of LFP features including network connectivity (Alagapan et al., 2023).”
BackgroundInfluentialIon channels as molecular targets of glioblastoma electrotherapy
Abed, T., Ganser, K., Eckert, F., Stransky, N., & Huber, S. M. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1133984 · Cited by 7 · see citing works
“In a renewed attempt to utilize DBS for treating depressive symptoms, individualizing types of electrical stimulation is increasingly tested in new trials (Drew, 2022; Sheth et al., 2022).”
BackgroundA biophysically constrained brain connectivity model based on stimulation-evoked potentials.
Schmid, W., Danstrom, I. A., Echevarria, M. C., Adkinson, J. A., Mattar, L. S., Banks, G. P., Sheth, S. A., Watrous, A. J., Heilbronner, S. R., Bijanki, K. R., et al. (2024) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2024.110106 · Cited by 6 · see citing works
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Self-citationGraph Theory and Modeling of Network Topology in Clinical Neurosurgery
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γ neuromodulations: unraveling biomarkers for neurological and psychiatric disorders
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“An alternative closed-loop strategy was explored by Sheth et al., who adopted a more comprehensive mapping approach [ 329 ].”
Navigating the FDA regulatory landscape
Scott, P. D., Bajaj, A., & McMullen, D. P. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01723-z · Cited by 5 · see citing works
“Invasive therapies using novel targeted deep brain stimulation (DBS) [39] and closed-loop stimulation [40] approaches are also building on existing platforms.”
BackgroundZhao, H., Zhang, S., Wang, Y., Zhang, C., Gong, Z., Zhang, M., Dai, W., Ran, Y., Shi, W., Dang, Y., et al. (2024) · iScience · doi:10.1016/j.isci.2024.108847 · Cited by 5 · see citing works
Network modeling: The explanatory power of activity flow models of brain function
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Fra̧czek, T. M., Zhou, Y., Kutcher, T. P., Bechtold, R. A., Chamarthi, S., Vanegas‐Arroyave, N., Goodman, W. K., Sheth, S. A., Herron, J. A., & Provenza, N. R. (2025) · Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) · doi:10.1109/embc58623.2025.11252732 · Cited by 4 · see citing works
“DBS has shown varying degrees of success in various other psychiatric disorders, including depression [20-22], Tourette syndrome [3], substance use disorders [4, 5], and eating disorders [6].”
Self-citationTowards objective, temporally resolved neurobehavioral predictors of emotional state
Kabotyanski, K. E., Yi, H., Hingorani, R., Robinson, B. S., Cowley, H., Fifer, M. S., Wester, B. A., Lamichhane, B., Sabharwal, A., Allawala, A. B., et al. (2024) · Brain stimulation · doi:10.1016/j.brs.2024.10.007 · Cited by 4 · see citing works
“In a cohort of 3 patients with treatment-resistant depression (TRD) undergoing intracranial monitoring as part of an ongoing clinical trial (NCT03437928) [5], we recently identified patterns of prefrontal neural activity that predicted depression severity [3].”
Self-citationMapping electrophysiological connectivity of pulvinar in seizure propagation and neuromodulation
Yao, Y., Wang, X., Zhao, B., Hu, W., Wang, L., Shao, X., Guo, Z., Yang, B., Li, Z., Cai, D., et al. (2025) · Epilepsia · doi:10.1111/epi.18537 · Cited by 4 · see citing works
“6,48,49 One limitation of this study is that the effects of pulvinar stimulation on interictal spikes and HFOs may not directly translate into clinical efficacy in controlling seizure frequency and severity.”
Physiotherapy for patients with depression: Recent research progress
Liu, H., Sun, J., Meng, S., & Sun, N. (2024) · World Journal of Psychiatry · doi:10.5498/wjp.v14.i5.635 · Cited by 5 · see citing works
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“Other methods use hybrid approaches, combining clinical and computational methods, usually by correlating the activation of fibre bundles (calculating the volume of tissue activated) with patients’ optimal clinical response 90–92 .”
InfluentialInsula uses overlapping codes for emotion in self and othersPreprint
Xiao, J., Adkinson, J. A., Allawala, A. B., Banks, G. P., Bartoli, E., Fan, X., Mocchi, M. M., Pascuzzi, B., Pulapaka, S., Franch, M. C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.04.596966 · Cited by 4 · see citing works
“Detailed methodologies have been outlined elsewhere (Sheth et al., 2022; Xiao et al., 2023).”
Self-citationTsuchiyagaito, A., Kuplicki, R., Misaki, M., Edwards, L. S., Camprodon, J. A., Fitzgerald, K. D., Khalsa, S. S., Philip, N. S., Paulus, M. P., & Guinjoan, S. M. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-025-02252-7 · Cited by 3 · see citing works
“Custom code has been deposited at https://github.com/ akitsuchiyagaito/LIFU_pilot.”
Costin, H., Brehar, F., Corlatescu, A.-D., & Prună, V. (2025) · Biomedicines · doi:10.3390/biomedicines13112691 · Cited by 5 · see citing works
“In this pioneering study conducted by Sheth et al. (2022) [74], the team used implemented stereo-EEG (sEEG) to map individual network dynamics and guide stimulation to two key regions: subcallosal cingulate (SCC) and VC/VS.”
Deep brain stimulation for Gilles de la Tourette syndrome
Johnson, K. A., Gunduz, A., & Okun, M. S. (2026) · Handbook of clinical neurology · doi:10.1016/b978-0-443-13554-5.00002-x · Cited by 3 · see citing works
Stereo-EEG-guided network modulation for psychiatric disorders: Interactive holographic planning
Noecker, A. M., Mlakar, J., Bijanki, K. R., Griswold, M. A., Pouratian, N., Sheth, S. A., & McIntyre, C. C. (2023) · Brain stimulation · doi:10.1016/j.brs.2023.11.003 · Cited by 3 · see citing works
“In attempts to better define the underlying neural targets for therapeutic DBS, investigators are rapidly expanding their use of imaging-based and electrophysiology-based approaches to map brain networks of interest for the treatment of psychiatric disorders [e.g. [13,14]].”
InfluentialSelf-citationCaruso, J. P., 5151 Harry Hines Blvd, D., Adenwalla, A., Venishetty, N., Tamimi, M. A., Bagley, C. A., & Aoun, S. G. (2024) · Journal of Orthopaedic Case Reports · doi:10.13107/jocr.2024.v14.i01.4152 · Cited by 3 · see citing works
Allawala, A. B., Bijanki, K. R., Adkinson, J. A., Oswalt, D. N., Tsolaki, E. C., Mathew, S. J., Mathura, R. K., Bartoli, E., Provenza, N. R., Watrous, A. J., et al. (2024) · Operative Neurosurgery · doi:10.1227/ons.0000000000001122 · Cited by 3 · see citing works
“Initial fi ndings from our fi rst patient is promising, 18 although the scienti fi c merits exist independently of patient therapeutic outcomes.”
InfluentialSelf-citationSadeghzadeh, S., Swaminathan, A., Bhanot, P., Steeman, S., Xu, A., Shah, V., Purger, D., & Buch, V. P. (2024) · Biological Psychiatry: Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2024.04.007 · Cited by 5 · see citing works
Wu, D., Qu, S., Sun, H., Zhou, S., Qu, X., Chen, Y., Hu, H., & Li, X. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111246 · Cited by 3 · see citing works
“The date used to support the present findings are available from the first author or the corresponding author a reasonable request.”
Unadkat, P., Quevedo, J., Soares, J. C., & Fenoy, A. J. (2024) · Discover Mental Health · doi:10.1007/s44192-024-00062-9 · Cited by 3 · see citing works
“This can then be used to trigger or titrate the stimulation when electrophysiological markers suggest an exaggerated depressive state [125, 126].”
BackgroundZhou, Y., Song, Y., Song, X., He, F., Xu, M., & Ming, D. (2025) · Cognitive Neurodynamics · doi:10.1007/s11571-024-10210-0 · Cited by 3 · see citing works
“In addition, DBS is effective for the treatment of major depressive disorder, Alzheimer disease and epilepsy (Sheth et al. 2022; Tatulian 2022; Vetkas et al. 2022).”
Wireless Device with Energy Management for Closed-Loop Deep Brain Stimulation (CLDBS)
Nordi, T. M., Ginja, G. A., Gounella, R. H., Fonoff, E. T., Colombari, E., Moreira, M. D. M. A. C., Afonso, J. A., Monteiro, V., Afonso, J. L., & Carmo, J. P. (2023) · Electronics · doi:10.3390/electronics12143082 · Cited by 2 · see citing works
Human single neuron recordings
Fu, Z., & Rutishauser, U. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-820480-1.00002-4 · Cited by 3 · see citing works
Di Passa, A.-M., Dabir, M., Fein, A., Khoshroo, S., McIntyre-Wood, C., Marsden, E., MacKillop, E., De Jesus, J., MacKillop, J., & Duarte, D. (2023) · JMIR Research Protocols · doi:10.2196/45213 · Cited by 2 · see citing works
“Research on other therapy options, such as vagus nerve stimulation [33,34] and deep brain stimulation [35-37], have continued to accumulate, offering further insight into these treatment options for psychiatric disorders.”
BackgroundNeural Interfaces: Applications, Innovative Approaches, Biocompatibility, Biomimetics
Zemlyanskov, M. S., Arsentiev, K. A., Shtol, V. S., Konovalova, S. P., Grinevich, V. P., & Евгеньевич, М. П. (2025) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093025040118 · Cited by 2 · see citing works
Betaine, a Potential Therapeutic Alternative for the Treatment of Depression
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Saal, J., KADLEC, K. H., Allawala, A. B., Johnston, L., Leriche, R. B., Vatsyayan, R., Han, Y., Kist, A., Ianni, T. D., Dawes, H. E., et al. (2025) · Neuromodulation Technology at the Neural Interface · doi:10.1016/j.neurom.2025.11.006 · Cited by 2 · see citing works
“…of our sEEG-based workflow is that short-term, stimulation-induced symptom relief will predict long-term clinical outcomes from long-term DBS. ,6-8 However, it is important to note that our methods are used to seek targets in which short-term stimulation is a sufficient condition for…”
Self-citationObsessive-compulsive disorder in primary tic disorders and Gilles de la Tourette syndrome
Worbe, Y., Courtin, E., & Burbaud, P. (2026) · Handbook of clinical neurology · doi:10.1016/b978-0-443-13554-5.00024-9 · Cited by 2 · see citing works
Danstrom, I. A., Adkinson, J. A., Liu, Z., Robinson, M. E., Oswalt, D. N., Banks, G. P., Maheshwari, A., Lin, L., Shofty, B., Hasen, M. A., et al. (2026) · Brain stimulation · doi:10.1016/j.brs.2026.103049 · Cited by 1 · see citing works
Self-citationSeilheimer, R. L., Qiu, L., Rocchio, G., Nho, Y., Campos, G., Horn, A., Rolle, C. E., Buch, V., Ganguly, T. M., Cristancho, M. A., et al. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.121349 · Cited by 2 · see citing works
Qiu, L., Halpern, C. H., & Barbosa, D. A. N. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02078-z · Cited by 2 · see citing works
“There is indeed growing acceptance in the scienti fi c community that different circuits may account for different phenotypes of MDD, which warrants more personalized approaches towards treating TRD with brain stimulation [6, 7].”
BackgroundComputational Neurosurgery in Deep Brain Stimulation
Germann, J., Gouveia, F. V., Beyn, M. E., Elias, G. J. B., & Lozano, A. M. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-64892-2_26 · Cited by 2 · see citing works
Nonpharmacological therapies for neurodegenerative disorders
Siddiq, A., Shrestha, S., Das, M., Chodnekar, S. Y., Wadan, A. S., Ayad, Y. W., & Ashraf, G. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-28822-7.00021-0 · Cited by 3 · see citing works
Al-Husinat, L., Al-Bataineh, M., Hayajneh, R., Haneyah, D., Alrawabdeh, Q., Melhem, R. B., Sharei, A. A., Ismail, M. I. A., Azzam, S., Sharie, S. A., et al. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1683991 · Cited by 2 · see citing works
Wiring up the brain to beat depression
Drew, L. (2022) · Nature · doi:10.1038/d41586-022-02209-6 · Cited by 2 · see citing works
Krauss, J. K., & Nagel, J. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-820480-1.00212-6 · Cited by 2 · see citing works
Saal, J., Khambhati, A. N., Chang, E. F., & Shirvalkar, P. R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.30.615930 · Cited by 2 · see citing works
“Recent studies have increasingly utilized iEEG electrodes for both recording neural activity and delivering electrical brain stimulation 2–4 .”
MethodInfluentialFeinsinger, A., & Pouratian, N. (2023) · Studies in neuroscience, psychology and behavioral economics · doi:10.1007/978-3-031-20910-9_6 · Cited by 1 · see citing works
Self-citation
- Authors
- Sheth, S. A., Bijanki, K. R., Metzger, B., Allawala, A., Pirtle, V., Adkinson, J. A., Myers, J., Mathura, R. K., Oswalt, D., Tsolaki, E., Xiao, J., Noecker, A., Strutt, A. M., Cohn, J. F., McIntyre, C. C., Mathew, S. J., Borton, D., Goodman, W., & Pouratian, N.
- Affiliations
- Baylor College of Medicine (US)
- Brown University (US)
- University of California, Los Angeles (US)
- Case Western Reserve University (US)
- University of Pittsburgh (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Sheth, Sameer A.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 92
- Issue
- 3
- Pages
- 246-251
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC9124238
- OpenAlex
- W3215550599
- Cited by
- 158
- References
- 28
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 51 · 2023: 39 · 2022: 10
- FWCI
- 11.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Robert and Janice Mcnair Foundation
- Dana Foundation
- Medtronic
- National Institutes of Health (K01 MH116364, UH3 NS103549, R01 MH114854, R21 NS104953, R01 MH106700, R01 NS105690, UH3 NS100549)
- Sage Therapeutics
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- deep brain stimulation, treatment-resistant depression, intracranial recordings, personalized neuromodulation, inverse solution, stimulation parameter optimization, depression remission
- MeSH terms
- Depression, Double-Blind Method, Humans, Parkinson Disease, Quality of Life, Deep Brain Stimulation, Depressive Disorder, Treatment-Resistant
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