Closed-loop neuromodulation in an individual with treatment-resistant depression
Open accessAbstract
Deep brain stimulation is a promising treatment for neuropsychiatric conditions such as major depression. It could be optimized by identifying neural biomarkers that trigger therapy selectively when symptom severity is elevated. We developed an approach that first used multi-day intracranial electrophysiology and focal electrical stimulation to identify a personalized symptom-specific biomarker and a treatment location where stimulation improved symptoms. We then implanted a chronic deep brain sensing and stimulation device and implemented a biomarker-driven closed-loop therapy in an individual with depression. Closed-loop therapy resulted in a rapid and sustained improvement in depression. Future work is required to determine if the results and approach of this n-of-1 study generalize to a broader population. This case report describes a biomarker-driven closed-loop therapy for depression using implanted electrodes to continually sense brain activity and automatically trigger direct brain electrical stimulation in high-depression states.
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Closed-loop DBS was recently piloted in a patient with treatment-resistant depression.
“Closed-loop DBS was recently piloted in a TRD patient [109].”
From Deep brain stimulation for depression. (2022) · cites this paper as [109]
Responsive VC/VS stimulation triggered by amygdala gamma increases resulted in over 400 daily biomarker detections and acute and sustained remission of depressive symptoms.
“This strategy resulted in over 400 daily depressive biomarker detections triggering 6-s stimulations, and acute and sustained remission of depressive symptoms.”
From Deep brain stimulation for depression. (2022) · cites this paper as [109]
During 10 days of intracranial mapping, amygdala gamma power correlated with high depressive symptom states measured several times daily.
“amygdala gamma power correlated with high depressive symptom states measured several times daily.”
From Deep brain stimulation for depression. (2022) · cites this paper as [109]
Cites
Harris, P. A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N., & Conde, J. G. (2009) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2008.08.010 · Cited by 51,384 · see citing works
The REDCap consortium: building an international community of software platform partners
Harris, P. A., Taylor, R., Minor, B. L., Elliott, V., Fernandez, M., O'Neal, L., McLeod, L., Delacqua, G., Delacqua, F., Kirby, J., et al. (2019) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2019.103208 · Cited by 24,013 · see citing works
Fundamentals of speech recognition
Rabiner, L. R., & Juang, B.-H. F. (1993) · Cited by 7,680 · see citing works
Dynamic Programming Algorithm Optimization for Spoken Word Recognition
Sakoe, H., & Chiba, S. (1978) · IEEE Transactions on Acoustics Speech and Signal Processing · doi:10.1109/tassp.1978.1163055 · Cited by 6,727 · see citing works
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 · see citing works
Functional and Effective Connectivity: A Review
Friston, K. J. (2011) · Brain Connectivity · doi:10.1089/brain.2011.0008 · Cited by 3,415 · see citing works
Bassett, D. S., & Sporns, O. (2017) · Nature Neuroscience · doi:10.1038/nn.4502 · Cited by 2,398 · see citing works
Fiber tracking: principles and strategies – a technical review
Mori, S., & van Zijl, P. C. M. (2002) · NMR in Biomedicine · doi:10.1002/nbm.781 · Cited by 2,019 · see citing works
Neurocircuitry of Mood Disorders
Price, J. L., & Drevets, W. C. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.104 · Cited by 1,606 · see citing works
Computing and Visualizing Dynamic Time Warping Alignments inR: ThedtwPackage
Toni Giorgino, A. (2009) · Journal of Statistical Software · doi:10.18637/jss.v031.i07 · Cited by 1,263 · see citing works
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 · see citing works
Functional connectivity in the human language system: a cortico-cortical evoked potential study.
Matsumoto, R., Nair, D., LaPresto, E., Najm, I., Bingaman, W., Shibasaki, H., & Lüders, H. (2004) · Brain : a journal of neurology · doi:10.1093/brain/awh246 · Cited by 688 · see citing works
Precision psychiatry: a neural circuit taxonomy for depression and anxiety
Williams, L. M. (2016) · The Lancet Psychiatry · doi:10.1016/s2215-0366(15)00579-9 · Cited by 641 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
The RNS System: responsive cortical stimulation for the treatment of refractory partial epilepsy
Sun, F. T., & Morrell, M. J. (2014) · Expert Review of Medical Devices · doi:10.1586/17434440.2014.947274 · Cited by 270 · see citing works
Mapping human brain networks with cortico-cortical evoked potentials
Keller, C. J., Honey, C. J., Mégevand, P., Entz, L., Ulbert, I., & Mehta, A. D. (2014) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2013.0528 · Cited by 244 · see citing works
State-dependent responses to intracranial brain stimulation in a patient with depression
Scangos, K. W., Makhoul, G. S., Sugrue, L. P., Chang, E. F., & Krystal, A. D. (2021) · Nature Medicine · doi:10.1038/s41591-020-01175-8 · Cited by 243 · see citing works
Self-citationDunner, D. L., Rush, A. J., Russell, J. M., Burke, M., Woodard, S., Wingard, P., & Allen, J. (2006) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v67n0501 · Cited by 234 · see citing works
Biomarkers for closed-loop deep brain stimulation in Parkinson disease and beyond
Bouthour, W., Mégevand, P., Donoghue, J. P., Lüscher, C., Birbaumer, N., & Krack, P. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0166-4 · Cited by 227 · see citing works
Fast wavelet transformation of EEG
Schiff, S. J., Aldroubi, A., Unser, M. A., & Sato, S. (1994) · Electroencephalography and Clinical Neurophysiology · doi:10.1016/0013-4694(94)90165-1 · Cited by 213 · see citing works
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. (2018) · Current Biology · doi:10.1016/j.cub.2018.10.026 · Cited by 181 · see citing works
An Amygdala-Hippocampus Subnetwork that Encodes Variation in Human Mood
Kirkby, L. A., Luongo, F. J., Lee, M. B., Nahum, M., Vleet, T. V., Rao, V. R., Dawes, H. E., Chang, E. F., & Sohal, V. S. (2018) · Cell · doi:10.1016/j.cell.2018.10.005 · Cited by 171 · see citing works
Self-citationTowards Large-Scale, Human-Based, Mesoscopic Neurotechnologies
Chang, E. F. (2015) · Neuron · doi:10.1016/j.neuron.2015.03.037 · Cited by 163 · see citing works
Self-citationTimmerby, N., Andersen, J. H., Søndergaard, S., Østergaard, S. D., & Bech, P. (2017) · Psychotherapy and Psychosomatics · doi:10.1159/000457131 · Cited by 134 · see citing works
Choi, K. S., Riva‐Posse, P., Gross, R. E., & Mayberg, H. S. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.2564 · Cited by 133 · see citing works
Sequenced Treatment Alternatives to Relieve Depression (STAR*D): Part 2: Study Outcomes
Howland, R. H. (2008) · Journal of Psychosocial Nursing and Mental Health Services · doi:10.3928/02793695-20081001-05 · Cited by 115 · see citing works
Yeung, A. W. K., & Wong, N. S. M. (2019) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2019.00086 · Cited by 111 · see citing works
Haq, I. U., Foote, K. D., Goodman, W. G., Wu, S. S., Sudhyadhom, A., Ricciuti, N., Siddiqui, M., Bowers, D., Jacobson, C. E., Ward, H. E., et al. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.03.009 · Cited by 105 · see citing works
Khambhati, A. N., Kahn, A. E., Costantini, J. G., Ezzyat, Y., Solomon, E. A., Gross, R. E., Jobst, B. C., Sheth, S. A., Zaghloul, K. A., Worrell, G. A., et al. (2019) · Network Neuroscience · doi:10.1162/netn_a_00089 · Cited by 62 · see citing works
Self-citationSequenced Treatment Alternatives to Relieve Depression (STAR*D): Part 1: Study Design
Howland, R. H. (2008) · Journal of Psychosocial Nursing and Mental Health Services · doi:10.3928/02793695-20080901-06 · Cited by 59 · see citing works
Mood Response to Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson's Disease
Campbell, M. C., BLACK, K. J., Weaver, P. M., et al. (2012) · Journal of Neuropsychiatry · doi:10.1176/appi.neuropsych.11030060 · Cited by 55 · see citing works
Salloum, N. C., D, M. F. M., Freeman, M. P., Flynn, M., Hoeppner, B. B., Hock, R. S., Cusin, C., Iosifescu, D. V., Trivedi, M. H., Sanacora, G., et al. (2018) · Depression and Anxiety · doi:10.1002/da.22875 · Cited by 50 · see citing works
Sokolov, A. A., Zeidman, P., Erb, M., Ryvlin, P., Pavlova, M. A., & Friston, K. J. (2018) · Brain Structure and Function · doi:10.1007/s00429-018-1760-8 · Cited by 40 · see citing works
Green light for deep brain stimulator incorporating neurofeedback
Waltz, E. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0664-3 · Cited by 10 · see citing works
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- Authors
- 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., Starr, P. A., Krystal, A. D., & Chang, E. F.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Scangos, Katherine W.
- ORCID
- Venue
- Nature Medicine
- Published
- 2021-10
- Volume
- 27
- Issue
- 10
- Pages
- 1696-1700
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC11219029
- OpenAlex
- W3202708773
- Semantic Scholar
- a53a77199ab2caf1c4d08f1e8738816d8039bf9c
- Cited by
- 535
- References
- 38
- Citations by year
- 2026: 108 · 2025: 103 · 2024: 113 · 2023: 136 · 2022: 66 · 2021: 9
- FWCI
- 38.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of California, San Francisco
- National Institute of Neurological Disorders and Stroke (K23NS110962, UH3NS123310)
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Keywords
- closed-loop neuromodulation, deep brain stimulation, treatment-resistant depression, major depressive disorder, neural markers, intracranial electrophysiology, focal electrical stimulation, personalized treatment
- MeSH terms
- Adult, Brain, Major Depressive Disorder, Electric Stimulation, Female, Humans, Severity of Illness Index, Biomarkers, Treatment Outcome, Deep Brain Stimulation
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