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State-dependent responses to intracranial brain stimulation in a patient with depression

A Publisher Correction to this article was published on 08 August 2022

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Deep brain stimulation is a promising treatment for severe depression, but lack of efficacy in randomized trials raises questions regarding anatomical targeting. We implanted multi-site intracranial electrodes in a severely depressed patient and systematically assessed the acute response to focal electrical neuromodulation. We found an elaborate repertoire of distinctive emotional responses that were rapid in onset, reproducible, and context and state dependent. Results provide proof of concept for personalized, circuit-specific medicine in psychiatry.

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Fig. 1: Mapping mood across the corticolimbic circuit.
Fig. 2: Characterization of response properties.

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The source data that support the findings in this report are available in the report itself, in the Supplementary Information and in our publicly available code. Source data are provided with this paper.

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  1. Disease, G. B. D., Injury, I. & Prevalence, C. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet 392, 1789–1858 (2018).

    Article  Google Scholar 

  2. Howland, R. H. Sequenced treatment alternatives to relieve depression (STAR*D). Part 2: study outcomes. J. Psychosoc. Nurs. Ment. Health Serv. 46, 21–24 (2008).

    PubMed  Google Scholar 

  3. Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

    Article  CAS  Google Scholar 

  4. Holtzheimer, P. E. et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 4, 839–849 (2017).

    Article  Google Scholar 

  5. Dougherty, D. D. et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol. Psychiatry 78, 240–248 (2015).

    Article  Google Scholar 

  6. Bergfeld, I. O. et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 73, 456–464 (2016).

    Article  Google Scholar 

  7. Scangos, K. W. & Ross, D. A. What we’ve got here is failure to communicate: improving interventional psychiatry with closed-loop stimulation. Biol. Psychiatry 84, e55–e57 (2018).

    Article  Google Scholar 

  8. Mayberg, H. S., Riva-Posse, P. & Crowell, A. L. Deep brain stimulation for depression: keeping an eye on a moving target. JAMA Psychiatry 73, 439–440 (2016).

    Article  Google Scholar 

  9. Malone, D. A. Jr. et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol. Psychiatry 65, 267–275 (2009).

    Article  Google Scholar 

  10. Fraguas, D. et al. Mental disorders of known aetiology and precision medicine in psychiatry: a promising but neglected alliance. Psychol. Med. 47, 193–197 (2017).

    Article  CAS  Google Scholar 

  11. Riva-Posse, P. et al. A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol. Psychiatry 23, 843–849 (2018).

    Article  CAS  Google Scholar 

  12. Choi, K. S., Riva-Posse, P., Gross, R. E. & Mayberg, H. S. Mapping the “depression switch” during intraoperative testing of subcallosal cingulate deep brain stimulation. JAMA Neurol. 72, 1252–1260 (2015).

    Article  Google Scholar 

  13. Tharin, S. & Golby, A. Functional brain mapping and its applications to neurosurgery. Neurosurgery 60, 185–201 (2007).

    PubMed  Google Scholar 

  14. Bishop, M. P., Elder, S. T. & Heath, R. G. Intracranial self-stimulation in man. Science 140, 394–396 (1963).

    Article  CAS  Google Scholar 

  15. Rao, V. R. et al. Direct electrical stimulation of lateral orbitofrontal cortex acutely improves mood in individuals with symptoms of depression. Curr. Biol. 28, 3893–3902 e3894 (2018).

    Article  CAS  Google Scholar 

  16. Kirkby, L. A. et al. An amygdala–hippocampus subnetwork that encodes variation in human mood. Cell 175, 1688–1700 (2018).

    Article  CAS  Google Scholar 

  17. Scangos, K. W. et al. Pilot study of an intracranial electroencephalography biomarker of depressive symptoms in epilepsy. J. Neuropsychiatry Clin. Neurosci. 32, 185–190 (2020).

    Article  Google Scholar 

  18. Timmerby, N., Andersen, J. H., Sondergaard, S., Ostergaard, S. D. & Bech, P. A systematic review of the clinimetric properties of the 6-item version of the Hamilton Depression Rating Scale (HAM-D6). Psychother. Psychosom. 86, 141–149 (2017).

    Article  CAS  Google Scholar 

  19. Inman, C. S. et al. Human amygdala stimulation effects on emotion physiology and emotional experience. Neuropsychologia 145, 106722 (2018).

    Article  Google Scholar 

  20. Machado, A. et al. Functional topography of the ventral striatum and anterior limb of the internal capsule determined by electrical stimulation of awake patients. Clin. Neurophysiol. 120, 1941–1948 (2009).

    Article  Google Scholar 

  21. Riva-Posse, P. et al. Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression. Biol. Psychiatry 76, 963–969 (2014).

    Article  Google Scholar 

  22. Campbell, M. C. et al. Mood response to deep brain stimulation of the subthalamic nucleus in Parkinson’s disease. J. Neuropsychiatry Clin. Neurosci. 24, 28–36 (2012).

    Article  Google Scholar 

  23. Salloum, N. C. et al. Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression. Depress. Anxiety 36, 235–243 (2019).

    Article  CAS  Google Scholar 

  24. Mori, S. & van Zijl, P. C. Fiber tracking: principles and strategies—a technical review. NMR Biomed. 15, 468–480 (2002).

    Article  Google Scholar 

  25. Feffer, K. et al. 1Hz rTMS of the right orbitofrontal cortex for major depression: safety, tolerability and clinical outcomes. Eur. Neuropsychopharmacol. 28, 109–117 (2018).

    Article  CAS  Google Scholar 

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This work was supported by National Institutes of Health award K23NS110962 (to K.W.S.), a NARSAD Young Investigator grant from the Brain and Behavioral Research Foundation (to K.W.S.) and the Ray and Dagmar Dolby Family Fund through the Department of Psychiatry at the University of California, San Francisco (to K.W.S., A.D.K., E.F.C. and L.P.S.). E.F.C. was supported by the National Institutes of Health (U01NS098971, R01MH114860, R01MH111444, R01DC015504, R01DC01237, UH3 NS109556, UH3NS115631 and R01 NS105675), the New York Stem Cell Foundation, the Howard Hughes Medical Institute, the McKnight Foundation, the Shurl and Kay Curci Foundation and the William K. Bowes Foundation. A.D.K. acknowledges support from the National Institutes of Health (P01AG019724, R01 HL142051-01, R01AG059794, R01DK117953, UH3 NS109556-01 and R01AG060477-01A1), PCORI, Janssen, Jazz, Axsome (AXS-05-301) and Reveal Biosensors. L.P.S. receives support from the National Institutes of Health (U24 DA041123).

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Authors and Affiliations



K.W.S., A.D.K. and E.F.C. initiated this work and supervised the study. K.W.S. drafted the manuscript, and G.S.M., K.W.S. and L.P.S. collected and analyzed the data. A.D.K. and E.G.C. finalized the manuscript. All authors approved this work and take responsibility for its integrity.

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Correspondence to Katherine W. Scangos.

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Competing interests

A.D.K. consults for Eisai, Evecxia, Ferring, Galderma, Harmony Biosciences, Idorsia, Jazz, Janssen, Merck, Neurocrine, Pernix, Sage, Takeda, Big Health, Millenium Pharmaceuticals, Otsuka Pharmaceuticals, and Neurawell. All other authors declare no competing interests.

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Peer review information Jerome Staal and Kate Gao were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Scangos, K.W., Makhoul, G.S., Sugrue, L.P. et al. State-dependent responses to intracranial brain stimulation in a patient with depression. Nat Med 27, 229–231 (2021).

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