Abstract
Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising therapy for treatment-resistant depression (TRD), but response rates in open-label studies were not replicated in a large multicenter trial. Identifying biomarkers of response could improve patient selection and outcomes. We examined SCC metabolic activity as both a predictor and marker of SCC DBS treatment response. Brain glucose metabolism (CMRGlu) was measured with [18F] FDG-PET at baseline and 6 months post DBS in 20 TRD patients in a double-blind randomized controlled trial where two stimulation types (long pulse width (LPW) n = 9 and short pulse width (SPW) n = 11) were used. Responders (n = 10) were defined by a ≥48% reduction in Hamilton Depression Rating Scale scores after 6 months. The response rates were similar with five responders in each stimulation group: LPW (55.6%) and SPW (44.5%). First, differences in SCC CMRGlu in responders and non-responders were compared at baseline. Then machine learning analysis was performed with a leave-one-out cross-validation using a Gaussian naive Bayes classifier to test whether baseline CMRGlu in SCC could categorize responders. Finally, we compared 6-month change in metabolic activity with change in depression severity. All analyses were controlled for age. Baseline SCC CMRGlu was significantly higher in responders than non-responders. The machine learning analysis predicted response with 80% accuracy. Furthermore, reduction in SCC CMRGlu 6 months post DBS correlated with symptom improvement (r(17) = 0.509; p = 0.031). This is the first evidence of an image-based treatment selection biomarker that predicts SCC DBS response. Future studies could utilize SCC metabolic activity for prospective patient selection.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–60.
Holtzheimer PE, Kelley ME, Gross RE, Filkowski MM, Garlow SJ, Barrocas A, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry. 2012;69:150–8.
Lozano AM, Giacobbe P, Hamani C, Rizvi SJ, Kennedy SH, Kolivakis TT, et al. A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg. 2012;116:315–22.
Merkl A, Schneider G-H, Schönecker T, Aust S, Kühl K-P, Kupsch A, et al. Antidepressant effects after short-term and chronic stimulation of the subgenual cingulate gyrus in treatment-resistant depression. Exp Neurol. 2013;249:160–8.
Puigdemont D, Pérez-Egea R, Portella MJ, Molet J, de Diego-Adeliño J, Gironell A, et al. Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression. Int J Neuropsychopharmacol. 2012;15:121–33.
Ramasubbu R, Anderson S, Haffenden A, Chavda S, Kiss ZHT. Double-blind optimization of subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study. J Psychiatry Neurosci. 2013;38:325–32.
Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry. 2017;4:839–49.
Hamani C, Mayberg H, Stone S, Laxton A, Haber S, Lozano AM. The subcallosal cingulate gyrus in the context of major depression. Biol Psychiatry. 2011;69:301–8.
Ramirez-Mahaluf JP, Perramon J, Otal B, Villoslada P, Compte A. Subgenual anterior cingulate cortex controls sadness-induced modulations of cognitive and emotional network hubs. Sci Rep. 2018;8:8566.
Dougherty DD, Weiss AP, Cosgrove GR, Alpert NM, Cassem EH, Nierenberg AA, et al. Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for treatment of major depression. J Neurosurg. 2003;99:1010–7.
Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386:824–7.
Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675–82.
Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. NeuroImage. 2004;22:409–18.
Dunlop BW, Rajendra JK, Craighead WE, Kelley ME, McGrath CL, Choi KS, et al. Functional connectivity of the subcallosal cingulate cortex and differential outcomes to treatment with cognitive-behavioral therapy or antidepressant medication for major depressive disorder. Am J Psychiatry. 2017;174:533–45.
Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830–43.
Liu Y, Du L, Li Y, Liu H, Zhao W, Liu D, et al. Antidepressant effects of electroconvulsive therapy correlate with subgenual anterior cingulate activity and connectivity in depression. Medicine. 2015;94:e2033.
Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008;64:461–7.
Nobler MS, Oquendo MA, Kegeles LS, Malone KM, Campbell CC, Sackeim HA, et al. Decreased regional brain metabolism after ect. Am J Psychiatry. 2001;158:305–8.
Siegle GJ, Thompson WK, Collier A, Berman SR, Feldmiller J, Thase ME, et al. Toward clinically useful neuroimaging in depression treatment: prognostic utility of subgenual cingulate activity for determining depression outcome in cognitive therapy across studies, scanners, and patient characteristics. Arch Gen Psychiatry. 2012;69:913–24.
Pizzagalli D, Pascual-Marqui RD, Nitschke JB, Oakes TR, Larson CL, Abercrombie HC, et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis. Am J Psychiatry. 2001;158:405–15.
Pizzagalli DA, Webb CA, Dillon DG, Tenke CE, Kayser J, Goer F, et al. Pretreatment rostral anterior cingulate cortex theta activity in relation to symptom improvement in depression: a randomized clinical trial. JAMA Psychiatry. 2018;75:547–54.
Conen S, Matthews JC, Patel NK, Anton-Rodriguez J, Talbot PS. Acute and chronic changes in brain activity with deep brain stimulation for refractory depression. J Psychopharmacol Oxf Engl. 2018;32:430–40.
Lipsman N, Lam E, Volpini M, Sutandar K, Twose R, Giacobbe P, et al. Deep brain stimulation of the subcallosal cingulate for treatment-refractory anorexia nervosa: 1 year follow-up of an open-label trial. Lancet Psychiatry. 2017;4:285–94.
Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry. 2010;67:110–6.
Dougherty DD, Chou T, Corse AK, Arulpragasam AR, Widge AS, Cusin C, et al. Acute deep brain stimulation changes in regional cerebral blood flow in obsessive-compulsive disorder. J Neurosurg. 2016;125:1087–93.
Le Jeune F, Vérin M, N’Diaye K, Drapier D, Leray E, Du Montcel ST, et al. Decrease of prefrontal metabolism after subthalamic stimulation in obsessive-compulsive disorder: a positron emission tomography study. Biol Psychiatry. 2010;68:1016–22.
Rauch SL, Dougherty DD, Malone D, Rezai A, Friehs G, Fischman AJ, et al. A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. J Neurosurg. 2006;104:558–65.
Suetens K, Nuttin B, Gabriëls L, Van Laere K. Differences in metabolic network modulation between capsulotomy and deep-brain stimulation for refractory obsessive-compulsive disorder. J Nucl Med. 2014;55:951–9.
Martín-Blanco A, Serra-Blasco M, Pérez-Egea R, de Diego-Adeliño J, Carceller-Sindreu M, Puigdemont D, et al. Immediate cerebral metabolic changes induced by discontinuation of deep brain stimulation of subcallosal cingulate gyrus in treatment-resistant depression. J Affect Disord. 2015;173:159–62.
Ramasubbu R, Clark DL, Golding S, Dobson KS, Mackie A, Haffenden A, et al. Long versus short pulse width subcallosal cingulate stimulation for treatment-resistant depression: a randomised, double-blind, crossover trial. Lancet Psychiatry. 2020;7:29–40.
Bewernick BH, Kayser S, Gippert SM, Switala C, Coenen VA, Schlaepfer TE. Deep brain stimulation to the medial forebrain bundle for depression- long-term outcomes and a novel data analysis strategy. Brain Stimul. 2017;10:664–71.
Kelley ME, Franco AR, Mayberg HS, Holtzheimer PE. The Illness Density Index (IDI): a longitudinal measure of treatment efficacy. Clin Trials. 2012;9:596–604.
van der Wal JM, Bergfeld IO, Lok A, Mantione M, Figee M, Notten P, et al. Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression. J Neurol Neurosurg Psychiatry. 2020;91:189–95.
Makris N, Goldstein JM, Kennedy D, Hodge SM, Caviness VS, Faraone SV, et al. Decreased volume of left and total anterior insular lobule in schizophrenia. Schizophr Res. 2006;83:155–71.
Frazier JA, Chiu S, Breeze JL, Makris N, Lange N, Kennedy DN, et al. Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. Am J Psychiatry. 2005;162:1256–65.
Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage. 2006;31:968–80.
Goldstein JM, Seidman LJ, Makris N, Ahern T, O’Brien LM, Caviness VS, et al. Hypothalamic abnormalities in schizophrenia: sex effects and genetic vulnerability. Biol Psychiatry. 2007;61:935–45.
Brett M, Anton J-L, Valabregue R, Poline J-B. Region of interest analysis using SPM toolbox (Abstract). In 8th international conference on Functional Mapping of the Human Brain. Sendai, Japan. Neuroimage. 2002:16.
Ashburner J, Friston KJ. Voxel-based morphometry–the methods. NeuroImage. 2000;11:805–21.
Bari AA, Mikell CB, Abosch A, Ben-Haim S, Buchanan RJ, Burton AW, et al. Charting the road forward in psychiatric neurosurgery: proceedings of the 2016 American Society for Stereotactic and Functional Neurosurgery workshop on neuromodulation for psychiatric disorders. J Neurol Neurosurg Psychiatry. 2018;89:886–96.
Konarski JZ, Kennedy SH, Segal ZV, Lau MA, Bieling PJ, McIntyre RS, et al. Predictors of nonresponse to cognitive behavioural therapy or venlafaxine using glucose metabolism in major depressive disorder. J Psychiatry Neurosci. 2009;34:175–80.
McGrath CL, Kelley ME, Dunlop BW, Holtzheimer PE, Craighead WE, Mayberg HS. Pretreatment brain states identify likely nonresponse to standard treatments for depression. Biol Psychiatry. 2014;76:527–35.
Baeken C, Marinazzo D, Everaert H, Wu G-R, Van Hove C, Audenaert K, et al. The impact of accelerated HF-rTMS on the subgenual anterior cingulate cortex in refractory unipolar major depression: insights from 18FDG PET brain imaging. Brain Stimul. 2015;8:808–15.
Dunlop BW, Mayberg HS. Neuroimaging-based biomarkers for treatment selection in major depressive disorder. Dialogues Clin Neurosci. 2014;16:479–90.
McIntyre CC, Grill WM, Sherman DL, Thakor NV. Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. J Neurophysiol. 2004;91:1457–69.
Berti V, Mosconi L, Pupi A. Brain: normal variations and benign findings in fluorodeoxyglucose-PET/computed tomography imaging. PET Clin. 2014;9:129–40.
Iremonger KJ, Anderson TR, Hu B, Kiss ZHT. Cellular mechanisms preventing sustained activation of cortex during subcortical high-frequency stimulation. J Neurophysiol. 2006;96:613–21.
Akil H, Gordon J, Hen R, Javitch J, Mayberg H, McEwen B, et al. Treatment resistant depression: a multi-scale, systems biology approach. Neurosci Biobehav Rev. 2018;84:272–88.
Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28–38.
Lawrence NS, Williams AM, Surguladze S, Giampietro V, Brammer MJ, Andrew C, et al. Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biol Psychiatry. 2004;55:578–87.
Anderson CJ, Anderson DN, Pulst SM, Butson CR, Dorval AD. Neural selectivity, efficiency, and dose equivalence in deep brain stimulation through pulse width tuning and segmented electrodes. BioRxiv. 2019:613133. https://doi.org/10.1101/613133.
Rive MM, van Rooijen G, Veltman DJ, Phillips ML, Schene AH, Ruhé HG. Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies. Neurosci Biobehav Rev. 2013;37:2529–53.
Cersosimo MG, Raina GB, Benarroch EE, Piedimonte F, Alemán GG, Micheli FE. Micro lesion effect of the globus pallidus internus and outcome with deep brain stimulation in patients with Parkinson disease and dystonia. Mov Disord. 2009;24:1488–93.
Bewernick BH, Kayser S, Sturm V, Schlaepfer TE. Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Neuropsychopharmacology. 2012;37:1975–85.
Lipsman N, McIntyre RS, Giacobbe P, Torres C, Kennedy SH, Lozano AM. Neurosurgical treatment of bipolar depression: defining treatment resistance and identifying surgical targets. Bipolar Disord. 2010;12:691–701.
Acknowledgements
We thank Dr. Mayberg for her guidance in the development of the PET protocol. We also thank Dr. Yatham Lakshmi and Dr. Vesna Sossi, at the University of British Columbia, for providing training in imaging analysis. This study was presented as a poster at the 73rd Society of Biological Psychiatry annual meeting on May 2018.
Author information
Authors and Affiliations
Contributions
ECB performed the imaging analyses and wrote the paper. RR/ZHTK conceptualized and designed the study of subcallosal cingulate deep brain stimulation for treatment-resistant depression. RR designed the PET study. ZHTK implanted the DBS system. RR performed initial psychiatric assessment and monthly clinical assessments to determine responders and non-responders. NDF performed the machine learning analysis. CPM assisted in developing the PET protocol, and PET image acquisition and storage. RR, ZHTK, ECB and DLC interpreted the results. All authors reviewed the final paper and provided comments.
Corresponding author
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Brown, E.C., Clark, D.L., Forkert, N.D. et al. Metabolic activity in subcallosal cingulate predicts response to deep brain stimulation for depression. Neuropsychopharmacol. 45, 1681–1688 (2020). https://doi.org/10.1038/s41386-020-0745-5
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41386-020-0745-5
This article is cited by
-
Applications of machine learning in deep brain stimulation for major depressive disorder: a systematic review and meta-analysis
Neurosurgical Review (2025)
-
Cortical signatures of sleep are altered following effective deep brain stimulation for depression
Translational Psychiatry (2024)
-
Whole brain network effects of subcallosal cingulate deep brain stimulation for treatment-resistant depression
Molecular Psychiatry (2024)
-
Deep brain stimulation for refractory major depressive disorder: a comprehensive review
Molecular Psychiatry (2024)
-
Perspectives of the European Association of Nuclear Medicine on the role of artificial intelligence (AI) in molecular brain imaging
European Journal of Nuclear Medicine and Molecular Imaging (2024)
