Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face-viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two-time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. This effect was not dependent on emotional valence. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices, which was not significantly different between responders and non-responders. These results suggest that vALIC DBS restores amygdala responsivity and behavioral vigilance in TRD, which may contribute to the DBS-induced antidepressant effect.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Mithani K, Davison B, Meng Y, Lipsman N. The anterior limb of the internal capsule: Anatomy, function, and dysfunction. Behav Brain Res. 2020;387:112588.
Bergfeld IO, Figee M. Deep Brain Stimulation for Depression. In: Fundamentals and Clinics of Deep Brain Stimulation. Springer, 2020, pp 279–90.
Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhé HG, Notten P, van Laarhoven J, et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2016;73:456–64.
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.
Millet B, Jaafari N, Polosan M, Baup N, Giordana B, Haegelen C, et al. Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate. Eur Neuropsychopharmacol. 2014;24:1229–39.
Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008;33:368–77.
Joormann J, Stanton CH. Examining emotion regulation in depression: A review and future directions. Behav Res Ther. 2016;86:35–49.
Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9:471–81.
Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry. 2003;54:515–28.
Hamilton JP, Etkin A, Furman DJ, Lemus MG, Johnson RF, Gotlib IH. Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of baseline activation and neural response data. Am J Psychiatry. 2012;169:693–703.
Stuhrmann A, Suslow T, Dannlowski U. Facial emotion processing in major depression: a systematic review of neuroimaging findings. Biol Mood Anxiety Disord. 2011;1:10.
Costafreda SG, Brammer MJ, David AS, Fu CH. Predictors of amygdala activation during the processing of emotional stimuli: a meta-analysis of 385 PET and fMRI studies. Brain Res Rev. 2008;58:57–70.
Esteban O, Birman D, Schaer M, Koyejo OO, Poldrack RA, Gorgolewski KJ. MRIQC: Advancing the automatic prediction of image quality in MRI from unseen sites. PLOS ONE. 2017;12:e0184661.
Guillaume B, Hua X, Thompson PM, Waldorp L, Nichols TE. Initiative AsDN. Fast and accurate modelling of longitudinal and repeated measures neuroimaging data. NeuroImage 2014;94:287–302.
Coenen VA, Panksepp J, Hurwitz TA, Urbach H, Mädler B. Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression. J Neuropsychiatry Clin Neurosci. 2012;24:223–36.
Fenoy AJ, Quevedo J, Soares JC. Deep brain stimulation of the “medial forebrain bundle”: a strategy to modulate the reward system and manage treatment-resistant depression. Mol Psychiatry. 2021;27:574–92.
Sah P, Faber EL, Lopez de Armentia M, Power J. The amygdaloid complex: anatomy and physiology. Physiol Rev. 2003;83:803–34.
Price JL. Comparative aspects of amygdala connectivity. Ann N. Y Acad Sci. 2003;985:50–8.
Figee M, Luigjes J, Smolders R, Valencia-Alfonso C-E, Van Wingen G, De, et al. Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder. Nat Neurosci. 2013;16:386–7.
Horn A, Wenzel G, Irmen F, Huebl J, Li N, Neumann W-J, et al. Deep brain stimulation-induced normalization of the human functional connectome in Parkinson’s disease. Brain 2019;142:3129–43.
Miocinovic S, Miller A, Swann NC, Ostrem JL, Starr PA. Chronic deep brain stimulation normalizes scalp EEG activity in isolated dystonia. Clin Neurophysiol. 2018;129:368–76.
Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol Psychiatry. 2001;6:13–34.
Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ. A meta‐analytic study of changes in brain activation in depression. Hum Brain Mapp. 2008;29:683–95.
Groenewold NA, Opmeer EM, de Jonge P, Aleman A, Costafreda SG. Emotional valence modulates brain functional abnormalities in depression: evidence from a meta-analysis of fMRI studies. Neurosci Biobehav Rev. 2013;37:152–63.
Runia N, Yücel DE, Lok A, de Jong K, Denys DA, van Wingen GA, et al. The neurobiology of treatment-resistant depression: a systematic review of neuroimaging studies. Neurosci Biobehav Rev. 2022;132:433–48.
Ferri J, Eisendrath SJ, Fryer SL, Gillung E, Roach BJ, Mathalon DH. Blunted amygdala activity is associated with depression severity in treatment-resistant depression. Cogn, Affect, Behav Neurosci. 2017;17:1221–31.
Redlich R, Bürger C, Dohm K, Grotegerd D, Opel N, Zaremba D, et al. Effects of electroconvulsive therapy on amygdala function in major depression–a longitudinal functional magnetic resonance imaging study. Psychol Med. 2017;47:2166–76.
Loureiro JR, Leaver A, Vasavada M, Sahib AK, Kubicki A, Joshi S, et al. Modulation of amygdala reactivity following rapidly acting interventions for major depression. Hum Brain Mapp. 2020;41:1699–710.
Todorov A. The role of the amygdala in face perception and evaluation. Motiv Emot. 2012;36:16–26.
Behrmann M, Geng JJ, Shomstein S. Parietal cortex and attention. Curr Opin Neurobiol. 2004;14:212–7.
Maddock RJ, Garrett AS, Buonocore MH. Posterior cingulate cortex activation by emotional words: fMRI evidence from a valence decision task. Hum Brain Mapp. 2003;18:30–41.
Grezes J, Valabregue R, Gholipour B, Chevallier C. A direct amygdala‐motor pathway for emotional displays to influence action: A diffusion tensor imaging study. Hum Brain Mapp. 2014;35:5974–83.
The authors would like to thank Frank van Thienen for his comments and suggestions on the grammar and punctuation of the manuscript. Funding: This investigator-initiated study was funded by Medtronic Inc (25 DBS systems, in kind) and a grant from ZonMw (nr. 171201008).
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This investigator-initiated study was funded by Medtronic Inc (25 DBS systems, in kind) and a grant from ZonMw (nr. 171201008). The funders had no role in the design, execution, and analysis of the study, nor in writing of the manuscript or the decision to publish. Nora Runia, Isidoor Bergfeld, Pepijn van den Munckhof, Rick Schuurman, Damiaan Denys, and Guido van Wingen currently execute an investigator-initiated clinical trial on deep brain stimulation for depression, which is funded by Boston Scientific (24 DBS systems in kind) and a grant of ZonMw (nr. 636310016). Rick Schuurman acts as consultant for Boston Scientific and Medtronic on educational events. All other authors do not declare any conflicts of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Runia, N., Bergfeld, I.O., de Kwaasteniet, B.P. et al. Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02030-1