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Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression


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.

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Fig. 1: vALIC DBS normalizes amygdala hyporesponsivity.
Fig. 2: Statistical maps showing PPI functional connectivity after active compared to sham DBS (seed: right amygdala).


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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).

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Authors and Affiliations



Funding acquisition: IB, RS, and DD. Conceptualization: RS, and DD. Investigation: IB, BK, JL, JvL, PN, GB, PM, RS, and DD. Project administration: IB. Methodology: NR and GW. Formal analysis, writing—original draft, and visualization: NR. Supervision: IB and GW. Writing—review & editing: all authors.

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Correspondence to Nora Runia or Guido A. van Wingen.

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Competing interests

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.

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Runia, N., Bergfeld, I.O., de Kwaasteniet, B.P. et al. Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression. Mol Psychiatry (2023).

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