Depression is associated with abnormal functioning of the reward circuitry. Several deep brain stimulation (DBS) targets for treatment-resistant depression (TRD) directly modulate white matter bundles of the reward circuitry. Here we investigated whether baseline reward processing in the brain is associated with ventral anterior limb of the internal capsule (vALIC) DBS outcome and whether vALIC DBS changes neural activity in the reward circuitry. We studied fifteen patients with TRD who performed a monetary reward task during functional magnetic resonance imaging (fMRI) before vALIC DBS surgery, after DBS parameter optimization, and during a sham-controlled crossover phase. Additionally, fifteen matched healthy controls were investigated twice to account for test-retest effects. We investigated brain responses to reward anticipation, loss anticipation, reward feedback and loss feedback. Results showed that lower baseline nucleus accumbens activation during loss anticipation and higher baseline caudate nucleus and midcingulate cortex activation during reward feedback processing were associated with worse DBS outcome. No significant changes in reward processing were observed following vALIC DBS in comparison to healthy controls or after active compared to sham stimulation. Instead, increased middle frontal gyrus responses following DBS to loss feedback was associated with better DBS outcome. These results suggest that DBS efficacy in TRD is related to individual differences in reward circuitry functioning at baseline and to changes in middle frontal gyrus responses following DBS.

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, P. Richard 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). P. Richard Schuurman acts as consultant for Boston Scientific and Medtronic on educational events. All other authors do not declare any conflicts of interest.

NTR2118

https://doi.org/10.1001/jamapsychiatry.2016.0152

This investigator-initiated study was funded by Medtronic Inc (25 DBS systems, in kind) and a research grant from ZonMw (nr. 171201008).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of Amsterdam University Medical Center, location AMC gave ethical approval for this work Ethics committee of St. Elisabeth Hospital, Tilburg gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors