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Metabolic activity in subcallosal cingulate predicts response to deep brain stimulation for depression.

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.

SUBMITTER: Brown EC

PROVIDER: S-EPMC7419290 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited.To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP).Open-label trial with a sham lead-in phase.Academic medical center. Patients Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation.Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation.A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase.The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration clinicaltrials.gov Identifier: NCT00367003.

Project description:The clinical utility of monitoring behavioral changes during intraoperative testing of subcallosal cingulate deep brain stimulation is unknown.To characterize the structural connectivity correlates of deep brain stimulation-evoked behavioral effects using probabilistic tractography in depression.Categorization of acute behavioral effects was conducted in 9 adults undergoing deep brain stimulation implantation surgery for chronic treatment-resistant depression in a randomized and blinded testing session at Emory University. Patients were studied from September 1, 2011, through June 30, 2013. Post hoc analyses of the structural tractography patterns mediating distinct categories of evoked behavioral effects were defined, including the best response overall. Data analyses were performed from May 1 through July 1, 2015.Categorization of stimulation-induced transient behavioral effects and delineation of the shared white matter tracts mediating response subtypes.Among the 9 patients, 72 active and 36 sham trials were recorded. The following stereotypical behavior patterns were identified: changes in interoceptive (noted changes in body state in 30 of 72 active and 4 of 36 sham trials) and in exteroceptive (shift in attention from patient to others in 9 of 72 active and 0 sham trials) awareness. The best response was a combination of exteroceptive and interoceptive changes at a single left contact for all 9 patients. Structural connectivity showed that the best response contacts had a pattern of connections to the bilateral ventromedial frontal cortex (via forceps minor and left uncinate fasciculus) and to the cingulate cortex (via left cingulum bundle), whereas behaviorally salient but nonbest contacts had only cingulate involvement. The involvement of the 3 white matter bundles during stimulation of the best contacts suggests a mechanism for the observed transient "depression switch."This analysis of transient behavior changes during intraoperative deep brain stimulation of the subcallosal cingulate and the subsequent identification of unique connectivity patterns may provide a biomarker of a rapid-onset depression switch to guide surgical implantation and to refine and optimize algorithms for the selection of contacts in long-term stimulation for treatment-resistant depression.

Project description:BackgroundDeep brain stimulation (DBS) of the subcallosal cingulate (SCC) is an emerging experimental therapy for treatment-resistant depression. New developments in SCC DBS surgical targeting are focused on identifying specific axonal pathways for stimulation that are estimated from preoperatively collected diffusion-weighted imaging (DWI) data. However, brain shift induced by opening burr holes in the skull may alter the position of the target pathways.ObjectivesQuantify the effect of electrode location deviations on tractographic representations for stimulating the target pathways using longitudinal clinical imaging datasets.MethodsPreoperative MRI and DWI data (planned) were coregistered with postoperative MRI (1 day, near-term) and CT (3 weeks, long-term) data. Brain shift was measured with anatomical control points. Electrode models corresponding to the planned, near-term, and long-term locations were defined in each hemisphere of 15 patients. Tractography analyses were performed using estimated stimulation volumes as seeds centered on the different electrode positions.ResultsMean brain shift of 2.2 mm was observed in the near-term for the frontal pole, which resolved in the long-term. However, electrode displacements from the planned stereotactic target location were observed in the anterior-superior direction in both the near-term (mean left electrode shift: 0.43 mm, mean right electrode shift: 0.99 mm) and long-term (mean left electrode shift: 1.02 mm, mean right electrode shift: 1.47 mm). DBS electrodes implanted in the right hemisphere (second-side operated) were more displaced from the plan than those in the left hemisphere. These displacements resulted in 3.6% decrease in pathway activation between the electrode and the ventral striatum, but 2.7% increase in the frontal pole connection, compared to the plan. Remitters from six-month chronic stimulation had less variance in pathway activation patterns than the non-remitters.ConclusionsBrain shift is an important concern for SCC DBS surgical targeting and can impact connectomic analyses.

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Metabolic activity in subcallosal cingulate predicts response to deep brain stimulation for depression.

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