Background Deep brain stimulation (DBS) of subcallosal cingulate white matter (SCC) is an evolving investigational treatment for major depression. Mechanisms of action are hypothesized to involve modulation of activity within a structurally defined network of brain regions involved in mood regulation. Diffusion tensor imaging (DTI) was used to model white matter connections within this network to identify those critical for successful antidepressant response to SCC DBS. Methods Pre-operative high-resolution MRI data, including DTI, were acquired in 16 patients with treatment-resistant depression who then received SCC DBS. Computerized tomography was used post-operatively to locate DBS contacts. The activation volume around the active contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts that traveled through each activation volume. Patient-specific tract maps were calculated using whole-brain analysis. Clinical evaluations of therapeutic outcome from SCC DBS were defined at 6 months and 2 years. Results Whole brain activation volume tractography (AVT) demonstrated that all DBS responders at six months (n=6) and 2 years (n=12) shared bilateral pathways from their activation volumes to (1) medial frontal cortex via forceps minor and uncinate fasciculus, (2) rostral and dorsal cingulate cortex via the cingulum bundle, and (3) subcortical nuclei. Non-responders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from non-responders. Conclusions Patient-specific AVT modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection.

Target identification and contact selection are known contributors to variability in efficacy across different clinical indications of deep brain stimulation surgery. A retrospective analysis of responders to subcallosal cingulate deep brain stimulation (SCC DBS) for depression demonstrated the common impact of the electrical stimulation on a stereotypic connectome of converging white matter bundles (forceps minor, uncinate fasciculus, cingulum and fronto-striatal fibers). To test the utility of a prospective connectomic approach for SCC DBS surgery, this pilot study used the four-bundle tractography “connectome blueprint” to plan surgical targeting in eleven participants with treatment-resistant depression. Before surgery, targets were selected individually using deterministic tractography. Selection of contacts for chronic stimulation was made by matching the postoperative probabilistic tractography map to the presurgical deterministic tractography map for each subject. Intraoperative behavioral responses were used as a secondary verification of location. A probabilistic tract map of all participants demonstrated inclusion of the four bundles as intended, matching the connectome blueprint previously defined. Eight of 11 patients (72.7%) were responders and 5 were remitters after 6 months of open-label stimulation. At one year, nine of 11 patients (81.8%) were responders, with six of them in remission. These results support the utility of a group probabilistic tractography map as a connectome blueprint for individualized, patient-specific, deterministic tractography targeting, confirming retrospective findings previously published. This new method represents a connectomic approach to guide future SCC DBS studies.

Objective To inform the first-line treatment choice between cognitive behavior therapy (CBT) or an antidepressant medication for treatment-naïve adults with major depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions. Method Functional magnetic resonance imaging resting state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122, 58 achieved remission (Hamilton Depression Rating Scale, HDRS) ≤7 at weeks 10 and 12); 24 were treatment failures (HDRS <30% decrease from baseline). A 2×2 ANOVA using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. ROC curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes. Results The resting state functional connectivity of three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication, and survived application of the subsample permutation tests: left anterior ventrolateral/insula prefrontal cortex, dorsal midbrain, and left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, we demonstrated overall classification rates of 72–78% for remission and 75–89% for treatment failure. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT. Conclusions Imaging-based depression subtypes defined using resting state functional connectivity differentially identified an individual’s probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models.

No abstract

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (P < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (P < 0.0005), as were circuits derived from patients with major depression versus other diagnoses (P < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites (P < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson's disease (P < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders.

Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCWM) is an experimental therapy for major depressive disorder (MDD). The specific axonal pathways that mediate the anti-depressant effects of DBS remain unknown. Patient-specific tractography-activation models (TAMs) are a new tool to help identify pathways modulated by DBS. TAMs consist of four basic components: 1) anatomical and diffusion-weighted imaging data acquired on the patient; 2) probabilistic tractography from the brain region surrounding the implanted DBS electrode; 3) finite element models of the electric field generated by the patient-specific DBS parameter settings; 4) application of the DBS electric field to multi-compartment cable models of axons, with trajectories defined by the tractography, to predict action potential generation in specific pathways. This study presents TAM predictions from DBS of the SCCWM in one MDD patient. Our findings suggest that small differences in electrode location can generate substantial differences in the directly activated pathways.

Retrospective tractography-based analyses are common in DBS research; however, intraoperative software tools for interactive selection of a tractography-based DBS target are not readily available. StimVision provides an academic research tool to assist clinical implementation of new DBS targeting strategies and postoperative evaluation of targeting outcome.

Subcallosal cingulate cortex deep brain stimulation (SCC-DBS) is an experimental therapy for treatment-resistant depression (TRD). Refinement and optimization of SCC-DBS will benefit from increased study of SCC electrophysiology in context of ongoing high-frequency SCC-DBS therapy. The study objective was a 7-mo observation of frequency-domain 1/ f slope in off-stimulation local field potentials (SCC-LFPs) alongside standardized measurements of depression severity in 4 patients undergoing SCC-DBS. SCC was implanted bilaterally with a combined neurostimulation-LFP recording system. Following a 1-mo off-stimulation postoperative phase with multiple daily recordings, patients received bilateral SCC-DBS therapy (130 Hz, 90 μs) and weekly resting-state SCC-LFP recordings over a 6-mo treatment phase. 1/ f slopes for each time point were estimated via linear regression of log-transformed Welch periodograms. General linear mixed-effects models were constructed to estimate pretreatment sources of 1/ f slope variance, and 95% bootstrap confidence intervals were constructed to estimate treatment phase 1/ f slope association with treatment response (50% decrease in preimplantation symptom severity). Results show the time of recording was a prominent source of pretreatment 1/ f slope variance bilaterally, with increased 1/ f slope magnitude observed during night hours (2300–0659). Increase in right 1/ f slope was observed in the setting of treatment response, with bootstrap analysis supporting this observation in 3 of 4 subjects. We conclude that 1/ f slope can be measured longitudinally in a combined SCC-DBS/LFP recording system and likely conforms to known 1/ f circadian variability. The preliminary evidence of 1/ f slope increase during treatment response suggests a potential utility as a candidate biomarker for ongoing development of adaptive TRD-neuromodulation strategies. NEW & NOTEWORTHY In four patients with treatment-resistant depression undergoing therapeutic deep brain stimulation (DBS), we present the first longitudinal observations of local field potentials (LFP) from the subcallosal cingulate region outside the postoperative period. Specifically, our results demonstrate that frequency-domain 1/ f activity is measurable in a combined DBS-LFP recording system and that right hemisphere recordings appear sensitive to mood state, thus suggesting a potential readout suitable for consideration in ongoing efforts to develop adaptive DBS delivery systems.