Justin Rajendra

Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

BACKGROUND Subcallosal cingulate white matter (SCC) deep brain stimulation (DBS) is an evolving investigational treatment for 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 was used to model white matter connections within this network to identify those critical for successful antidepressant response. METHODS Preoperative high-resolution magnetic resonance imaging data, including diffusion tensor imaging, were acquired in 16 patients with treatment-resistant depression, who then received SCC DBS. Computerized tomography was used postoperatively to locate DBS contacts. The activation volume around the contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts traveling 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 demonstrated that all DBS responders at 6 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. Nonresponders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from nonresponders. CONCLUSIONS Patient-specific activation volume tractography modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection.

White Matter Integrity Is a Stronger Predictor of Motor Function Than BOLD Response in Patients With Stroke

Objective. Neuroimaging techniques, such as diffusion tensor imaging (DTI) and blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging (fMRI), provide insights into the functional reorganization of the cortical motor system after stroke. This study explores the relationship between upper extremity motor function, white matter integrity, and BOLD response of cortical motor areas. Methods. Seventeen patients met study inclusion criteria; of these 12 completed DTI assessment of white matter integrity and 9 completed fMRI assessment of motor-related activation. Primary clinical outcome measures were the Wolf Motor Function Test (WMFT) and the upper limb portion of the Fugl-Meyer (FM) motor assessment. Structural integrity of the posterior limb of the internal capsule was assessed by examining the fractional anisotropy (FA) asymmetry in the PLIC. Laterality index of motor cortical areas was measured as the BOLD response in each patient during a finger pinch task. Linear regression analyses were performed to determine whether clinical outcome was associated with structural or functional MRI measures. Results. There were strong relationships between clinical outcome measures and FA asymmetry (eg, FM score [R 2 = .655, P = .001] and WMFT asymmetry score [R 2 = .651, P < .002]) but relationships with fMRI measures were weaker. Conclusion. Clinical motor function is more closely related to the white matter integrity of the internal capsule than to BOLD response of motor areas in patients 3 to 9 months after stroke. Thus, use of DTI to assess white matter integrity in the internal capsule may provide more useful information than fMRI to interpret motor deficits following supratentorial brain injury.

A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression

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 11 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 post-operative probabilistic tractography map to the pre-surgical 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, 9 of 11 patients (81.8%) were responders, with 6 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.

Functional Connectivity of the Subcallosal Cingulate Cortex And Differential Outcomes to Treatment With Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder

OBJECTIVE The purpose of this article was to inform the first-line treatment choice between cognitive-behavioral therapy (CBT) or an antidepressant medication for treatment-naive 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 MRI 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 participants, 58 achieved remission (Hamilton Depression Rating Scale [HAM-D] score ≤7 at weeks 10 and 12), and 24 had treatment failure (<30% decrease from baseline in HAM-D score). A 2×2 analysis of variance using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. Receiver operating characteristic curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes. RESULTS The resting-state functional connectivity of the following 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: the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and the left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, overall classification rates of 72%-78% for remission and 75%-89% for treatment failure was demonstrated. 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 individuals 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.

Brain Activation in Primary Motor and Somatosensory Cortices during Motor Imagery Correlates with Motor Imagery Ability in Stroke Patients

Aims. While studies on healthy subjects have shown a partial overlap between the motor execution and motor imagery neural circuits, few have investigated brain activity during motor imagery in stroke patients with hemiparesis. This work is aimed at examining similarities between motor imagery and execution in a group of stroke patients. Materials and Methods. Eleven patients were asked to perform a visuomotor tracking task by either physically or mentally tracking a sine wave force target using their thumb and index finger during fMRI scanning. MIQ-RS questionnaire has been administered. Results and Conclusion. Whole-brain analyses confirmed shared neural substrates between motor imagery and motor execution in bilateral premotor cortex, SMA, and in the contralesional inferior parietal lobule. Additional region of interest-based analyses revealed a negative correlation between kinaesthetic imagery ability and percentage BOLD change in areas 4p and 3a; higher imagery ability was associated with negative and lower percentage BOLD change in primary sensorimotor areas during motor imagery.

Enhanced corticospinal excitability with physiologically heightened sympathetic nerve activity.

Corticospinal excitability is modulated differently with norepinephrine and dopamine agonists, although both monoamines are released with heightened sympathetic nerve activity. The purpose of this study was to investigate the influence of physiological heightening of sympathetic nerve activity on corticospinal excitability in healthy humans. Subjects were divided into control and experimental groups. In each participant, motor-evoked potentials (MEPs) were measured from the resting first dorsal interosseous muscle of the right hand with transcranial magnetic stimulation (TMS) in two trials separated by 1 h. In the experimental group, sympathetic nerve activity was physiologically heightened during the second trial by applying lower body negative pressure (LBNP). In the control group, sympathetic nerve activity was not altered between the two trials. MEP peak-to-peak amplitude increased from trial 1 to trial 2 in the experimental group only. This increase was evident at a TMS intensity of 130% resting motor threshold and higher. It was concluded that physiological heightening of sympathetic nerve activity with LBNP enhances corticospinal excitability.

Initial Unilateral Exposure to Deep Brain Stimulation in Treatment-Resistant Depression Patients Alters Spectral Power in the Subcallosal Cingulate

Background: High-frequency Deep Brain Stimulation (DBS) of the subcallosal cingulate (SCC) region is an emerging strategy for treatment-resistant depression (TRD). This study examined changes in SCC local field potentials (LFPs). The LFPs were recorded from the DBS leads following transient, unilateral stimulation at the neuroimaging-defined optimal electrode contact. The goal was identifying a putative electrophysiological measure of target engagement during implantation. Methods: Fourteen consecutive patients underwent bilateral SCC DBS lead implantation. LFP recordings were collected from all electrodes during randomized testing of stimulation on each DBS contact (eight total). Analyses evaluated changes in spectral power before and after 3 min of unilateral stimulation at the contacts that later facilitated antidepressant response, as a potential biomarker of optimal contact selection in each hemisphere. Results: Lateralized and asymmetric power spectral density changes were detected in the SCC with acute unilateral SCC stimulation at those contacts subsequently selected for chronic, therapeutic stimulation. Left stimulation induced broadband ipsilateral decreases in theta, alpha, beta and gamma bands. Right stimulation effects were restricted to ipsilateral beta and gamma decreases. These asymmetric effects contrasted with identical white matter stimulation maps used in each hemisphere. More variable ipsilateral decreases were seen with stimulation at the adjacent “suboptimal” contacts, but changes were not statistically different from the “optimal” contact in either hemisphere despite obvious differences in impacted white matter bundles. Change in theta power was, however, most robust and specific with left-sided optimal stimulation, which suggested a putative functional biomarker on the left with no such specificity inferred on the right. Conclusion: Hemisphere-specific oscillatory changes can be detected from the DBS lead with acute intraoperative testing at contacts that later engender antidepressant effects. Our approach defined potential target engagement signals for further investigation, particularly left-sided theta decreases following initial exposure to stimulation. More refined models combining tractography, bilateral SCC LFP, and cortical recordings may further improve the precision and specificity of these putative biomarkers. It may also optimize and standardize the lead implantation procedure and provide input signals for next generation closed-loop therapy and/or monitoring technologies for TRD.

Quantifying the axonal pathways directly stimulated in therapeutic subcallosal cingulate deep brain stimulation

Deep 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 patient‐specific computational models. This connectomic‐based biophysical modeling strategy has proven successful in improving the clinical response to SCC DBS therapy, but the DBS models used to date have been relatively simplistic, limiting the precision of the pathway activation estimates. Therefore, we used the most detailed patient‐specific foundation for DBS modeling currently available (i.e., field‐cable modeling) to evaluate SCC DBS in our most recent cohort of six subjects, all of which were responders to the therapy. We quantified activation of four major pathways in the SCC region: forceps minor (FM), cingulum bundle (CB), uncinate fasciculus (UF), and subcortical connections between the frontal pole and the thalamus or ventral striatum (FP). We then used the percentage of activated axons in each pathway as regressors in a linear model to predict the time it took patients to reach a stable response, or TSR. Our analysis suggests that stimulation of the left and right CBs, as well as FM are the most likely therapeutic targets for SCC DBS. In addition, the right CB alone predicted 84% of the variation in the TSR, and the correlation was positive, suggesting that activation of the right CB beyond a critical percentage may actually protract the recovery process.