Andrea Crowell

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.

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.

Characterizing the therapeutic response to deep brain stimulation for treatment-resistant depression: a single center long-term perspective

The number of depressed patients treated with deep brain stimulation (DBS) is relatively small. However, experience with this intervention now spans more than 10 years at some centers, with study subjects typically monitored closely. Here we describe one center’s evolving impressions regarding optimal patient selection for DBS of the subcallosal cingulate (SCC) as well as observations of short- and long-term patterns in antidepressant response and mood reactivity. A consistent time course of therapeutic response with distinct behavioral phases is observed. Early phases are characterized by changes in mood reactivity and a transient and predictable worsening in self ratings prior to stabilization of response. It is hypothesized that this characteristic recovery curve reflects the timeline of neuroplasticity in response to DBS. Further investigation of these emerging predictable psychiatric, biological, and psychosocial patterns will both improve treatment optimization and enhance understanding and recognition of meaningful DBS antidepressant effects.

Toward an Understanding of the Neural Circuitry of Major Depressive Disorder Through the Clinical Response to Deep Brain Stimulation of Different Anatomical Targets

Deep brain stimulation has been proposed as a treatment for treatment-resistant depression. To date, multiple brain targets have been tested in single case studies and case series. The target regions with the most evidence to support their use are the subcallosal cingulate, ventral capsule/ventral striatum, nucleus accumbens, and medial forebrain bundle. Treatment effects of stimulation at each target share some commonalities, including similar response and remission rates, a relatively slow and progressive time course of treatment response, with a comparatively fast depressive relapse after discontinuation of stimulation. Response is maintained over time, and in some cases improves over years. Similarities may be at least partially attributable to overlap in white matter pathways between targets. Careful attention to mood and somatic effects seen with acute stimulation may differentiate primary vs. secondary treatment effects and mechanisms between the target regions. Understanding which symptoms are primarily affected, and the time course of response and relapse, will shed light on the biological mechanisms underlying DBS effects and depression pathology.

Deep Brain Stimulation for Depression: Keeping an Eye on a Moving Target.

The article by Bergfeld et al1 in this issue of JAMA Psychiatry reports the resultsofan investigator-initiated trialofdeepbrain stimulation (DBS) to the ventral anterior limb of the internal capsule (vALIC) for treatment-resistantdepression (TRD).Deep brain stimulation for TRD is an evolving experimental therapy with a range of different gray and white matter targets currently under study.2 Although this is not the first report of vALIC DBS for TRD, it used a robust but underutilized trial design: an open-label, extended optimization period followed by a blinded, randomized, discontinuation experiment once a stable response was achieved. This design is incontrast to themore typicalblindedrandomizationat stimulationonsetused inmostpsychiatry treatment trials. The40% open-label response rate demonstrated by Bergfeld et al1 is similar to that reported in the first open-label study of vALIC DBS for TRD.3 However, it is the second phase of this study— discriminating effects of active vs sham stimulation—that is most compelling. This critical differential effect was not demonstrated in the recent industry-sponsored randomized clinical trial4 that used the more traditional, up-front active vs sham design. With increasing interest in targeted circuit modulation for depression and other psychiatric disorders, the Bergfeld et al1 study further highlights the need to seriously consider customized trial designs in planning any invasive device trials, be it DBS, vagus nerve stimulation, or a future novel technology. The Bergfeld et al1 study also tacitly reveals the risk of a rigidly fixed optimization period evenwhen unblinded treatment is delivered. The team modified the protocol and increased the duration of the optimization period to accommodate experimental observations of variability in the time needed to reach a stable response. These modifications provide new insights into intersubject variability with vALIC stimulation. Specifically, the implicit instability of theDBS response reported in this study provides new evidence that experimental studiesusing invasivedevicesmight best be structured so that they are not prematurely terminated at an arbitrary timepoint. Suchanapproachwill enableamorecomplete characterizationof the trajectory and timeline of behavioral changes in individualparticipantsprior to initiating largescale, industry-sponsored trials.Anopen-label adaptivedesign may be the most prudent approach for a high-risk procedure performed in avulnerable population. PatientswithTRDwho are enrolled in such studies have, by definition, already exhausted available approved options. Unlike studies of medication, psychotherapy, electroconvulsive therapy, or repetitive transcranialmagnetic stimulation,patientswith implanted devices continue to receive the experimental therapy beyond theprotocol-definedendpoint.Therefore, continueddata collection aspart of ongoing clinicalmanagement shouldbe considered both an opportunity and an ethical mandate, since it provides needed information on the course and long-termeffect of the intervention needed to fully evaluate its clinical viability.5 Beyond issues of trial design, sources of patient variability that might predict the likelihood of DBS response are also critical andremainunclear.Matchingapatient to thebest treatment as well as avoiding therapies that are unlikely to be effective are the goals for treatment selection for patients at all stages of depression.6 Patient heterogeneity in TRD, specifically, remainsanunexploredvariable in theBergfeldetal1 study aswell as otherDBS studies. At present, TRD is definednot by illness features, but by treatment failures. Published studies have yet to identify any clinical clues on demographic or behavioralvariables thatmightcharacterize responders toagiven target or support implantation in one brain region over another. Given that attempts to identify these variables may be hindered by the relatively few patients enrolled in any individual trial, it would be beneficial for the field to develop databases or registries that might enable such examination. Independent ofwhichDBS target is being investigated in a given trial, surgical accuracyandcontact selectionarenotonly potential contributors to response,butarevariables that canbe systematicallyevaluatedandrectified.Specificfiberbundlesand effects in remote targets canbedetermined.7Asourgroup8has learned fromstudiesof subcallosal cingulatewhitematterDBS for TRD, such characterization reliably distinguished responders from nonresponders at 6 months and 2 years of ongoing stimulation.Suchanalyses forvALICDBSmightsimilarlydifferentiatepatientswhoachievedastableresponserelativelyquickly comparedwithnonresponders ormorebrittle patients leading torefinedmethods in futurestudies. If theoptimalcombination of white matter bundles is defined for vALIC DBS, the more perplexingproblemof instability of response canbe examined without this confounding factor. As the field considers the potential use of a flexible trial design as used in the Bergfeld et al1 vALIC DBS study, it is important to avoid a one-size-fits-all approach for other targets. Some DBS studies9 show a rapid onset of antidepressant effects and require relatively fewadjustments.Others, as in this case, appear to have more difficulty achieving a stable response state and, in theabsenceof flexibility todetermine that Related article page 456 Opinion

Microfabricated polymer-based neural interface for electrical stimulation/recording, drug delivery, and chemical sensing - development

We present here a microfabricated, multi-functional neural interface with the ability to selectively apply electrical and chemical stimuli, while simultaneously monitoring both electrical and chemical activity in the brain. Such a comprehensive approach is required to understand and treat neuropsychiatric disorders, such as major depressive disorder (MDD), and to understand the mechanisms underlying treatments, such as pharmaceutical therapies and deep brain stimulation (DBS). The polymer-based, multi-functional neural interface is capable of electrical stimulation and recording, targeted drug delivery, and electrochemical sensing. A variety of different electrode and fluidic channel arrangements are possible with this fabrication process. Preliminary testing has shown the suitability of these neural interfaces for in vivo electrical stimulation and recording, as well as in vitro chemical sensing. Testing of the in vitro drug delivery and combined in vivo functionalities this neural interface are currently underway.

Test-retest reliability of a stimulation-locked evoked response to deep brain stimulation in subcallosal cingulate for treatment resistant depression

Deep brain stimulation (DBS) to the subcallosal cingulate cortex (SCC) is an emerging therapy for treatment resistant depression. Precision targeting of specific white matter fibers is now central to the model of SCC DBS treatment efficacy. A method to confirm SCC DBS target engagement is needed to reduce procedural variance across treatment providers and to optimize DBS parameters for individual patients. We examined the reliability of a novel cortical evoked response that is time‐locked to a 2 Hz DBS pulse and shows the propagation of signal from the DBS target. The evoked response was detected in four individuals as a stereotyped series of components within 150 ms of a 6 V DBS pulse, each showing coherent topography on the head surface. Test–retest reliability across four repeated measures over 14 months met or exceeded standards for valid test construction in three of four patients. Several observations in this pilot sample demonstrate the prospective utility of this method to confirm surgical target engagement and instruct parameter selection. The topography of an orbital frontal component on the head surface showed specificity for patterns of forceps minor activation, which may provide a means to confirm DBS location with respect to key white matter structures. A divergent cortical response to unilateral stimulation of left (vs. right) hemisphere underscores the need for feedback acuity on the level of a single electrode, despite bilateral presentation of therapeutic stimulation. Results demonstrate viability of this method to explore patient‐specific cortical responsivity to DBS for brain‐circuit pathologies.

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.

Simulated Patients and Scenarios to Assess and Teach Psychiatry Residents

The role and utility of simulated and standardized patients in medical education has evolved tremendously since its first introduction in 1963. The United States Medical Licensing Examination (USMLE) routinely uses standardized patients in the assessment of clinical skills to assess a candidate’s ability to elicit information, perform exams, and communicate clinically relevant findings. Psychiatry has been slower to adopt the use of simulated or standardized patients, partly due to the difficulty in creating scenarios depicting valid emotions [1, 2]. However, there are several areas of psychiatric education that lend themselves well to using a simulated patient or simulated scenario for learner assessment or for teaching. Here, we share examples from several programs where simulation has helped enhance teaching and assessment of residents. We address some of the practical issues in working with simulated patients. Finally, we briefly review the advantages and disadvantages of using simulation in psychiatric education. We do not intend this to be an exhaustive review of the use of simulated patients in psychiatry, but rather representative examples of ways simulated patients have been used successfully in residency training. To clarify our use of language related to this pedagogical method, we define “simulated patient” as any person who is not an actual patient and is being utilized to play the role of a patient in a learning or testing encounter; a “standardized patient” is a subset of simulated patients for which a person has been specially trained to act as a patient so that specific symptoms or signs can be demonstrated and/or feedback given to a learner.

Discriminating clinical phases of recovery from major depressive disorder using the dynamics of facial expression

We used several metrics of variability to extract unsupervised features from video recordings of patients before and after deep brain stimulation (DBS) treatment for major depressive disorder (MDD). Our goal was to quantify the treatment effects on facial expressivity. Multiscale entropy (MSE) was used to capture the temporal variability in pixel intensity level at multiple time-scales. A dynamic latent variable model (DLVM) was used to learn a low dimensional (D = 20) set of dynamic factors that explain the observed covariance across the high-dimensional pixels (M = 30 × 30) within each video frame and across time. Our preliminary results indicate that unsupervised features learned from these video recordings can distinguish different phases of depression and recovery. The overarching goal of this research is to develop more refined markers of clinical response to treatment for depression.We used several metrics of variability to extract unsupervised features from video recordings of patients before and after deep brain stimulation (DBS) treatment for major depressive disorder (MDD). Our goal was to quantify the treatment effects on facial expressivity. Multiscale entropy (MSE) was used to capture the temporal variability in pixel intensity level at multiple time-scales. A dynamic latent variable model (DLVM) was used to learn a low dimensional (D = 20) set of dynamic factors that explain the observed covariance across the high-dimensional pixels (M = 30 × 30) within each video frame and across time. Our preliminary results indicate that unsupervised features learned from these video recordings can distinguish different phases of depression and recovery. The overarching goal of this research is to develop more refined markers of clinical response to treatment for depression.