Time-frequency signatures evoked by single-pulse deep brain stimulation to the subcallosal cingulate.

Precision targeting of specific white matter bundles that traverse the subcallosal cingulate (SCC) has been linked to efficacy of deep brain stimulation (DBS) for treatment resistant depression (TRD). Methods to confirm optimal target engagement in this heterogenous region are now critical to establish an objective treatment protocol. As yet unexamined are the time-frequency features of the SCC evoked potential (SCC-EP), including spectral power and phase-clustering. We examined these spectral features-evoked power and phase clustering-in a sample of TRD patients (n = 8) with implanted SCC stimulators. Electroencephalogram (EEG) was recorded during wakeful rest. Location of electrical stimulation in the SCC target region was the experimental manipulation. EEG was analyzed at the surface level with an average reference for a cluster of frontal sensors and at a time window identified by prior study (50-150 ms). Morlet wavelets generated indices of evoked power and inter-trial phase clustering. Enhanced phase clustering at theta frequency (4-7 Hz) was observed in every subject and was significantly correlated with SCC-EP magnitude, but only during left SCC stimulation. Stimulation to dorsal SCC evinced stronger phase clustering than ventral SCC. There was a weak correlation between phase clustering and white matter density. An increase in evoked delta power (2-4 Hz) was also coincident with SCC-EP, but was less consistent across participants. DBS evoked time-frequency features index mm-scale changes to the location of stimulation in the SCC target region and correlate with structural characteristics implicated in treatment optimization. Results also imply a shared generative mechanism (inter-trial phase clustering) between evoked potentials evinced by electrical stimulation and evoked potentials evinced by auditory/visual stimuli and behavioral tasks. Understanding how current injection impacts downstream cortical activity is essential to building new technologies that adapt treatment parameters to individual differences in neurophysiology.

Analyzing Non-verbal Behavior Throughout Recovery in a Sample of Depressed Patients Receiving Deep Brain Stimulation.

BACKGROUND: Traditional rating scales for depression rely heavily on patient self-report, and lack detailed measurement of non-verbal behavior. However, there is evidence that depression is associated with distinct non-verbal behaviors, assessment of which may provide useful information about recovery. This study examines non-verbal behavior in a sample of patients receiving Deep Brain Stimulation (DBS) treatment of depression, with the purpose to investigate the relationship between non-verbal behaviors and reported symptom severity. METHODS: Videotaped clinical interviews of twelve patients participating in a study of DBS for treatment-resistant depression were analyzed at three time points (before treatment and after 3 months and 6 months of treatment), using an ethogram to assess the frequencies of 42 non-verbal behaviors. The Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS-17) were also collected at all time points. RESULTS: Factor analysis grouped non-verbal behaviors into three factors: react, engage/fidget, and disengage. Two-way repeated measures ANOVA showed that scores on the three factors change differently from each other over time. Mixed effects modelling assessed the relationship between BDI score and frequency of non-verbal behaviors, and provided evidence that the frequency of behaviors related to reactivity and engagement increase as BDI score decreases. LIMITATIONS: This study assesses a narrow sample of patients with a distinct clinical profile at limited time points. CONCLUSIONS: Non-verbal behavior provides information about clinical states and may be reliably quantified using ethograms. Non-verbal behavior may provide distinct information compared to self-report.

Flattening the emotional distress curve: A behavioral health pandemic response strategy for COVID-19.

This article proposes a framework for managing the behavioral health impacts of the COVID-19 global pandemic. This framework aligns and should be integrated with an existing public health pandemic intervals model. It includes six phases of a behavioral health pandemic response strategy: preplanning, response readiness, response mobilization, intervention, continuation, and amelioration. The ways behavioral health specialists can capitalize on their competence in the leadership, prevention, education, service, research, and advocacy domains within each behavioral health pandemic response phase are articulated. Behavioral health expertise can help ensure a more comprehensive, effective pandemic response that facilitates the flattening of the curve of disease spread, along with the corresponding emotional distress curve. A case illustration, the Caring Communities (CC) initiative, is offered as an exemplar of action steps in the leadership, prevention, education, service, research, and advocacy domains that behavioral health professionals can take within each of the behavioral health pandemic response phases. Key CC action steps include providing support groups, offering virtual wellness breaks, participating in educational outreach, creating and disseminating wellness guides, launching and leading a virtual behavioral health clinic for health care staff, participating in behavioral health research and program evaluation, and engaging in advocacy initiatives aimed at improving behavioral health care and addressing and reducing health disparities. Finally, recommendations for optimizing behavioral health contributions to future pandemic responses are proffered. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.

OBJECTIVE: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression. METHODS: Long-term outcome data were collected for 28 patients (20 with major depressive disorder and seven with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder) receiving SCC DBS for 4-8 years. RESULTS: Response and remission rates were maintained at ≥50% and ≥30%, respectively, through years 2-8 of the follow-up period. Three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. Of 28 participants, 14 completed ≥8 years of follow-up, 11 completed ≥4 years, and three dropped out before 8 years. The procedure itself was generally safe and well tolerated, and there were no side effects of acute or chronic stimulation. The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications. There were no suicides. CONCLUSIONS: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS.

Field potential 1/f activity in the subcallosal cingulate region as a candidate signal for monitoring deep brain stimulation for treatment-resistant depression.

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.

Autonomic arousal elicited by subcallosal cingulate stimulation is explained by white matter connectivity.

BACKGROUND: Subcallosal cingulate deep brain stimulation (SCC DBS) is an experimental treatment for severe depression. Surgery is performed with awake patients and intraoperative stimulation produces acute behavioral responses in select contacts. While there have been reports on the relationship between acute intraoperative behaviors and their relation to the location of the contacts, there are no descriptions of the physiological changes that accompany them. OBJECTIVE: The present study sought to examine these physiological readouts, and their association with the anatomical substrates that generated them. METHODS: Nine patients with severe, treatment-resistant depression were tested intraoperatively. The stimulation protocol consisted of 12 three-minute, sham-controlled, double-blind trials. Changes in heart rate and skin conductance were recorded during each stimulation cycle. Probabilistic tractography between the stimulated contacts and predefined regions of the mood regulation network was performed. RESULTS: Acute intraoperative SCC stimulation produced increases in autonomic sympathetic response that correlated with the salience of the behavioral responses. The autonomic changes were observed within seconds of initiating acute stimulation and prior to verbalization of subjective experiences. The probabilistic tractography analysis suggested that structural connectivity between the stimulated area and the midcingulate cortex is the primary pathway that mediates autonomic responsivity to SCC DBS. CONCLUSIONS: These findings demonstrate that acute SCC stimulation produces autonomic and behavioral changes in the operating room that are explained by the modulation of networks associated with long term antidepressant response. Intraoperative autonomic recordings paired with careful behavioral observations and precise anatomical mapping aid in the identification and classification of the intraoperative phenomena.

Do Relational and Self-Definitional Traits Influence Deep Brain Stimulation Device Preference?

Personality psychodynamics have been shown to influence individual responses to psychiatric treatments, including medication. Increasingly, neuromodulation therapies have become available for severe and treatment-resistant depression. This study aims to evaluate patient response to an implanted neurostimulator battery within the framework of relational versus self-definitional personality traits. Relational development is interpersonally oriented and disruptions along this pathway lead to dependency on others for a sense of security and self-worth. Self-definitional development is characterized by autonomy strivings and disruptions lead to self-critical feelings of failing to meet expectations. Patients drawn from a larger study of deep brain stimulation (DBS) for treatment-resistant depression were switched from a non-rechargeable to a rechargeable battery type to maintain stimulation therapy. This switch entailed taking greater personal responsibility for device maintenance and allowed for fewer battery replacement surgeries. Twenty-six patients completed the Depressive Experiences Questionnaire (DEQ) and a questionnaire surveying their preference for DBS battery type. Results show that the DEQ dependency subscale, and more specifically the neediness component of the subscale, is associated with patient preference for the non-rechargeable battery. This suggests that individuals with higher relational needs prefer treatment options that increase contact with and need for medical caregivers and may prioritize this aspect of an intervention over alternative considerations. In contrast, individuals with more self-critical personality traits did not have a battery type preference, indicating that self-definitional needs were not predictive of battery preference. The link between an individual's personality psychodynamics and response to biomedical interventions, including neuromodulation and treatments that incorporate medical devices, deserves further attention.

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.

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.

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.

Oscillations in sensorimotor cortex in movement disorders: an electrocorticography study.

Movement disorders of basal ganglia origin may arise from abnormalities in synchronized oscillatory activity in a network that includes the basal ganglia, thalamus and motor cortices. In humans, much has been learned from the study of basal ganglia local field potentials recorded from temporarily externalized deep brain stimulator electrodes. These studies have led to the theory that Parkinson's disease has characteristic alterations in the beta frequency band (13-30 Hz) in the basal ganglia-thalamocortical network. However, different disorders have rarely been compared using recordings in the same structure under the same behavioural conditions, limiting straightforward assessment of current hypotheses. To address this, we utilized subdural electrocorticography to study cortical oscillations in the three most common movement disorders: Parkinson's disease, primary dystonia and essential tremor. We recorded local field potentials from the arm area of primary motor and sensory cortices in 31 subjects using strip electrodes placed temporarily during routine surgery for deep brain stimulator placement. We show that: (i) primary motor cortex broadband gamma power is increased in Parkinson's disease compared with the other conditions, both at rest and during a movement task; (ii) primary motor cortex high beta (20-30 Hz) power is increased in Parkinson's disease during the 'stop' phase of a movement task; (iii) the alpha-beta peaks in the motor and sensory cortical power spectra occur at higher frequencies in Parkinson's disease than in the other two disorders; and (iv) patients with dystonia have impaired movement-related beta band desynchronization in primary motor and sensory cortices. The findings support the emerging hypothesis that disease states reflect abnormalities in synchronized oscillatory activity. This is the first study of sensorimotor cortex local field potentials in the three most common movement disorders.

Activities of dicationic compounds against Trichomonas vaginalis.

We evaluated 44 novel cationic compounds for activity against metronidazole-sensitive and -resistant Trichomonas vaginalis isolates. Six compounds in three different structural classes demonstrated 50% inhibitory concentrations as low as 1 microM against both sensitive and resistant isolates, suggesting a mode of action independent of parasite biochemical pathways that confer resistance to 5-nitroimidazoles.

In vitro metronidazole and tinidazole activities against metronidazole-resistant strains of Trichomonas vaginalis.

The in vitro activities of tinidazole and metronidazole against Trichomonas vaginalis isolates clinically resistant to metronidazole were compared. Minimal lethal concentrations (MLCs) of tinidazole were significantly lower than MLCs of metronidazole. Increased metronidazole resistance correlated with increased tinidazole resistance. These data support a role for tinidazole in the treatment of trichomoniasis.