The Management of Posttraumatic Stress Disorder and Acute Stress Disorder: Synopsis of the 2023 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

DESCRIPTION: The U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) worked together to revise the 2017 VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. This article summarizes the 2023 clinical practice guideline (CPG) and its development process, focusing on assessments and treatments for which evidence was sufficient to support a recommendation for or against. METHODS: Subject experts from both departments developed 12 key questions and reviewed the published literature after a systematic search using the PICOTS (population, intervention, comparator, outcomes, timing of outcomes measurement, and setting) method. The evidence was then evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. Recommendations were made after consensus was reached; they were based on quality and strength of evidence and informed by other factors, including feasibility and patient perspectives. Once the draft was peer reviewed by an external group of experts and their inputs were incorporated, the final document was completed. RECOMMENDATIONS: The revised CPG includes 34 recommendations in the following 5 topic areas: assessment and diagnosis, prevention, treatment, treatment of nightmares, and treatment of posttraumatic stress disorder (PTSD) with co-occurring conditions. Six recommendations on PTSD treatment were rated as strong. The CPG recommends use of specific manualized psychotherapies over pharmacotherapy; prolonged exposure, cognitive processing therapy, or eye movement desensitization and reprocessing psychotherapy; paroxetine, sertraline, or venlafaxine; and secure video teleconferencing to deliver recommended psychotherapy when that therapy has been validated for use with video teleconferencing or when other options are unavailable. The CPG also recommends against use of benzodiazepines, cannabis, or cannabis-derived products. Providers are encouraged to use this guideline to support evidence-based, patient-centered care and shared decision making to optimize individuals' health outcomes and quality of life.

Whole brain network effects of subcallosal cingulate deep brain stimulation for treatment-resistant depression.

Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood flow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15 O]-water and 5 [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

The acceptability and feasibility of screening, brief intervention, and referral to treatment for pain management among new England veterans with chronic pain: A pilot study.

OBJECTIVES: Musculoskeletal disorders often lead to chronic pain in Veterans. Chronic pain puts sufferers at risk for substance misuse, and early intervention is needed for both conditions. This pilot study tested the feasibility and acceptability of a Screening, Brief Intervention, and Referral to Treatment for Pain Management intervention (SBIRT-PM) to help engage Veterans seeking disability compensation for painful musculoskeletal disorders in multimodal pain treatment and to reduce risky substance use, when indicated. METHODS: This pilot study enrolled 40 Veterans from 8 medical centers across New England in up to 4 sessions of telephone-based counseling using a motivational interviewing framework. Counseling provided education about, and facilitated engagement in, multimodal pain treatments. Study eligibility required Veterans be engaged in no more than 2 Veteran Affairs (VA) pain treatment modalities, and study participation involved a 12-week postassessment and semistructured interview about the counseling process. RESULTS: Majorities of enrolled Veterans screened positive for comorbid depression and problematic substance use. Regarding the offered counseling, 80% of participants engaged in at least one session, with a mean of 3 sessions completed. Ninety percent of participants completed the postassessment. Numerically, most measures improved slightly from baseline to week 12. In semistructured interviews, participants described satisfaction with learning about new pain care services, obtaining assistance connecting to services, and receiving support from their counselors. DISCUSSION: It was feasible to deliver SBIRT-PM to Veterans across New England to promote engagement in multimodal pain treatment and to track study outcomes over 12 weeks. Preliminary results suggest SBIRT-PM was well-received and has promise for the targeted outcomes.

Defining focal brain stimulation targets for PTSD using neuroimaging.

INTRODUCTION: Focal brain stimulation has potential as a treatment for posttraumatic stress disorder (PTSD). In this review, we aim to inform selection of focal brain stimulation targets for treating PTSD by examining studies of the functional neuroanatomy of PTSD and treatment response. We first briefly review data on brain stimulation interventions for PTSD. Although published data suggest good efficacy overall, the neurobiological rationale for each stimulation target is not always clear. METHODS: Therefore, we assess pre- and post-treatment (predominantly psychotherapy) functional neuroimaging studies in PTSD to determine which brain changes seem critical to treatment response. Results of these studies are presented within a previously proposed functional neural systems model of PTSD. RESULTS: While not completely consistent, research suggests that downregulating the fear learning and threat and salience detection circuits (i.e., amygdala, dorsal anterior cingulate cortex and insula) and upregulating the emotion regulation and executive function and contextual processing circuits (i.e., prefrontal cortical regions and hippocampus) may mediate PTSD treatment response. CONCLUSION: This literature review provides some justification for current focal brain stimulation targets. However, the examination of treatment effects on neural networks is limited, and studies that include the stimulation targets are lacking. Further, additional targets, such as the cingulate, medial prefrontal cortex, and inferior parietal lobe, may also be worth investigation, especially when considering how to achieve network level changes. Additional research combining PTSD treatment with functional neuroimaging will help move the field forward by identifying and validating novel targets, providing better rationale for specific treatment parameters and personalizing treatment for PTSD.

Neurocognitive mechanisms of poor social connection in posttraumatic stress disorder: Evidence for abnormalities in social working memory.

BACKGROUND: Poor social connection is a central feature of posttraumatic stress disorder (PTSD), but little is known about the neurocognitive processes associated with social difficulties in this population. We examined recruitment of the default network and behavioral responses during social working memory (SWM; i.e., maintaining and manipulating social information on a moment-to-moment basis) in relation to PTSD and social connection. METHODS: Participants with PTSD (n = 31) and a trauma-exposed control group (n = 21) underwent functional magnetic resonance imaging while completing a task in which they reasoned about two or four people's relationships in working memory (social condition) and alphabetized two or four people's names in working memory (nonsocial condition). Participants also completed measures of social connection (e.g., loneliness, social network size). RESULTS: Compared to trauma-exposed controls, individuals with PTSD reported smaller social networks (p = .032) and greater loneliness (p = .038). Individuals with PTSD showed a selective deficit in SWM accuracy (p = .029) and hyperactivation in the default network, particularly in the dorsomedial subsystem, on trials with four relationships to consider. Moreover, default network hyperactivation in the PTSD group (vs. trauma-exposed group) differentially related to social network size and loneliness (p's < .05). Participants with PTSD also showed less resting state functional connectivity within the dorsomedial subsystem than controls (p = .002), suggesting differences in the functional integrity of a subsystem key to SWM. CONCLUSIONS: SWM abnormalities in the default network may be a basic mechanism underlying poorer social connection in PTSD.

Twenty-year trends in use of electroconvulsive therapy among homeless and domiciled veterans with mental illness.

BACKGROUND: To examine socioeconomic disparities in use of electroconvulsive therapy (ECT) among homeless or unstably housed (HUH) veterans with mental illness. METHODS: National data from medical records in years 2000 to 2019 on 4 to 6 million veterans with mental illness, including 140 000 to 370 000 homeless veterans served annually from the U.S. Department of Veterans Affairs (VA) healthcare system, were analyzed to examine ECT utilization and changes in utilization over time. RESULTS: ECT utilization was higher among HUH veterans (58-104 per 1000) than domiciled veterans with mental illness (9-15 per 1000) across years with a trend toward increasing use of ECT use among HUH veterans over time. Among HUH and domiciled veterans who received ECT, veterans received an average of 5 to 9 sessions of ECT. There were great regional differences in rates of ECT utilization among HUH and domiciled veterans with the highest overall rates of ECT use at VA facilities in the Northeast and Northwest regions of the country. DISCUSSION: ECT is commonly and safely used in HUH veterans in a comprehensive healthcare system, but geographic and local factors may impede access to ECT for veterans who may benefit from this treatment. Efforts should be made to reduce barriers to ECT in the HUH population.

Identifying response and predictive biomarkers for Transcranial magnetic stimulation outcomes: protocol and rationale for a mechanistic study of functional neuroimaging and behavioral biomarkers in veterans with Pharmacoresistant depression.

BACKGROUND: Although repetitive transcranial magnetic stimulation ('TMS') is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge we evaluate neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate. We evaluate whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes. This study is designed as a pragmatic, mechanistic trial partnering with the National Clinical TMS Program of the Veteran's Health Administration. METHODS: Target enrollment consists of 100 veterans with pharmacoresistant Major Depressive Disorder (MDD). All veterans will receive a clinical course of TMS and will be assessed at 'baseline' pre-TMS commencement, 'first week' after initiation of TMS (targeting five sessions) and 'post-treatment' at the completion of TMS (targeting 30 sessions). Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires. Multivariate linear mixed models will be used to assess whether neural targets change with TMS as a function of dose (Aim 1), whether extent and change of neural target relates to and predicts extent of behavioral performance (Aim 3), and whether extent of neural target change predicts improvement in symptom severity, suicidality, and quality of life (Aim 3). For all three aims, we will also assess the contribution of baseline moderators such as biological sex and age. DISCUSSION: To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD. The results of this trial will allow providers to select suitable candidates for TMS treatment and better predict treatment response by assessing circuit connectivity and cognitive-behavioral performance at baseline and during early treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663481 , December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020.

Mental Health and Behavior of College Students During the COVID-19 Pandemic: Longitudinal Mobile Smartphone and Ecological Momentary Assessment Study, Part II.

BACKGROUND: Since late 2019, the lives of people across the globe have been disrupted by COVID-19. Millions of people have become infected with the disease, while billions of people have been continually asked or required by local and national governments to change their behavioral patterns. Previous research on the COVID-19 pandemic suggests that it is associated with large-scale behavioral and mental health changes; however, few studies have been able to track these changes with frequent, near real-time sampling or compare these changes to previous years of data for the same individuals. OBJECTIVE: By combining mobile phone sensing and self-reported mental health data in a cohort of college-aged students enrolled in a longitudinal study, we seek to understand the behavioral and mental health impacts associated with the COVID-19 pandemic, measured by interest across the United States in the search terms coronavirus and COVID fatigue. METHODS: Behaviors such as the number of locations visited, distance traveled, duration of phone use, number of phone unlocks, sleep duration, and sedentary time were measured using the StudentLife mobile smartphone sensing app. Depression and anxiety were assessed using weekly self-reported ecological momentary assessments, including the Patient Health Questionnaire-4. The participants were 217 undergraduate students. Differences in behaviors and self-reported mental health collected during the Spring 2020 term, as compared to previous terms in the same cohort, were modeled using mixed linear models. RESULTS: Linear mixed models demonstrated differences in phone use, sleep, sedentary time and number of locations visited associated with the COVID-19 pandemic. In further models, these behaviors were strongly associated with increased interest in COVID fatigue. When mental health metrics (eg, depression and anxiety) were added to the previous measures (week of term, number of locations visited, phone use, sedentary time), both anxiety and depression (P<.001) were significantly associated with interest in COVID fatigue. Notably, these behavioral and mental health changes are consistent with those observed around the initial implementation of COVID-19 lockdowns in the spring of 2020. CONCLUSIONS: In the initial lockdown phase of the COVID-19 pandemic, people spent more time on their phones, were more sedentary, visited fewer locations, and exhibited increased symptoms of anxiety and depression. As the pandemic persisted through the spring, people continued to exhibit very similar changes in both mental health and behaviors. Although these large-scale shifts in mental health and behaviors are unsurprising, understanding them is critical in disrupting the negative consequences to mental health during the ongoing pandemic.

Mental Health and Behavior of College Students During the Early Phases of the COVID-19 Pandemic: Longitudinal Smartphone and Ecological Momentary Assessment Study.

BACKGROUND: The vast majority of people worldwide have been impacted by coronavirus disease (COVID-19). In addition to the millions of individuals who have been infected with the disease, billions of individuals have been asked or required by local and national governments to change their behavioral patterns. Previous research on epidemics or traumatic events suggests that this can lead to profound behavioral and mental health changes; however, researchers are rarely able to track these changes with frequent, near-real-time sampling or compare their findings to previous years of data for the same individuals. OBJECTIVE: By combining mobile phone sensing and self-reported mental health data among college students who have been participating in a longitudinal study for the past 2 years, we sought to answer two overarching questions. First, have the behaviors and mental health of the participants changed in response to the COVID-19 pandemic compared to previous time periods? Second, are these behavior and mental health changes associated with the relative news coverage of COVID-19 in the US media? METHODS: Behaviors such as the number of locations visited, distance traveled, duration of phone usage, number of phone unlocks, sleep duration, and sedentary time were measured using the StudentLife smartphone sensing app. Depression and anxiety were assessed using weekly self-reported ecological momentary assessments of the Patient Health Questionnaire-4. The participants were 217 undergraduate students, with 178 (82.0%) students providing data during the Winter 2020 term. Differences in behaviors and self-reported mental health collected during the Winter 2020 term compared to previous terms in the same cohort were modeled using mixed linear models. RESULTS: During the first academic term impacted by COVID-19 (Winter 2020), individuals were more sedentary and reported increased anxiety and depression symptoms (P<.001) relative to previous academic terms and subsequent academic breaks. Interactions between the Winter 2020 term and the week of the academic term (linear and quadratic) were significant. In a mixed linear model, phone usage, number of locations visited, and week of the term were strongly associated with increased amount of COVID-19-related news. When mental health metrics (eg, depression and anxiety) were added to the previous measures (week of term, number of locations visited, and phone usage), both anxiety (P<.001) and depression (P=.03) were significantly associated with COVID-19-related news. CONCLUSIONS: Compared with prior academic terms, individuals in the Winter 2020 term were more sedentary, anxious, and depressed. A wide variety of behaviors, including increased phone usage, decreased physical activity, and fewer locations visited, were associated with fluctuations in COVID-19 news reporting. While this large-scale shift in mental health and behavior is unsurprising, its characterization is particularly important to help guide the development of methods to reduce the impact of future catastrophic events on the mental health of the population.

A Measure to Assess Perceptions and Knowledge About Electroconvulsive Therapy: Development and Psychometric Properties.

OBJECTIVES: Although electroconvulsive therapy (ECT) has been found to be one of the most robust and rapid treatments for severe depression, it is widely underused partly because of negative perceptions and inaccurate knowledge about the treatment. METHODS: The 18-item ECT Perception and Knowledge (ECT-PK) measure was developed through a systematic review of the literature, subject matter expert ratings, and examination of content validity. The ECT-PK consists of Perception and Knowledge subscales, which were tested on a national sample of 1091 US adults who screened positive for depression in 2018 through Amazon's Mechanical Turk platform. RESULTS: Evaluation of the ECT-PK subscales found that both subscales demonstrated good construct validity, criterion validity, and internal consistency reliability. Participants who had higher Perception and Knowledge subscale scores were significantly more likely to report that they were willing to try ECT. The ECT-PK revealed that many participants reported fears about pain, brain damage, and memory loss resulting from ECT, and had inaccurate knowledge about ECT being outdated or lacking scientific evidence. CONCLUSIONS: Together, these results showed that the ECT-PK is an efficient and effective contemporary tool to measure the perception and knowledge of ECT, and highlights areas in need of psychoeducation.

Deep brain stimulation for psychiatric disorders.

Medications, psychotherapy, and other treatments are effective for many patients with psychiatric disorders. However, with currently available interventions, a substantial number of patients experience incomplete resolution of symptoms, and relapse rates are high. In the search for better treatments, increasing interest has focused on focal neuromodulation. This focus has been driven by improved neuroanatomical models of mood, thought, and behavior regulation, as well as by more advanced strategies for directly and focally altering neural activity. Deep brain stimulation (DBS) is one of the most invasive focal neuromodulation techniques available; data have supported its safety and efficacy in a number of movement disorders. Investigators have produced preliminary data on the safety and efficacy of DBS for several psychiatric disorders, as well. In this review, we describe the development and justification for testing DBS for various psychiatric disorders, carefully consider the available clinical data, and briefly discuss potential mechanisms of action.

Neurocognitive Effects of Repetitive Transcranial Magnetic Stimulation With a 2-Coil Device in Treatment-Resistant Major Depressive Disorder.

BACKGROUND: Neurocognitive dysfunction is an understudied and undertreated aspect of psychiatric research and treatment. There is emerging evidence to suggest that repetitive transcranial magnetic stimulation (rTMS) may possess neurocognition-enhancing capabilities. METHODS: This study examined the neurocognitive data from a randomized, double-blind, sham-controlled trial of an investigational 2-coil rTMS device in antidepressant treatment or treatment-intolerant major depressive disorder patients. This device has the potential to stimulate deeper areas of the brain than the Food and Drug Administration-approved TMS devices, which primarily stimulate cortical brain areas and may therefore have different neurocognitive adverse effects. Patients received 20 daily rTMS treatments (10-Hz stimulation; either active or sham) with coil centers positioned over the left dorsolateral prefrontal cortex and dorsomedial prefrontal cortex. Neurocognitive safety was evaluated at baseline and within 72 hours of final treatment session with a computerized battery assessing aspects of attention and memory in 84 participants. RESULTS: There were no observed negative neurocognitive effects of the 2-coil rTMS device. A significant effect of active rTMS was observed on the quality of episodic memory. There were no observed effects for attention or working memory. Baseline quality of episodic memory predicted depression treatment response and remission, in that lower baseline episodic memory was associated with greater likelihood of depression response/remission. This was observed in logistic regression analyses controlling for treatment and baseline depressive symptoms. CONCLUSIONS: The 2-coil rTMS device is a cognitively safe treatment for treatment-resistant depression that may possess episodic memory-enhancing capabilities. Furthermore, baseline episodic memory may reflect an important predictor of subsequent depression treatment response/remission to rTMS.

Effects of Transcranial Magnetic Stimulation on the Cognitive Control of Emotion: Potential Antidepressant Mechanisms.

Depression negatively impacts quality of life and is associated with high mortality rates. Recent research has demonstrated that improvement in depression symptoms with transcranial magnetic stimulation (TMS) to the dorsolateral prefrontal cortex (DLPFC) may involve changes in the cognitive control network, a regulatory system modulating the function of cognitive and emotional systems, composed of the DLPFC, dorsal anterior cingulate, and posterior parietal cortices. Transcranial magnetic stimulation to the DLPFC node of the cognitive control network may have antidepressant efficacy via direct effects on cognitive control processes involved in emotion regulation. This review provides a review of the impact of TMS on cognitive control processes, especially those related to emotion regulation, and posits that these effects are critical to the mechanism of action of TMS for depression. Treatment implications and future directions for study are discussed.

Considering Eligibility for Studies of Deep Brain Stimulation for Treatment-Resistant Depression: Insights From a Clinical Trial in Unipolar and Bipolar Depression.

BACKGROUND: While electroconvulsive therapy (ECT) is the most effective treatment for major depression (major depressive disorder [MDD]), deep brain stimulation (DBS) has shown efficacy in patients who have not received benefit from ECT. Studies of DBS are small, and a better understanding of which eligibility criteria lead to exclusion may help achieve a more appropriate balance between scientific rigor and generalizability in future trials. We assessed the rate and reasons for exclusion from a study of DBS for treatment-resistant MDD and bipolar type II (BPII) depression. METHODS: One thousand ninety-eight adults were screened for a study of DBS for MDD or BPII. Reasons for exclusion were documented. Descriptive statistics were calculated for each reason for exclusion for the entire sample as well as the self-reported MDD and BPII subgroups. RESULTS: Ninety-eight percent (98%) of patients screened were excluded. Exclusion due to lack of interest or inability to relocate to the study site was high (41%). Following this, primary reasons for exclusion were lack of prior ECT and presence of psychiatric/general medical comorbidity. Patients with MDD were more likely to be excluded because of inadequate ECT, whereas patients with BPII depression were more likely to be excluded for comorbid psychiatric diagnoses and not meeting minimum severity criteria. CONCLUSIONS: A surprisingly high number of potential participants were excluded because of lack of adequate ECT. This suggests that many patients self-identifying as "treatment resistant" have not truly exhausted available, evidence-based treatments. Overall exclusion rate was high, with key differences in exclusion reasons between the MDD and BPII subgroups. These findings can inform design of future clinical trials for treatment-resistant unipolar and bipolar depression.Clinicaltrials.gov Identifier: NCT00367003.

Neuropsychological function before and after subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression.

BACKGROUND: Treatment-resistant depression (TRD) is a pervasive and difficult to treat condition for which deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) is an emerging therapeutic option. However, neuropsychological safety data for this novel treatment have only been published for a small number of subjects. Moreover, little is known regarding the neuropsychological profile present in TRD patients at baseline, prior to initiation of DBS therapy. This report describes the neuropsychological effects of TRD and acute and chronic DBS of the SCCwm in patients with unipolar and bipolar TRD. METHODS: Patients with TRD (N = 17) were compared to a healthy control group (N = 15) on subtests from the Cambridge Neuropsychological Test Automated Battery and the Stroop Task. Patients were then tested again at subsequent time points of 1 and 6 months following the initiation of chronic DBS of the SCCwm. RESULTS: Patients with TRD showed similar levels of performance to healthy controls on most neuropsychological measures, with the exception that the TRD group had slower processing speed. Patients with bipolar TRD, relative to those with unipolar TRD, obtained lower scores on measures of executive function and memory only at baseline. With acute and chronic SCCwm DBS, neuropsychological function improved in multiple domains including processing speed and executive function (planning, set shifting, response inhibition), and memory remained stable. CONCLUSIONS: Patients with TRD show slowed processing speed but otherwise largely preserved neuropsychological functioning. DBS of the SCCwm does not result in worsening of any aspect of neuropsychological function and may improve certain domains. Future research is warranted to better understand the effects of TRD and DBS on neuropsychological function.

No change in neuropsychological functioning after receiving repetitive transcranial magnetic stimulation treatment for major depression.

Early studies of transcranial magnetic stimulation (TMS) have shown no adverse effects on neuropsychological function. However, further research using higher TMS intensities as well as a greater number of TMS pulses and with larger sample sizes is needed. We studied 68 patients with major depressive disorder who were randomized to receive either 15 sessions of sham or real TMS at 110% of the estimated prefrontal cortex threshold to the left dorsolateral prefrontal cortex. Each session consisted of 32 5-second trains of 10-Hz repetitive TMS at 110% adjusted motor threshold. A total of 24,000 pulses were given. Neuropsychological function was assessed before and immediately after TMS treatment with a battery of 8 tests. Using a higher TMS intensity as well as a greater number of pulses and having a larger sample size compared with most previous studies, this study found no negative neuropsychological effects of TMS. Changes in neuropsychological function were unrelated to changes in depression.

The impact of chronic pain on brain gene expression.

Background: Chronic pain affects one fifth of American adults, contributing significant public health burden. Chronic pain mechanisms can be further understood through investigating brain gene expression. Methods: We tested differentially expressed genes (DEGs) in chronic pain, migraine, lifetime fentanyl and oxymorphone use, and with chronic pain genetic risk in four brain regions (dACC, DLPFC, MeA, BLA) and imputed cell type expression data from 304 postmortem donors. We compared findings across traits and with independent transcriptomics resources, and performed gene-set enrichment. Results: We identified two chronic pain DEGs: B4GALT and VEGFB in bulk dACC. We found over 2000 (primarily BLA microglia) chronic pain cell type DEGs. Findings were enriched for mouse microglia pain genes, and for hypoxia and immune response. Cross-trait DEG overlap was minimal. Conclusions: Chronic pain-associated gene expression is heterogeneous across cell type, largely distinct from that in pain-related traits, and shows BLA microglia are a key cell type.

Design of a randomized clinical trial of brief couple therapy for PTSD augmented with intranasal oxytocin.

BACKGROUND: Leveraging military veterans' intimate relationships during treatment has the potential to concurrently improve posttraumatic stress disorder (PTSD) symptoms and relationship quality. Cognitive-Behavioral Conjoint Therapy (CBCT) and an 8-session Brief Cognitive-Behavioral Conjoint Therapy (bCBCT) are manualized treatments designed to simultaneously improve PTSD and relationship functioning for couples in which one partner has PTSD. Although efficacious in improving PTSD, the effects of CBCT on relationship satisfaction are small, especially among veterans. Intranasal oxytocin, which targets mechanisms of PTSD and relationship quality, may enhance the efficacy of bCBCT. METHOD/DESIGN: The purpose of this 4-year clinical trial is to compare the outcomes of bCBCT augmented with intranasal oxytocin versus bCBCT plus placebo. We will also explore potential mechanisms of action: self-reported communication skills, empathy, and trust. We will recruit 120 dyads (i.e., veteran with PTSD and their intimate partner) from the VA San Diego Healthcare System. Veterans will be administered 40 international units of oxytocin (n = 60) or placebo (n = 60) 30 min before each of 8 bCBCT sessions delivered via telehealth. Clinical and functioning outcomes will be assessed at five timepoints (baseline, mid-treatment, post-treatment, and 3- and 6-month follow-up). CONCLUSION: Study findings will reveal the efficacy of oxytocin-assisted brief couple therapy for PTSD, which could serve as highly scalable option for couples coping with PTSD, as well as provide preliminary evidence of interpersonal mechanisms of change. CLINICALTRIALS: govIdentifier:NCT06194851.