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BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is an evidence-based treatment for pharmacoresistant major depressive disorder (MDD), however, the evidence in veterans has been mixed. To this end, VA implemented a nationwide TMS program that included evaluating clinical outcomes within a naturalistic design. TMS was hypothesized to be safe and provide clinically meaningful reductions in MDD and posttraumatic stress disorder (PTSD) symptoms. METHODS: Inclusion criteria were MDD diagnosis and standard clinical TMS eligibility. Of the 770 patients enrolled between October 2017 and March 2020, 68.4% (n=521) met threshold-level PTSD symptom criteria. Treatments generally used standard parameters (e.g., left dorsolateral prefrontal cortex, 120% motor threshold, 10Hz, 3000 pulses/treatment). Adequate dose was operationally defined as 30 sessions. MDD and PTSD symptoms were measured using the 9-item patient health questionnaire (PHQ-9) and PTSD checklist for DSM-5 (PCL-5), respectively. RESULTS: Of the 770 who received at least one session, TMS was associated with clinically meaningful (Cohen’s d>1.0) and statistically significant (all p

BackgroundTo examine socioeconomic disparities in use of electroconvulsive therapy (ECT) among homeless or unstably housed (HUH) veterans with mental illness.MethodsNational 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.ResultsECT 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.DiscussionECT 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.

Brain circuit functioning and connectivity between specific regions allow us to learn, remember, recognize and think as humans. In this paper, we ask the question if mobile sensing from phones can predict brain functional connectivity. We study the brain resting-state functional connectivity (RSFC) between the ventromedial prefrontal cortex (vmPFC) and the amygdala, which has been shown by neuroscientists to be associated with mental illness such as anxiety and depression. We discuss initial results and insights from the NeuroSence study, an exploratory study of 105 first year college students using neuroimaging and mobile sensing across one semester. We observe correlations between several behavioral features from students' mobile phones and connectivity between vmPFC and amygdala, including conversation duration (r=0.365, p

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.

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 (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 (non-social 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 social working memory 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 social working memory. CONCLUSIONS: Social working memory abnormalities in the default network may be a basic mechanism underlying poorer social connection in PTSD.

Background Veterans with significant chronic pain from musculoskeletal disorders are at risk of substance misuse. Veterans whose condition is the result of military service may be eligible for a disability pension. Department of Veterans Affairs compensation examinations, which determine the degree of disability and whether it was connected to military service, represent an opportunity to engage Veterans in pain management and substance use treatments. A multisite randomized clinical trial is testing the effectiveness and cost-effectiveness of Screening, Brief Intervention, and Referral to Treatment for Pain Management (SBIRT-PM) for Veterans seeking compensation for musculoskeletal disorders. This telephone-based intervention is delivered through a hub-and-spoke configuration. Design This study is a two-arm, parallel-group, 36-week, multisite randomized controlled single-blind trial. It will randomize 1,100 Veterans experiencing pain and seeking service-connection for musculoskeletal disorders to either SBIRT-PM or usual care across eight New England VA medical centers. The study balances pragmatic with explanatory methodological features. Primary outcomes are pain severity and number of substances misused. Nonpharmacological pain management and substance use services utilization are tracked in the trial. Summary Early trial enrollment targets were met across sites. SBIRT-PM could help Veterans, at the time of their compensation claims, use multimodal pain treatments and reduce existing substance misuse. Strategies to address COVID-19 pandemic impacts on the SBIRT-PM protocol have been developed to maintain its pragmatic and exploratory integrity.

For many decades, psychiatric treatment has been primarily guided by two major paradigms of psychopathology: a neurochemical paradigm leading to the development of medications and a psychological paradigm resulting in the development of psychotherapies. A third paradigm positing that psychiatric dysfunction results from abnormal communication within a network of brain regions that regulate mood, thought, and behavior has gained increased attention over the past several years and underlies the development of multiple neuromodulation and neurostimulation therapies. This neural circuit paradigm is not new. In the late 19th and early 20th centuries, it was a common way of understanding psychiatric illness and led to several of our earliest somatic therapies. However, with the rise of effective medications and evidence-based psychotherapies, this paradigm went mostly dormant. Its recent reemergence resulted from a growing recognition that medications and psychotherapy leave many patients inadequately treated, along with technological advances that have revolutionized our ability to understand and modulate the neural circuitry involved in psychiatric disorders. In this overview, the authors review the history and current state of neuromodulation for psychiatric illness and specifically focus on these approaches as a treatment for depression, as this has been the primary indication for these interventions over time.

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 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.

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.

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.

Background:Since late 2019, the lives of people across the globe have been disrupted by COVID-19. Millions of people have become infected; billions 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, but 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.Objectives: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 pandemic, measured by search term interest in "coronavirus" and "covid fatigue" across the United States.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 mobile smartphone sensing app. Depression and anxiety were assessed using weekly self-reported Ecological Momentary Assessments (EMAs), including the Patient Health Questionnaire-4 (PHQ-4). 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 observed differences in phone usage, sleep, sedentary time and the 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 (e.g., depression and anxiety) were added to the previous measures (week of term, number of locations visited, phone usage, sedentary time), both anxiety and depression (_P_

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 (PCOVID 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.

Novel treatments that target neurobiological alterations associated with childhood trauma, particularly among those with posttraumatic stress disorder (PTSD), could mitigate negative outcomes for these at-risk individuals. PTSD is characterized by abnormalities within the brain's salience network and reward circuitry, which are modulated by intranasal oxytocin. Using a double-blind, randomized, placebo-controlled crossover design, we tested whether intranasal oxytocin (24 international units) influenced functional coupling of the amygdala with the anterior insula (AI), dorsal anterior cingulate cortex, and nucleus accumbens in response to implicitly presented fearful, angry, and happy faces among childhood trauma-exposed individuals with (n = 16, 9 women) and without PTSD (n = 18, 12 women). Psychophysiological interaction analyses revealed that oxytocin effects were limited to amygdala-AI connectivity in the fear condition, distinct for men and women, and not impacted by PTSD diagnosis. In response to fear faces, oxytocin reduced left amygdala-left AI connectivity for women but not men; reduced left amygdala-right AI connectivity among women, but increased this connectivity in men; and reduced right amygdala-right anterior insula connectivity for men, but increased it for women. Results suggest that intranasal oxytocin modulates threat salience among childhood trauma-exposed individuals and that these effects vary as a function of gender and hemisphere.

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.

Background Across college campuses, the prevalence of clinically relevant depression or anxiety is affecting more than 27% of the college population at some point between entry to college and graduation. Stress and self-esteem have both been hypothesized to contribute to depression and anxiety levels. Although contemporaneous relationships between these variables have been well-defined, the causal relationship between these mental health factors is not well understood, as frequent sampling can be invasive, and many of the current causal techniques are not well suited to investigate correlated variables. Objective This study aims to characterize the causal and contemporaneous networks between these critical mental health factors in a cohort of first-year college students and then determine if observed results replicate in a second, distinct cohort. Methods Ecological momentary assessments of depression, anxiety, stress, and self-esteem were obtained weekly from two cohorts of first-year college students for 40 weeks (1 academic year). We used the Peter and Clark Momentary Conditional Independence algorithm to identify the contemporaneous (t) and causal (t-1) network structures between these mental health metrics. Results All reported results are significant at P Conclusions This paper is an initial attempt to describe the contemporaneous and causal relationships among these four mental health metrics in college students. We replicated previous research identifying concurrent relationships between these variables and extended them by identifying causal links among these metrics. These results provide support for the vulnerability model of depression and anxiety. Understanding how causal factors impact the evolution of these mental states over time may provide key information for targeted treatment or, perhaps more importantly, preventative interventions for individuals at risk for depression and anxiety.

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 (PPP=.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.

BackgroundWorldwide, the vast majority of people have been impacted by COVID-19. While millions of individuals have become infected, 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 suggest this can lead to profound behavioral and mental health changes, but rarely are researchers able to track these changes with frequent, near real-time sampling or compare these to previous years of data on the same individuals.ObjectivesWe seek to answer two overarching questions by combining mobile phone sensing and self-reported mental health data among college students participating in a longitudinal study for the past two years. First, have behaviors and mental health changed in response to the COVID-19 pandemic as compared to previous time periods within the same participants? Second, did behavior and mental health changes track the relative news coverage of COVID-19 in the US media?MethodsBehaviors were measured using the StudentLife mobile smartphone sensing app. Depression and anxiety were assessed using weekly self-reported Ecological Momentary Assessments (EMAs). Differences in behaviors and self-reported mental health collected during the Winter 2020 term (the term in which the coronavirus pandemic started), as compared to prevous terms in the same cohort, were modeled using mixed linear models.ResultsDuring the initial COVID-19 impacted academic term (Winter 2020), individuals were more sedentary and reported increased anxiety and depression symptoms (P

A few studies have examined the durability of transcranial magnetic stimulation (TMS) antidepressant benefit once patients remitted. This study examined the long-term durability of clinical benefit from TMS using a protocol-specified TMS taper and either continuation pharmacotherapy or naturalistic follow-up.Patients were remitters from an acute double-blind sham-controlled trial of TMS (n = 18), or from an open-label extension in patients who did not respond to the acute trial (n = 43). Long-term durability of TMS acute effect was examined in remitters over a 12-week follow-up. Relapse, defined as 24-item Hamilton Depression Rating Scale (HDRS-24) ≥20, was the primary outcome.Of 61 remitters in the acute trial, five entered naturalistic follow-up and 50 entered the TMS taper. Thirty-two patients completed TMS taper and 1-, 2-, and 3-month follow-up. At 3-month visit, 29 of 50 (58%) were classified as in remission (HDRS-24 ≤10), two of 50 (4%) as partial responders (30%≤ HDRS-24 reduction50% from baseline), and one of 50 (2%) met criteria for relapse. During the entire 3-month follow-up, five of the 37 patients relapsed (relapse rate = 13.5%), but four of them regained remission by the end of the study. The average time to relapse in these five patients was 7.2 ± 3.3 weeks. Patients who relapsed had higher depression scores at 1 month.While one third of the sample was lost to follow-up, our results demonstrate that most patients contributing to observations experienced persistence of benefit from TMS followed by pharmacotherapy or no medication. Longer follow-up and more rigorous studies are needed to explore the true long-term durability of remission produced by TMS.

Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) has potential as a therapeutic intervention for patients with severe treatment-resistant depression (TRD). This chapter reviews the evolution of the research support for SCC DBS. It begins with a key publication that posited a putative neural circuit hypothesis for depression and TRD; this line of research culminated in identification of the SCC as a key node involved in the antidepressant response to somatic interventions. The clinical testing of SCC DBS is then reviewed, from the first proof-of-concept study up to a large, multi-site, randomized clinical trial. The next steps in SCC DBS research are then highlighted via a focus on two papers that describe the development and early testing of a circuit-based, imaging-guided approach to SCC DBS for TRD.

Objective Over the past decade, the Department of Veterans Affairs (VA) has experienced a sizeable shift in its approach to pain. The VA’s 2009 Pain Management Directive introduced the Stepped Care Model, which emphasizes an interdisciplinary approach to pain management involving pain referrals and management from primary to specialty care providers. Additionally, the Opioid Safety Initiative and 2017 VA/Department of Defense (DoD) clinical guidelines on opioid prescribing set a new standard for reducing opioid use in the VA. These shifts in pain care have led to new pain management strategies that rely on multidisciplinary teams and nonpharmacologic pain treatments. The goal of this study was to examine how the cultural transformation of pain care has impacted providers, the degree to which VA providers are aware of pain care services at their facilities, and their perceptions of multidisciplinary care and collaboration across VA disciplines. Methods We conducted semistructured phone interviews with 39 VA clinicians in primary care, mental health, pharmacy, and physical therapy/rehabilitation at eight Veterans Integrated Service Network medical centers in New England. Results We identified four major themes concerning interdisciplinary pain management approaches: 1) the culture of VA pain care has changed dramatically, with a greater focus on nonpharmacologic approaches to pain, though many “old school” providers continue to prefer medication options; 2) most facilities in this sample have no clear roadmap about which pain treatment pathway to follow, with many providers unaware of what treatment to recommend when; 3) despite multiple options for pain treatment, VA multidisciplinary teams generally work together to ensure that veterans receive coordinated pain care; and 4) veteran preferences for care may not align with existing pain care pathways. Conclusions The VA has shifted its practices regarding pain management, with a greater emphasis on nonpharmacologic pain options. The proliferation of nonpharmacologic pain management strategies requires stakeholders to know how to choose among alternative treatments.

Depression has been increasingly recognized as a systems-level disorder; thus, treatments that target critical brain regions in order to influence the function of brain circuits are an important area of study. Deep brain stimulation (DBS), a therapeutic modality initially used in movement disorders, was first applied to treatment-resistant depression (TRD) in 2005. Multiple groups around the world have treated several hundred TRD patients with DBS on an investigational basis. There is no current single accepted protocol for DBS in TRD; variation is possible both in anatomic site and stimulation parameters. The purpose of this article is to discuss the current state of knowledge for DBS in TRD as it relates to patient selection, anatomic target selection and optimization, and stimulation parameters.

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

Summary Background Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. Methods Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4–6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. Findings Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. Interpretation This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. Funding Abbott (previously St Jude Medical).

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.

The depressive syndrome includes a number of symptoms that are clinically diverse. Research in the past decades has consistently demonstrated that the cingulate cortex plays an essential role in these manifestations. With anatomic studies initially showing volumetric changes, followed by the insights that functional imaging and physiology contributed to neuroscience and psychiatry, the distinct areas of the cingulate subdivisions were seen to have unique contributions. The subcallosal cingulate, with its functional responsivity to mood states and to antidepressant therapies, has been identified as a central node within the mood regulation network. In this chapter, detailed descriptions of the anatomic and functional changes that are seen in depression will be discussed. Finally, a focus on the development of deep brain stimulation in the subcallosal cingulate area will be used to emphasize the conceptualization of a network model with the cingulate as a hub, where engagement of remote areas of the depression network is needed to treat depression.

BACKGROUND Across college campuses, the prevalence of clinically relevant depression or anxiety is affecting more than 27% of the college population at some point between entry to college and graduation. Stress and self-esteem have both been hypothesized to contribute to depression and anxiety levels. Although contemporaneous relationships between these variables have been well-defined, the causal relationship between these mental health factors is not well understood, as frequent sampling can be invasive, and many of the current causal techniques are not well suited to investigate correlated variables. OBJECTIVE This study aims to characterize the causal and contemporaneous networks between these critical mental health factors in a cohort of first-year college students and then determine if observed results replicate in a second, distinct cohort. METHODS Ecological momentary assessments of depression, anxiety, stress, and self-esteem were obtained weekly from two cohorts of first-year college students for 40 weeks (1 academic year). We used the Peter and Clark Momentary Conditional Independence algorithm to identify the contemporaneous (t) and causal (t-1) network structures between these mental health metrics. RESULTS All reported results are significant at Pt-1 rp, cohort 1 [C1]=–0.082, cohort 2 [C2]=–0.095) and itself (t-1 rp, C1=0.388, C2=0.382) in both cohorts. Anxiety was causally influenced by stress (t-1 rp, C1=0.095, C2=0.104), self-esteem (t-1 rp, C1=–0.067, C2=–0.064, P=.002), and itself (t-1 rp, of C1=0.293, C2=0.339) in both cohorts. A causal link between anxiety and depression was observed in the first cohort (t-1 rp, C1=0.109) and only observed in the second cohort with a more liberal threshold (t-1 rp, C2=0.044, P=.03). Self-esteem was only causally influenced by itself (t-1 rp, C1=0.389, C2=0.393). Stress was only causally influenced by itself (t-1 rp, C1=0.248, C2=0.273). Anxiety had positive contemporaneous links to depression (t rp, C1=0.462, C2=0.444) and stress (t rp, C1=0.354, C2=0.358). Self-esteem had negative contemporaneous links to each of the other three mental health metrics, with the strongest negative relationship being stress (t rp, C1=–0.334, C2=–0.340), followed by depression (t rp, C1=–0.302, C2=–0.274) and anxiety (t rp, C1=–0.256, C2=–0.208). Depression had positive contemporaneous links to anxiety (previously mentioned) and stress (t rp, C1=0.250, C2=0.231). CONCLUSIONS This paper is an initial attempt to describe the contemporaneous and causal relationships among these four mental health metrics in college students. We replicated previous research identifying concurrent relationships between these variables and extended them by identifying causal links among these metrics. These results provide support for the vulnerability model of depression and anxiety. Understanding how causal factors impact the evolution of these mental states over time may provide key information for targeted treatment or, perhaps more importantly, preventative interventions for individuals at risk for depression and anxiety.

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.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.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.In8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS.

As investigators look to “next-generation” deep brain stimulation (DBS) approaches, renewed enthusiasm is emerging for DBS for psychiatric disorders. This commentary on Chapter 13 (“Informed Consent for Next-Generation Deep Brain Stimulation Psychiatric Research: Engaging End Users to Understand Risks and Improve Practice”) provides additional insight into the challenges related to informed consent described by Klein. We argue that the sorts of vulnerability described by Klein warrant further attention, in particular, to help address the question of whether patients with psychiatric disorders are uniquely vulnerable, in ways that patients with other illnesses are not. Ethics research, such as that conducted by Klein, in which end users of brain-based devices are interviewed, is critical. It will also be important to compare brain-based intervention research with other forms of research; we do not want to end up engaging in ethics “exceptionalism” as a result of failure to conduct rigorous studies on ethics-related questions.

Objective To determine the antidepressant mechanism of action for repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (DLPFC) in healthy women. Our primary hypothesis was that a single session of left DLPFC rTMS, compared with a session of right DLPFC rTMS, would result in better (reduced) negative nonaffective switch costs in healthy women. Background The antidepressant mechanism of action for rTMS is not clear. It is possible that rTMS to the DLPFC improves emotion regulation, which could be a part of its antidepressant mechanism. Methods Twenty-five healthy women were randomized to receive left high-frequency (HF) rTMS versus right HF rTMS in one session and then contralateral stimulation during a second session. Emotion regulation was assessed via switch costs for reappraisal of negatively valenced information on an affective flexibility task. Results For negative nonaffective switch costs, the interaction effect in the two-way ANOVA was not significant (F1,19=3.053, P=0.097). Given that left HF rTMS is the approved treatment for depression, post hoc t tests were completed with particular interest in the left-side findings. These tests confirmed that negative nonaffective switch costs significantly improved immediately after left rTMS (t1,19=2.664, P=0.015) but not right rTMS. Conclusions These findings suggest that left DLPFC HF rTMS may lead to antidepressant effects by improving the regulation of emotion.

The depressive syndrome includes a number of symptoms that are clinically diverse. Research in the past decades has consistently demonstrated that the cingulate cortex plays an essential role in these manifestations. With anatomic studies initially showing volumetric changes, followed by the insights that functional imaging and physiology contributed to neuroscience and psychiatry, the distinct areas of the cingulate subdivisions were seen to have unique contributions. The subcallosal cingulate, with its functional responsivity to mood states and to antidepressant therapies, has been identified as a central node within the mood regulation network. In this chapter, detailed descriptions of the anatomic and functional changes that are seen in depression will be discussed. Finally, a focus on the development of deep brain stimulation in the subcallosal cingulate area will be used to emphasize the conceptualization of a network model with the cingulate as a hub, where engagement of remote areas of the depression network is needed to treat depression.

Deep brain stimulation (DBS) of the subcallosal cingulate has emerged as a promising therapy for treatment-resistant depression (TRD). To date, all studies have employed bilateral stimulation; however, the physiology of affect and pathophysiology of depression are known to be asymmetric across hemispheres. Unilateral stimulation may provide efficacy while decreasing risk. Five patients were exposed to unilateral open-label DBS to the subcallosal cingulate for 12 weeks each to the left and then right hemispheres in a double-blind, crossover fashion. After 12 weeks of stimulation to each hemisphere, bilateral stimulation was initiated, and patients were followed for 12 additional weeks. Additionally, nine months of long-term follow up data were collected. Left, but not right, unilateral stimulation was associated with significant decrease in depression scores; with bilateral stimulation, all patients improved and one patient remitted. No serious adverse events were associated with surgery or acute or chronic stimulation. This small study suggests that unilateral DBS to the subcallosal cingulate may be an effective treatment for TRD. All patients improved with bilateral stimulation, though antidepressant effects following 12 weeks were modest. These findings contrast somewhat with prior open-label trials, though duration of bilateral stimulation was shorter in this trial. The current study continues to confirm safety of implantation and use of DBS to the subcallosal cingulate for patients with TRD and highlights the importance of personalization of therapy, for example by hemisphere, in future trials.

Depression is an often debilitating disorder affecting a person’s ability to work and function. Treatment-resistant depression (TRD) leads to many interventions and significant health care costs. Deep brain stimulation (DBS) is an emerging potential intervention for those with TRD who have undergone adequate medication, therapy, and rTMS/ECT trials, but who continue to suffer from unremitting depressive symptoms. The latest clinical safety and efficacy data of DBS for TRD is presented in this review. Since the origin of DBS is rooted in specific neuroanatomical targets, the discussion is organized according to target brain region. Relevant neuroimaging and animal studies are discussed, when available, as to how they shed light on possible mechanisms of action. Lastly, critical ethical issues related to informed consent and decision-making capacity are considered.

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 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.

Until recently, therapeutic development in psychiatry was targeted solely toward symptom reduction. While this is a worthwhile goal, it has yielded little progress in improved therapeutics in the last several decades in the field of mood disorders. Recent advancements in our understanding of pathophysiology suggests that an impairment of neuroplasticity may be a critical part of the development of neuropsychiatric disorders. Interventions that enhance or modulate neuroplasticity often reduce depressive symptoms when applied as stand-alone treatments. Unfortunately, when treatments are discontinued, the disease state often returns as patients relapse. However, treatments that enhance or modulate plasticity not only reduce symptom burden, but also may provide an opportune window wherein cognitive or behavioral interventions could be introduced to harness a state of enhanced neuroplasticity and lead to improved longer-term clinical outcomes. Here, we review the potential of synergistically combining plasticity-enhancing and behavioral therapies to develop novel translational treatment approaches for depression. After reviewing relevant neuroplasticity deficits in depression, we survey biological treatments that appear to reverse such deficits in humans, including N-methyl-D-aspartate receptor modulators (ketamine, D-cycloserine), electroconvulsive therapy, and transcranial brain stimulation. We then review evidence that either directly or indirectly supports the hypothesis that a robust enhancement of neuroplasticity through these methods might promote the uptake of cognitive and behavioral interventions to enhance longer-term treatment outcomes through a synergistic effect. We identify key missing pieces of evidence and discuss future directions to enhance this emerging line of research.

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.

As smartphone usage has become increasingly prevalent in our society, so have rates of depression, particularly among young adults. Individual differences in smartphone usage patterns have been shown to reflect individual differences in underlying affective processes such as depression (Wang et al., 2018). In the current study, a positive relationship was identified between smartphone screen time (e.g., phone unlock duration) and resting-state functional connectivity (RSFC) between the subgenual cingulate cortex (sgCC), a brain region implicated in depression and antidepressant treatment response, and regions of the ventromedial/orbitofrontal cortex (OFC), such that increased phone usage was related to stronger connectivity between these regions. This cluster was subsequently used to constrain subsequent analyses looking at individual differences in depressive symptoms in the same cohort and observed partial replication in a separate cohort. Similar analyses were subsequently performed on metrics of circadian rhythm consistency showing a negative relationship between connectivity of the sgCC and OFC. The data and analyses presented here provide relatively simplistic preliminary analyses which replicate and provide an initial step in combining functional brain activity and smartphone usage patterns to better understand issues related to mental health. Smartphones are a prevalent part of modern life and the usage of mobile sensing data from smartphones promises to be an important tool for mental health diagnostics and neuroscience research.