Faculty Bibliography

BACKGROUND:Poor quality of life, sleep problems, anhedonia, and negative metacognitions are common in anxiety and depression. To examine the nature of the relationship between these features and the role of metacognitions, anhedonia, and quality of life in anxiety and depression, we conducted a complex network analysis with items of self-report measures assessing quality of life, sleep, negative thinking styles, anxiety, and depression. METHODS:Participants were 226 treatment seeking individuals with a primary DSM-5 diagnosis of generalized anxiety disorder. Node centrality, strength, expected influence, community, and bridge estimation were calculated using partial correlation coefficients and glasso regularization. RESULTS:Results revealed that anhedonia was the most central node followed by quality of life nodes. Moreover, anhedonia exhibited the highest strength and expected influence, which were both stable, reliable metrics within the network. Metacognitions were not central nodes in the network, but were strong bridge symptoms between communities. LIMITATIONS/CONCLUSIONS:The results are limited by the cross-sectional nature of the data and the administration of self-report scales at one time-point, despite different rating anchors. CONCLUSION/CONCLUSIONS:These findings suggest that anhedonia is a crucial element for the association between quality of life, sleep problems, and negative cognitions.

BACKGROUND:Alterations in resting-state functional connectivity (rsFC) have been reported in posttraumatic stress disorder (PTSD). Here, we examined pre- and post-treatment rsFC during a randomized clinical trial to characterize alterations and examine predictors of treatment response. METHODS:Sixty-four combat veterans with PTSD were randomly assigned to prolonged exposure (PE) plus placebo, sertraline plus enhanced medication management, or PE plus sertraline. Symptom assessment and resting-state functional magnetic resonance imaging (fMRI) scans occurred before and after treatment. Twenty-nine trauma-exposed combat veterans without PTSD served as a control group at intake. Seed-based and region of interest (ROI)-to-ROI connectivities, as well as an exploratory connectome-based approach were used to analyze rsFC patterns. Based on previously reported findings, analyses focused on Salience Network (SN) and Default-Mode Network (DMN). RESULTS:At intake, patients with PTSD showed greater DMN-dorsal attention network (DAN) connectivity (between ventromedial prefrontal cortex and superior parietal lobule; family-wise error corrected p = .011), greater SN-DAN connectivity (between insula and middle frontal gyrus; corrected p = .003), and a negative correlation between re-experiencing symptoms and within-DMN connectivity (between posterior cingulate cortex (PCC) and middle temporal gyrus; corrected p < .001). We also found preliminary evidence for associations between rsFC and treatment response. Specifically, high responders (≥50% PTSD symptom improvement), compared with low responders, had greater SN-DMN segregation (i.e., less pre-treatment amygdala-PCC connectivity; p = .011) and lower pre-treatment global centrality (p = .042). CONCLUSIONS:Our findings suggest neural abnormalities in PTSD and may inform future research examining neural biomarkers of PTSD treatment response.

Although prolonged exposure (PE) and SSRI antidepressants are effective in treating posttraumatic stress disorder (PTSD), previous studies have shown that some symptoms tend to persist. The current study compared sertraline hydrochloride plus enhanced medication management (EMM), PE plus placebo, or PE plus sertraline hydrochloride in the likelihood of each individual PTSD symptom persisting in veterans with a PTSD diagnosis. We compared the likelihood of individual PTSD symptoms persisting in those with versus without a PTSD diagnosis at posttreatment. We found no significant differences across conditions in which symptoms were likely to persist posttreatment. Among those without a PTSD diagnosis at posttreatment, sleeping difficulties (63.0%), hypervigilance (47.3%), and nightmares (45.0%) were most likely to persist. Findings indicate no consistent differences in residual symptoms between PE and medications, and shared decision making with patients is encouraged in selecting treatments. Gold standard treatments (e.g., CBT-I) may be warranted for residual symptoms like insomnia.

Health care workers are on the front lines of the recent pandemic, facing significant challenges to their physical and mental health. This article details the efforts undertaken by a health care system and two academically affiliated hospital systems to provide emotional support to their frontline staff. The multipronged approach describes coordinating efforts to decrease duplication of services and to increase centralization of information. This included enhancing pathways for faculty, staff, and trainees to obtain individual and group treatment and to have access to highquality self-help resources. Continuous feedback has been elicited to ensure that efforts are consistent with expressed needs and in turn services undergo modifications as needed. This article seeks to provide an overview of how one health system has thus far approached the important issue of staff support as well as the challenges experienced and lessons learned along the way.

BACKGROUND:Posttraumatic stress disorder (PTSD) has been associated with exaggerated threat processing and deficits in emotion modulation circuitry. It remains unknown how neural circuits are associated with response to evidence-based treatments for PTSD. METHOD/METHODS:We examined associations between PTSD symptoms and indicators of neural response in key emotion processing and modulation regions. Fifty-six military Veterans with PTSD were randomly assigned to one of three evidence-based treatments (prolonged exposure, sertraline, and PE plus sertraline) in a randomized clinical trial ("PROGrESS"; 2018, Contemp Clin Trials, 64, 128-138). Twenty-seven combat-exposed controls (CCs) served as a comparison group at pretreatment. Before and after PTSD treatment, functional magnetic resonance imaging was used to assess brain activation and connectivity during the validated Shifted Attention Emotion Appraisal Task (2003, J Neurosci, 23, 5627-5633; 2013, Biol Psychiatry, 73, 1045-1053). RESULTS:Greater activation in emotion processing (anterior insula) and modulation (prefrontal cortex) regions and increased connectivity between attentional control (dorsolateral prefrontal cortex and superior parietal cortex) and emotion processing (amygdala) regions, at pretreatment, were associated with subsequent PTSD symptom improvement. CONCLUSIONS:This study is one of the first to examine task-based activation and functional connectivity in a PTSD treatment trial, and provides evidence to suggest that activation in and connectivity between emotion processing and modulation regions are important predictors of treatment response.

BACKGROUND:Telemedicine is a strategy for overcoming barriers to access evidence-based psychotherapy. Digital modalities that operate outside session-based treatment formats, such as ongoing two-way messaging, may further address these challenges. However, no study to date has established suitability criteria for this medium. METHODS:A large outpatient sample (n = 10,718) engaged in daily messaging with licensed clinicians from a telemedicine provider. Patients consisted of individuals from urban and rural settings in all 50 states of the US, who signed up to the telemedicine provider. Using a longitudinal design, symptoms changes were observed during a 12 week treatment course. Symptoms were assessed from baseline every three weeks using the Patient Health Questionnaire (PHQ-9) for depression, and the Generalized Anxiety Disorder (GAD-7) for anxiety. Demographics and engagement metrics, such as word count for both patients and therapists, were also assessed. Growth mixture modeling was used to tease apart symptoms trajectories, and identify predictors of treatment response. RESULTS:Two subpopulations had GAD-7 and PHQ-9 remission outcomes (Recovery and Acute Recovery, 30.7% of patients), while two others showed amelioration of symptoms (Depression and Anxiety Improvement, 36.9% of patients). Two subpopulations experienced no changes in symptoms (Chronic and Elevated Chronic, 32.4% of patients). Higher use of written communication, patient characteristics, and engagement metrics reliably distinguished patients with the greatest level of remission (Recovery and Acute Recovery groups). CONCLUSIONS:Remission of depression and anxiety symptoms was observed during delivery of psychotherapy through messaging. Improvement rates were consistent with face-to-face therapy, suggesting the suitability of two-way messaging psychotherapy delivery. Characteristics of improving patients were identified and could be used for treatment recommendation. These findings suggest the opportunity for further research, to directly compare messaging delivery with a control group of treatment as usual. TRIAL REGISTRATION/BACKGROUND:Clinicaltrials.gov Identifier: NCT03699488, Retrospectively Registered October 8, 2018.

Importance/UNASSIGNED:The Research Domain Criteria project of the National Institute of Mental Health aims to guide neuropsychiatry toward precision medicine. Its inception was partly in response to the overlap of clinical manifestations between different DSM-IV diagnoses within a category. For example, anxiety disorders comprise a DSM-IV category that includes diagnoses that differ from each other but are all characterized by dysregulated fear levels. Whether DSM-IV-based and Research Domain Criteria-based analytic approaches provide distinct or similar information with regard to the fear circuitry of individuals with anxiety disorders has not been directly tested. Objective/UNASSIGNED:To use a threat conditioning and extinction protocol to conduct categorical (DSM-IV-based) and dimensional (Research Domain Criteria-based) assessments of psychophysiological, neural, and psychometric responses in individuals with and without anxiety disorders. Design, Setting, and Participants/UNASSIGNED:This cross-sectional study was conducted at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston between March 2013 and May 2015. Functional magnetic resonance imaging was used to assess psychophysiological, neural, and psychometric responses among adults aged 18 to 65 years with specific phobia, generalized anxiety disorder, social anxiety disorder, and panic disorder as well as a control group of adults without anxiety disorders. Data were analyzed between May 2018 and April 2019. Exposures/UNASSIGNED:A 2-day threat conditioning and extinction protocol. Main Outcomes and Measures/UNASSIGNED:Skin conductance responses and blood oxygenated level-dependent responses were measured during the threat and extinction protocol. The categorical analysis was performed by grouping participants based on their primary DSM-IV diagnosis. The dimensional analysis was performed by regrouping participants, irrespective of their diagnoses, based on their skin conductance responses to shock delivery during threat conditioning. Results/UNASSIGNED:This cross-sectional study of 114 adults aged 18 to 65 years included 93 participants (34 men and 59 women; mean [SD] age, 29.7 [11.1] years) with at least 1 anxiety disorder (specific phobia, generalized anxiety disorder, social anxiety disorder, or panic disorder) and 21 participants (11 men and 10 women) without an anxiety disorder. The categorical DSM-IV-based approach indicated that all anxiety disorder groups exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall (ηp2 = 0.15; P = .004). The Research Domain Criteria-based approach revealed that higher arousal to the unconditioned stimulus was associated with higher threat responses during extinction recall (for skin conductance responses, ηp2 = 0.21; P = .01 and in functional magnetic resonance imaging results, ηp2 = 0.12; P = .02). The direct comparison of DSM-IV-based vs Research Domain Criteria-based results did not yield significant findings (ηp2 values ranged from 0.02 to 0.078; P values ranged from .09 to .98), suggesting no overlap between the approaches. Conclusions and Relevance/UNASSIGNED:The data obtained from both approaches indicated complementary yet distinct findings. The findings highlight the validity and importance of using both categorical and dimensional approaches to optimize understanding of the etiology and treatment of anxiety symptoms.

Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) commonly co-occur in combat veterans, and this comorbidity has been associated with higher levels of distress and more social and economic costs compared to one disorder alone. In a secondary analysis of a multisite randomized controlled trial of a sample of veterans with combat-related PTSD, we examined the associations among pre-, peri-, and postdeployment adversity, social support, and clinician-diagnosed comorbid MDD. Participants completed the Deployment Risk and Resilience Inventory and the Beck Depression Inventory-II as well as structured clinical interviews for diagnostic status. Among 223 U.S. veterans of the military operations in Iraq and Afghanistan (86.9% male) with primary combat-related PTSD, 69.5% had current comorbid MDD. After adjustment for sex, a linear regression model indicated that more concerns about family disruptions during deployment, f² = 0.065; more harassment during deployment, f² = 0.020; and lower ratings of postdeployment social support, f² = 0.154, were associated with more severe self-reported depression symptoms. Interventions that enhance social support as well as societal efforts to foster successful postdeployment reintegration are critical for reducing the mental health burden associated with this highly prevalent comorbidity in veterans with combat-related PTSD.

Pituitary adenylate cyclase activating polypeptide (PACAP, gene Adcyap1) is a neuropeptide and hormone thought to play a critical role in stress response (Stroth et al., Ann NY Acad Sci 1220:49-59, 2011; Hashimoto et al., Curr Pharm Des 17:985-989, 2011). Research in humans implicates PACAP as a useful biomarker for the severity of psychiatric symptoms in response to psychological stressors, and work in rodent models suggests that PACAP manipulation exerts downstream effects on peripheral hormones and behaviors linked to the stress response, providing a potential therapeutic target. Prior work has also suggested a potential sex difference in PACAP effects due to differential estrogen regulation of this pathway. Therefore, we examined serum PACAP and associated PAC1R genotype in a cohort of males and females with a primary diagnosis of generalized anxiety disorder (GAD) and nonpsychiatric controls. We found that, while circulating hormone levels were not associated with a GAD diagnosis overall (p = 0.19, g = 0.25), PACAP may be associated with GAD in females (p = 0.04, g = 0.33). Additionally, among patients with GAD, the risk genotype identified in the PTSD literature (rs2267735, CC genotype) was associated with higher somatic anxiety symptom severity in females but lower somatic anxiety symptom severity in males (-3.27, 95%CI [-5.76, -0.77], adjusted p = 0.03). Taken together, the associations between the risk genotype, circulating PACAP, and somatic anxiety severity were stronger among females than males. These results indicate a potential underlying biological etiology for sex differences in stress-related anxiety disorders that warrants further study.