Prototyping Apps for the Management of Sleep, Fatigue, and Behavioral Health in Austere Far-Forward Environments: Development Study.

BACKGROUND: Military service inherently includes frequent periods of high-stress training, operational tempo, and sustained deployments to austere far-forward environments. These occupational requirements can contribute to acute and chronic sleep disruption, fatigue, and behavioral health challenges related to acute and chronic stress and disruption of team dynamics. To date, there is no centralized mobile health platform that supports self- and supervised detection, monitoring, and management of sleep and behavioral health issues in garrison and during and after deployments. OBJECTIVE: The objective of this study was to adapt a clinical decision support platform for use outside clinical settings, in garrison, and during field exercises by medics and soldiers to monitor and manage sleep and behavioral health in operational settings. METHODS: To adapt an existing clinical decision support digital health platform, we first gathered system, content, and context-related requirements for a sleep and behavioral health management system from experts. Sleep and behavioral health assessments were then adapted for prospective digital data capture. Evidence-based and operationally relevant educational and interventional modules were formatted for digital delivery. These modules addressed the management and mitigation of sleep, circadian challenges, fatigue, stress responses, and team communication. Connectivity protocols were adapted to accommodate the absence of cellular or Wi-Fi access in deployed settings. The resulting apps were then tested in garrison and during 2 separate field exercises. RESULTS: Based on identified requirements, 2 Android smartphone apps were adapted for self-monitoring and management for soldiers (Soldier app) and team supervision and intervention by medics (Medic app). A total of 246 soldiers, including 28 medics, received training on how to use the apps. Both apps function as expected under conditions of limited connectivity during field exercises. Areas for future technology enhancement were also identified. CONCLUSIONS: We demonstrated the feasibility of adapting a clinical decision support platform into Android smartphone-based apps to collect, save, and synthesize sleep and behavioral health data, as well as share data using adaptive data transfer protocols when Wi-Fi or cellular data are unavailable. The AIRE (Autonomous Connectivity Independent System for Remote Environments) prototype offers a novel self-management and supervised tool to augment capabilities for prospective monitoring, detection, and intervention for emerging sleep, fatigue, and behavioral health issues that are common in military and nonmilitary high-tempo occupations (eg, submarines, long-haul flights, space stations, and oil rigs) where medical expertise is limited.

Associations of health care staff burnout with negative health and organizational outcomes in the U.S. military health system.

RATIONALE: Burnout is a personal and occupational phenomenon that has been associated with negative physical and psychological outcomes in medical staff. Additionally, there are implications for healthcare organizations, as those staff who are burned out are more likely to have lower productivity or leave the organization. As with the Covid-19 pandemic, future national emergencies and potentially large-scale conflicts will require similar and likely even larger scale responses from the U.S. Military Health System, thus it is important to understand burnout in this population so that the readiness of the staff and the military can remain at a high level. OBJECTIVE: This assessment was designed to examine levels of burnout among United States Military Health System (MHS) staff working at Army installations and the factors that influence the development of burnout. METHODS: Anonymous data was collected from 13,558 active-duty U.S. Soldiers and civilian MHS employees. Burnout was measured using the Copenhagen Burnout Inventory and the Mini-Z. RESULTS: Results showed nearly half of staff who responded (48%) reported being burned out, an increase since last measured in 2019 (31%). Factors related to increased burnout included concerns about work/life balance and workload, low job satisfaction and feeling disconnected from others. Burnout was associated with increases in adverse physical and behavioral health (BH) outcomes. CONCLUSIONS: Results indicate that burnout is a common problem across MHS Army staff and is related to significant adverse health consequences for the individual and reduced retention of staff for the organization. These findings highlight the need to address burnout through policies that standardize health care delivery policies and practices, providing support to leadership to promote a healthy workplace, and individual support to those who experience burnout.

Development of Training to Prepare Army Medics to Address Behavioral Health Needs of Soldiers in Far-Forward Environments Utilizing Mobile App Technology.

INTRODUCTION: Multi-domain operational combat environments will likely restrict key components of current behavioral health (BH) service delivery models. Combat teams in far-forward outposts or extended missions may need to rely on their own internal assets to manage combat and operational stress reactions for extended periods of time. As such, combat medics are expected to take on additional responsibilities as providers of BH support for isolated teams. As they receive limited BH training, medics require additional training to sufficiently respond to combat and operational stress reactions in their assigned teams. This study provided combat medics with a BH training and a mobile application-based support tool that would assist them in identifying and responding to BH concerns in their soldiers. The current analysis examines pre- to post-training changes in attitudes related to utilizing BH skills. MATERIALS AND METHODS: We created a brief training aimed to increase medics' ability and confidence regarding managing BH issues. Its development was part of a study on the feasibility of the Soldier and Medic Autonomous Connectivity Independent System for Remote Environments (AIRE) apps (NOCTEM, LLC), a digital system designed for far-forward BH and sleep monitoring and management. Participants were combat medics from two Army combat brigades preparing for a training rotation through a combat training center (CTC). A total of 16 medics consented to participation with nine medics available at the follow-up after the field exercise. Medics were surveyed before the training and after their return from the CTC. RESULTS: In pre-training surveys, most medics indicated it was within their scope to assess for stress/anxiety, suicidal risk, stress reaction, and sleep problems; assist soldiers with optimizing work performance; and provide interventions for BH concerns and sleep problems. Less than half believed it was within their scope to assess and address team communication issues or provide intervention for stress reactions. After the CTC rotation, more medics endorsed that it was in their scope to provide interventions for acute stress reactions to traumatic events. Before the CTC rotation, at most 60% of the group felt at least moderately confident in utilizing the BH skills of discussing problems, assessing for concerns, and providing interventions. After CTC, the confidence levels for each skill increased or remained the same for most medics. Intervention skills had the highest proportion of medics (66%) reporting increased confidence in using the skills. CONCLUSIONS: A larger proportion of medics believed it was within their scope of work and felt confident in assessing BH problems, and a smaller proportion believed it is within their scope of work and felt confident in applying interventions. The training increased most medics' confidence to administer interventions for BH and team communication issues. Similar training programs can help medics serve as support for a wide variety of circumstances when the brigade's mental health teams are inaccessible. Additionally, the Medic AIRE app expanded the ability to evaluate and provide interventions without extensive training in treatment modalities or BH conditions. This concept shows promise for providing medics with actionable tools when training time is limited such as during preparation for extended deployments.

Far Forward Behavioral Health Service Delivery in Future Combat Environments: A Qualitative Needs Assessment.

INTRODUCTION: It is expected that future multi-domain operational (MDO) combat environments will be characterized by limited capabilities for immediate combat stress control support services for soldiers or immediate evacuation from theater. The operational requirements of the future battlefield make it unlikely that current models for behavioral health (BH) treatment could be implemented without significant adjustments. We conducted a qualitative study with Special Forces medics and operators and soldiers who had deployed to austere conditions in small groups in an effort to inform construction of a BH service delivery model for an MDO environment. The objectives of this study were (1) characterizing stressors and BH issues that were encountered and (2) describing mitigation strategies and resources that were useful or needed in these types of deployments. MATERIALS AND METHODS: Six focus groups were conducted at three army installations with 23 active duty soldiers, including three groups of medics using a semi-structured interview guide focused on stressors they encountered during deployments to austere conditions, and the impact of those stressors on mission and focus. Focus group recordings were transcribed, imported into NVivo software (version 12), and independently coded by two researchers. An analysis was then conducted to develop themes across participants. The study was reviewed by the Walter Reed Army Institute of Research Human Subjects Protection Board. RESULTS: Behavioral health concerns were commonly cited as a stressor in far forward environments. Other common stressors included ineffective or inexperienced leaders, as well as poor team dynamics (e.g., communication and cohesion). Four primary strategies were mentioned as mitigations for deployment stressors: leadership, morale, resilience training, and strength of the team. When asked about resources or training that would have helped with these types of deployments, participants frequently mentioned the availability of BH providers and development of new and realistic BH skills trainings for non-providers and leaders. CONCLUSIONS: Current models for treating BH problems need to be adapted for the future MDO environments in which soldiers will be expected to deploy. Understanding what issues need to be addressed in these environments and how they can best be delivered is an important first step. This study is the first to use qualitative results from those who have already deployed to such environments to describe the stressors and BH issues that were most commonly encountered, the mitigation strategies used, and the resources that were useful or needed.

Behavioral Health Provider Attitudes Toward Behavioral Health Profiles in the U.S. Army.

INTRODUCTION: U.S. Army healthcare providers' use of profiles to document and communicate behavioral health (BH) condition limitations to commanders is vital to understanding both the individual soldier's BH readiness for missions and, as an aggregate, the unit's overall BH readiness status. Quantitative work exploring the link between soldier attitudes toward BH profiles and treatment utilization found that profiles may actually promote increases in treatment-seeking behavior in those receiving conventional BH services. BH provider attitudes on the subject, however, have not been quantitatively explored. Using data from the recently described Behavioral Health Readiness and Decision-Making Instrument (B-REDI) study, the current inquiry addresses this by examining BH providers' pre-/post-B-REDI attitudes toward BH profiles, including therapeutic alliance, to better understand how BH profiles may impact BH treatment. METHODS: This study was approved by the WRAIR Institutional Review Board and is part of the larger B-REDI study. BH providers (n = 307) across five installations supporting active duty U.S. Army Divisions completed surveys longitudinally across three time points from September 2018 to March 2019. The survey specific to this study included five items, developed by WRAIR, assessing BH provider attitudes toward BH profiles. Of the providers who completed the survey, 250 (81%) consented to participate in the study and 149 (60%) completed the 3-month follow-up survey. RESULTS: Over 80% of BH providers expressed agreement with each of three items assessing rationale for issuing BH profiles in both the pre- and post B-REDI period. Specifically, most providers agreed that profiles facilitate commander support to the soldier, afford soldiers resources for recovery, and give commanders increased understanding of soldier health for mission planning. Twenty-six percent of BH providers agreed, 46% were neutral, and 28% disagreed on whether profile impact on the soldier was positive or not in the pre-B-REDI period, but there was a significant positive trend relative to baseline in the post B-REDI period. The vast majority of providers (≥94%) did not endorse agreement that BH profiles negatively impact therapeutic alliance in either the pre- or post-B-REDI period. CONCLUSIONS: Assuming that therapeutic alliance and perceptions of BH profile impact on soldiers are useful proxy measures of how treatment utilization may be affected by profiling, this inquiry fails to establish any meaningful negative association between them. This may provide some additional reassurance to BH providers and policymakers that efforts to improve readiness decision-making, such as B-REDI, and increased profiling in conventional military BH settings may not negatively impact treatment utilization rates.

Results of the Behavioral Health Readiness Evaluation and Decision-Making Instrument Study.

INTRODUCTION: Recent reports have demonstrated behavioral health (BH) system and individual provider challenges to BH readiness success. These pose a risk to winning on the battlefield and present a significant safety issue for the Army. One of the most promising areas for achieving better BH readiness results lies in improving readiness decision-making support for BH providers. The Walter Reed Army Institute of Research (WRAIR) has taken the lead in addressing this challenge by developing and empirically testing such tools. The results of the Behavioral Health Readiness Evaluation and Decision-Making Instrument (B-REDI) field study are herein described. METHODS: The B-REDI study received WRAIR Institutional Review Board approval, and BH providers across five U.S. Army Forces Command installations completed surveys from September 2018 to March 2019. The B-REDI tools/training were disseminated to 307 providers through random clinic assignments. Of these, 250 (81%) providers consented to participate and 149 (60%) completed both initial and 3-month follow-up surveys. Survey items included a wide range of satisfaction, utilization, and proficiency-level outcome measures. Analyses included examinations of descriptive statistics, McNemar's tests pre-/post-B-REDI exposure, Z-tests with subgroup populations, and chi-square tests with demographic comparisons. RESULTS: The B-REDI resulted in broad, statistically significant improvements across the measured range of provider proficiency-level outcomes. Net gains in each domain ranged from 16.5% to 22.9% for knowledge/awareness (P = .000), from 11.1% to 15.8% for personal confidence (P = .001-.000), and from 6.2% to 15.1% for decision-making/documentation (P = .035-.002) 3 months following B-REDI initiation, and only one (knowledge) failed to maintain a statistically significant improvement in all of its subcategories. The B-REDI also received high favorability ratings (79%-97% positive) across a wide array of end-user satisfaction measures. CONCLUSIONS: The B-REDI directly addresses several critical Army BH readiness challenges by providing tangible decision-making support solutions for BH providers. Providers reported high degrees of end-user B-REDI satisfaction and significant improvements in all measured provider proficiency-level domains. By effectively addressing the readiness decision-making challenges Army BH providers encounter, B-REDI provides the Army BH health care system with a successful blueprint to set the conditions necessary for providers to make more accurate and timely readiness determinations. This may ultimately reduce safety and mission failure risks enterprise-wide, and policymakers should consider formalizing and integrating the B-REDI model into current Army BH practice.

Methodology of the U.S. Army's Suicide Prevention Leadership Tool Study: The Behavioral Health Readiness and Suicide Risk Reduction Review (R4).

INTRODUCTION: The Secretary of the U.S. Army issued two directives in late 2017 to directly combat the problem of suicide in the U.S. Army. The first was to develop an Army tool to assist commanders and first-line leaders in preventing suicide and improving behavioral health (BH) outcomes, which has been previously published as the BH Readiness and Risk Reduction Review (R4). The second was to conduct an evaluation study of the tool with Army units in the field. This study is the first to empirically examine the Army's tool-based methods for identifying and caring for the health and welfare of soldiers at risk for suicide, and this article outlines the methodology employed to study the effectiveness of the R4 tools and accomplish the Secretary's second directive. METHODS: The Walter Reed Army Institute of Research Institutional Review Board approved the R4 study. The study employed a repeated measurements in pre/post quasi-experimental design, including a nonequivalent but comparable business-as-usual control group. The R4 intervention consisted of the R4 tools, accompanying instructions, and an orientation. Samples were drawn from two geographically separated U.S. Army divisions in the continental United States, each composed of four comparable brigades. Study implementation consisted of three phases and three data collections over the course of 12 months. Soldiers completed anonymous survey instruments to assess a range of health factors, behaviors, characteristics, tool-related decision-making processes, and the frequency, type, and quality of interactions between soldiers and leaders. RESULTS: The R4 study commenced on May 6, 2019, and concluded on June 4, 2020. Sample size goals were achieved for both the divisions at all three data collection time points. CONCLUSIONS: The methodology of the R4 study is critical for the U.S. Army from both a precedential and an outcome-based standpoint. Despite the use of many previous tools and programs for suicide prevention, this is the first time the Army has been able to empirically test the effectiveness of tool-supported decision-making among Army units in a rigorous fashion. The methodology of such a test is a critical marker for future interventional inquiries on the subject of suicide in the Army, and the results will allow for more informed decision-making by leaders when approaching these ongoing challenges.

Mental Health Service Utilization and Perceived Barriers to Receiving Care in Deployed Soldiers.

INTRODUCTION: Scant research has examined mental health treatment utilization and barriers to care in deployed U.S. soldiers. This study aims to assess mental health treatment utilization in deployed soldiers, including providers used and barriers to care. MATERIALS AND METHODS: U.S. Army soldiers (n = 2,412) in a combat environment were surveyed on psychiatric symptoms, mental health help received, sources of care, and perceived barriers to care by Mental Health Advisory teams from 2009 to 2013. RESULTS: Of the 25% of soldiers at mental health risk, 37% received mental health help, with 18% receiving help from a provider. Nonprovider sources of care were utilized significantly more frequently than providers. Soldiers at mental health risk reported significantly greater anticipated career-related stigma, organizational barriers to care, self-reliance views, and negative attitudes toward care, yet these constructs did not differ between who did or did not receive help. Soldiers who received help from providers exclusively reported significantly more anticipated career-related stigma and fewer organizational barriers to care than those that received no help. Soldiers who spent no time living outside the forward operating base and soldiers with six or more types of combat exposures were more likely to receive help. CONCLUSIONS: Prevalence of common psychopathology and receipt of care in a combat environment was similar to previous reports from postdeployment settings. Nonprovider sources of care were more frequently utilized as compared to an in-Garrison report. Findings suggest important differences exist in sources of help and barriers to care in deployed vs. postdeployment environments. The hypothesized barriers to care did not preclude receiving any help, however, less than one-half of soldiers at mental health risk received help. Thus, future research should identify factors that have the greatest influence on help seeking behavior in both deployed and Garrison settings.

Soldier Attitudes Toward Behavioral Health Profiles in the US Army.

INTRODUCTION: Behavioral health (BH) readiness is a critical component of U.S. Army personnel readiness. Medical providers issue BH profiles in order to communicate BH-related duty limitations to the commander and reflect BH force readiness on both micro/macro-levels. A recent report indicates BH profile underutilization may be significantly elevating U.S. Army safety and mission-failure risks, and a study of BH provider decision-making suggests some providers may be hesitant to use profiles due to concerns that soldiers' attitudes toward BH profiles may negatively impact treatment utilization. This potential link, however, has not been empirically examined. This study addresses this gap by assessing soldiers' attitudes towards BH profiles to better understand how BH profiles may impact treatment utilization and explore for any BH profile-related stigma effect. METHODS: Approved by the Walter Reed Army Institute of Research (WRAIR) Institutional Review Board as part of the Land Combat Study II, the survey specific to this study included eight WRAIR-developed items assessing soldier attitudes toward BH profiles. Soldiers (N = 1,043) from two active duty U.S. Army brigades completed cross-sectional, anonymous surveys in 2017-2018. Soldier self-reported BH care utilization was assessed and used to create sub-groups for analysis. RESULTS: A majority of soldiers indicated that being placed on a BH profile would make them as or more likely to seek (71%) and no more or less likely to drop out (84%) of BH care. Among soldiers who had received BH care, BH profiles were associated with more favorable treatment seeking attitudes among those inclined to access conventional BH services and less favorable treatment seeking and maintenance attitudes among those inclined to access BH services from sources incapable of issuing profiles. Negative attitudes towards BH profiles were significantly more prevalent when compared to physical injury profiles, except in the group who had received BH care from a source incapable of issuing a profile. No significant proportional differences were observed among soldiers toward the rationale for BH profiles. Almost all soldiers (95% or greater) preferred their BH condition not come to the commander's attention during pre-deployment screening (SRP), choosing either BH profile or crisis options instead. CONCLUSIONS: Results suggest soldiers who would be less likely to seek or more likely to drop out of BH care due to a BH profile may be those that are less likely to access conventional BH services in the first place. This may provide some preliminary reassurance to conventional providers that increased BH profiling practices may not be inversely proportional to the amount of BH care delivered and may encourage treatment-seeking behaviors among the population they serve. Soldiers seeking BH care from sources incapable of issuing a profile may be sensitive to a potential BH profile-related stigma effect (possibly more global profile-related effect in this group), which should be factored into policy outreach efforts. A BH profile represents a more palatable BH duty limitation disclosure option for many soldiers, and supports the merits of a disclosure process that is earlier than SRP for promoting risk mitigation and more honest appraisals of BH mission-readiness levels.

Prescription opioid use among individuals with serious mental illness.

Prevalence and correlates of prescription opioid use were explored in individuals with serious mental illness (SMI) by examining a sample of adults from two inner city community psychiatry clinics. Of 271 participants, 12.9% (n = 35) were on a prescribed opioid. Being on an opioid was significantly associated with history of heroin use and active prescription sedative-hypnotic use, including benzodiazepine use. Concurrent use of opioids with sedative-hypnotics was significantly associated with suicidal ideation. The results highlight risks of prescription opioid use in those with SMI, particularly in combination with prescription sedative-hypnotics.

Delays in Seeking General Medical Services and Measurable Abnormalities Among Individuals With Serious Mental Illness.

OBJECTIVE: The study explored the association of delays in seeking general medical care with elevated blood pressure and metabolic abnormalities among individuals with serious mental illness. METHODS: Association of delays in medical care with blood pressure, serum hemoglobin A1c (HbA1C), and lipids was assessed among patients at two inner-city community mental health centers. RESULTS: Of 271 participants, 62% reported delays in seeking general medical care due to attitudinal and financial barriers. Care delay was associated with abnormalities in measured blood pressure (adjusted odds ratio [AOR]=2.14, p=.029) and HbA1c (AOR=3.18, p=.026). Care delay was not associated with abnormalities in lipid profiles. CONCLUSIONS: This study found that delays in seeking general medical care are common and are associated with clinical markers linked with common medical conditions. The results may help to explain the elevated morbidity and mortality associated with serious mental illness.

A Systematic Review of Evidence for the Clubhouse Model of Psychosocial Rehabilitation.

The Clubhouse Model has been in existence for over sixty-five years; however, a review that synthesizes the literature on the model is needed. The current study makes use of the existing research to conduct a systematic review of articles providing a comprehensive understanding of what is known about the Clubhouse Model, to identify the best evidence available, as well as areas that would benefit from further study. Findings are summarized and evidence is classified by outcome domains. Fifty-two articles met the selection criteria of Randomized Clinical Trials (RCT's), quasi-experimental studies, or observational studies for domains of employment (N = 29); quality of life/satisfaction (N = 10); reductions in psychiatric hospitalization(s) (N = 10); social relationships (N = 10); education (N = 3); and health promotion activities (N = 2). RCT results support the efficacy of the Clubhouse Model in promoting employment, reducing hospitalization(s), and improving quality of life. Quasi-experimental and observational studies offer support in education and social domains. The findings from this review indicate that Clubhouses are a promising practice but additional studies using rigorous methods that report the strength of the outcomes are needed to evaluate Clubhouse programs with fidelity to the Clubhouse Model.

Social network, recovery attitudes and internal stigma among those with serious mental illness.

BACKGROUND: Social network size and strength is an important determinant of overall health. AIMS: This study describes the extent and strength of the social network among a sample of individuals with serious mental illness (SMI) and explores the relationship between an individual's social network and their experience of internal stigma and recovery attitudes. METHODS: Over a 2-year period, consecutive new patients with SMI attending two community mental health clinics were recruited and interviewed using a comprehensive battery of assessments including assessment of internalized stigma, recovery attitudes and symptom severity. RESULTS: Among the 271 patients interviewed, social network size was small across all diagnostic categories. In adjusted results, the number of friends and support from relatives and friends was significantly related to the personal confidence and hope recovery attitude ( p < .05). The number of relatives and friends and support from relatives was significantly related to internalized stigma ( p < .05). Frequency of contact with relatives or friends was not related to either recovery factors or internalized stigma. CONCLUSION: There is a significant positive relationship between the size and perceived strength of an individual's social network and internalized stigma and some recovery attitudes. Clinical programs that address any of these factors could potentially improve outcomes for this population.

Cognitive profiles and heritability estimates in the Old Order Amish.

OBJECTIVE: This study aimed to establish the applicability of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in the Old Order Amish (OOA) and to assess the genetic contribution toward the RBANS total score and its cognitive domains using a large family-based sample of OOA. PARTICIPANTS AND METHODS: RBANS data were collected in 103 OOA individuals from Lancaster County, Pennsylvania, including 85 individuals without psychiatric illness and 18 individuals with current psychiatric diagnoses. RESULTS: The RBANS total score and all five cognitive domains of in nonpsychiatric OOA were within half a SD of the normative data of the general population. The RBANS total score was highly heritable (h=0.51, P=0.019). OOA with psychiatric diagnoses had a numerically lower RBANS total score and domain scores compared with the nonpsychiatric participants. CONCLUSION: The RBANS appears to be a suitable cognitive battery for the OOA population as measurements obtained from the OOA are comparable with normative data in the US population. The heritability estimated from the OOA is in line with heritabilities of other cognitive batteries estimated in other populations. These results support the use of RBANS in cognitive assessment, clinical care, and behavioral genetic studies of neuropsychological functioning in this population.

Disrupted glucocorticoid--Immune interactions during stress response in schizophrenia.

Glucocorticoid and immune pathways typically interact dynamically to optimize adaptation to stressful environmental challenges. We tested the hypothesis that a dysfunctional glucocorticoid-immune relationship contributes to abnormal stress response in schizophrenia. Saliva samples from 34 individuals with schizophrenia (20 male, 14 female) and 40 healthy controls (20 male, 20 female) were collected prior to and at 3 time points following completion of a computerized psychological challenge meant to be frustrating. Salivary concentrations of cortisol and interleukin-6 (IL-6) and their response to the challenge were examined. Both cortisol and IL-6 significantly increased in response to stress in the combined sample (both p<.05). In controls, the rise in cortisol following the challenge was negatively correlated to the subsequent changes in IL-6 (r=-.461, p=.003), such that rise of cortisol immediately after stress predicts subsequently lower IL-6 levels. In contrast, this relationship was positive in schizophrenia patients (r=.379, p=.027). The trends were significantly different (Z=3.7, p=.0002). This stress paradigm induces a rise in both cortisol and IL-6. In healthy controls, a more robust acute cortisol response was associated with a steeper decline of IL-6 levels following stress, corresponding to the expected anti-inflammatory effects of cortisol. Patients exhibited the opposite relationship, suggesting an inability to down-regulate inflammatory responses to psychological stress in schizophrenia; or even a paradoxical increase of IL-6 response. This finding may partially underlie abnormalities in inflammatory and stress pathways previously found in the illness, implicating dysregulated stress response in the chronic inflammatory state in schizophrenia.

Heritability of complex white matter diffusion traits assessed in a population isolate.

INTRODUCTION: Diffusion weighted imaging (DWI) methods can noninvasively ascertain cerebral microstructure by examining pattern and directions of water diffusion in the brain. We calculated heritability for DWI parameters in cerebral white (WM) and gray matter (GM) to study the genetic contribution to the diffusion signals across tissue boundaries. METHODS: Using Old Order Amish (OOA) population isolate with large family pedigrees and high environmental homogeneity, we compared the heritability of measures derived from three representative DWI methods targeting the corpus callosum WM and cingulate gyrus GM: diffusion tensor imaging (DTI), the permeability-diffusivity (PD) model, and the neurite orientation dispersion and density imaging (NODDI) model. These successively more complex models represent the diffusion signal modeling using one, two, and three diffusion compartments, respectively. RESULTS: We replicated the high heritability of the DTI-based fractional anisotropy (h(2) = 0.67) and radial diffusivity (h(2) = 0.72) in WM. High heritability in both WM and GM tissues were observed for the permeability-diffusivity index from the PD model (h(2) = 0.64 and 0.84), and the neurite density from the NODDI model (h(2) = 0.70 and 0.55). The orientation dispersion index from the NODDI model was only significantly heritable in GM (h(2) = 0.68). CONCLUSION: DWI measures from multicompartmental models were significantly heritable in WM and GM. DWI can offer valuable phenotypes for genetic research; and genes thus identified may reveal mechanisms contributing to mental and neurological disorders in which diffusion imaging anomalies are consistently found. Hum Brain Mapp 37:525-535, 2016. © 2015 Wiley Periodicals, Inc.

Cortisol Reactivity to Stress and Its Association With White Matter Integrity in Adults With Schizophrenia.

OBJECTIVES: Although acute hypothalamic-pituitary-adrenal axis response to stress is often adaptive, prolonged responses may have detrimental effects. Many components of white matter structures are sensitive to prolonged cortisol exposure. We aimed to identify a behavioral laboratory assay for cortisol response related to brain pathophysiology in schizophrenia. We hypothesized that an abnormally prolonged cortisol response to stress may be linked to abnormal white matter integrity in patients with schizophrenia. METHODS: Acute and prolonged salivary cortisol response was measured outside the scanner at pretest and then at 0, 20, and 40 minutes after a psychological stress task in patients with schizophrenia (n = 45) and controls (n = 53). Tract-averaged white matter was measured by 64-direction diffusion tensor imaging in a subset of patients (n = 30) and controls (n = 33). RESULTS: Patients who did not tolerate the psychological stress task and quit had greater acute (t = 2.52 [p = .016] and t = 3.51 [p = .001] at 0 and 20 minutes) and prolonged (t = 3.62 [p = .001] at 40 minutes) cortisol reactivity compared with patients who finished the task. Abnormally prolonged cortisol reactivity in patients was significantly associated with reduced white matter integrity (r = -0.468, p = .009). Regardless of task completion status, acute cortisol response was not related to the white matter measures in patients or controls. CONCLUSIONS: This paradigm was successful at identifying a subset of patients whose cortisol response was associated with brain pathophysiology. Abnormal cortisol response may adversely affect white matter integrity, partly explaining this pathology observed in schizophrenia. Prolonged stress responses may be targeted for intervention to test for protective effects against white matter damages.

Cumulative stress pathophysiology in schizophrenia as indexed by allostatic load.

BACKGROUND: The etiopathophysiology of schizophrenia has long been linked to stress and the influence of stress is important in all stages of the illness. Previous examinations of perceived stress and acute stress responses may not capture this longitudinal stress pathophysiology. We hypothesized that the cumulative negative effects of stress, indexed by allostatic load (AL), would be elevated in schizophrenia, and that the AL paradigm would be relevant to our understanding of pathophysiology in schizophrenia. METHODS: We assessed allostatic load in 30 patients with schizophrenia (SZ; mean age = 33; 17 males) and 20 healthy controls (HC; mean age = 35; 12 males) using 13 cardiovascular, metabolic, neuroendocrine and immune biomarkers. Participants' perceived stress over the past month, functional capacity and psychiatric symptoms were also measured. RESULTS: Controlling for age, SZ had significantly higher AL as compared to HC (p = 0.007). Greater AL was present in both early course and chronic SZ, and was associated with reduced functional capacity (p = 0.006) and more psychotic symptoms (p = 0.048) in SZ. Current level of perceived stress was not significantly elevated in SZ or associated with AL in either group. CONCLUSIONS: The higher AL found in SZ may reflect increased bodily "wear and tear", possibly caused by more chronic stress exposure or maladaptive responses to stress over time, although additional research is required to differentiate these causes. The higher AL is similarly present in early and chronic SZ, suggesting primary maladaptive stress physiology rather than secondary effects from medications or chronic illness.

Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia.

Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient-control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination.

Interrater reliability of the modified Monitoring of Side Effects Scale for assessment of adverse effects of psychiatric medication in clinical and research settings.

The assessment of adverse effects of psychiatric medications is important in clinical and research settings because they are often associated with medication discontinuation, symptom exacerbation, and reduced quality of life. Currently available assessment tools are either limited with regard to the number and variety of included adverse effects or are not practical for use in most clinical or research settings owing to specialized rater training required and administration length. This report describes a modification of the Monitoring of Side Effects Scale (MOSES), an established adverse effect rating scale, by adding severity anchors to improve its reliability and ease of use. Interrater reliability was good for 7 of the 8 bodily adverse effects assessed, with intraclass correlation coefficients ranging from 0.76 to 0.91 in a sample of patients with severe mental illness. This modified version of the Monitoring of Side Effects Scale holds promise as a useful tool for assessing medication adverse effects in clinical and research settings.