Initial development of tools to identify child abuse and neglect in pediatric primary care.

BACKGROUND: Child abuse and neglect (CAN) is prevalent, associated with long-term adversities, and often undetected. Primary care settings offer a unique opportunity to identify CAN and facilitate referrals, when warranted. Electronic health records (EHR) contain extensive information to support healthcare decisions, yet time constraints preclude most providers from thorough EHR reviews that could indicate CAN. Strategies that summarize EHR data to identify CAN and convey this to providers has potential to mitigate CAN-related sequelae. This study used expert review/consensus and Natural Language Processing (NLP) to develop and test a lexicon to characterize children who have experienced or are at risk for CAN and compared machine learning methods to the lexicon + NLP approach to determine the algorithm's performance for identifying CAN. METHODS: Study investigators identified 90 CAN terms and invited an interdisciplinary group of child abuse experts for review and validation. We then used NLP to develop pipelines to finalize the CAN lexicon. Data for pipeline development and refinement were drawn from a randomly selected sample of EHR from patients seen at pediatric primary care clinics within a U.S. academic health center. To explore a machine learning approach for CAN identification, we used Support Vector Machine algorithms. RESULTS: The investigator-generated list of 90 CAN terms were reviewed and validated by 25 invited experts, resulting in a final pool of 133 terms. NLP utilized a randomly selected sample of 14,393 clinical notes from 153 patients to test the lexicon, and .03% of notes were identified as CAN positive. CAN identification varied by clinical note type, with few differences found by provider type (physicians versus nurses, social workers, etc.). An evaluation of the final NLP pipelines indicated 93.8% positive CAN rate for the training set and 71.4% for the test set, with decreased precision attributed primarily to false positives. For the machine learning approach, SVM pipeline performance was 92% for CAN + and 100% for non-CAN, indicating higher sensitivity than specificity. CONCLUSIONS: The NLP algorithm's development and refinement suggest that innovative tools can identify youth at risk for CAN. The next key step is to refine the NLP algorithm to eventually funnel this information to care providers to guide clinical decision making.

Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance.

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently have proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

How handling extreme C-reactive protein (CRP) values and regularization influences CRP and depression criteria associations in network analyses.

Increasingly, it has been recognized that analysis at the symptom, rather than diagnostic, level will drive progress in the field of immunopsychiatry. Network analysis offers a useful tool in this pursuit with the ability to identify associations between immune markers and individual symptoms, independent of all other variables modeled. However, investigation into how methodological decisions (i.e., including vs. excluding participants with C-reactive protein (CRP) >10 mg/L, regularized vs. nonregularized networks) influence results is necessary to establish best practices for the use of network analysis in immunopsychiatry. In a sample of 3,464 adult participants from the 2015-2016 National Health and Nutrition Examination Survey dataset, this study found consistent support for associations between CRP and fatigue and changes in appetite and some support for additional CRP-criterion associations. Methodologically, results consistently demonstrated that including individuals with CRP >10 mg/L and estimating nonregularized networks provided better estimates of these associations. Thus, we recommend considering the use of nonregularized networks in immunopsychiatry and inclusion of cases with CRP values >10 mg/L when testing the association between CRP and depression criteria, unless contraindicated by the research question being tested. Additionally, results most consistently suggest that CRP is uniquely related to fatigue and changes in appetite, supporting their inclusion in an immunometabolic phenotype of depression. Finally, these associations suggest that fatigue and changes in appetite might be particularly receptive to anti-inflammatory treatments. However, future research with more nuanced measures is necessary to parse out whether appetite increases or decreases drive this association. Further, longitudinal research is an important next step to test how these relationships manifest over time.

Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder.

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: -6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

Acetyl-l-carnitine deficiency in patients with major depressive disorder.

The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.

Executive dysfunction in depression in adolescence: the role of inflammation and higher body mass.

BACKGROUND: There is substantial evidence that many depressed individuals experience impaired executive functioning. Understanding the causes of executive dysfunction in depression is clinically important because cognitive impairment is a substantial contributor to functional impairment. This study investigated whether elevated levels of an inflammatory cytokine [interleukin-6 (IL-6)] and/or higher body mass index (BMI) concurrently and/or prospectively accounted for the relationship between depressive symptoms and impaired executive functioning in adolescents. METHODS: A diverse, community sample of adolescents (N = 288; mean age = 16.33; 51.4% female; 59.0% African-American) completed assessments of height and weight, IL-6, depressive symptoms, and self-report/behavioral measures of executive functioning (selective attention, switching attention) and future orientation annually over 3 years. Adolescents experiencing acute illness or medical conditions that affect inflammation were excluded from analyses. Path analysis within a structural equation modeling framework simultaneously examined the concurrent and prospective relationships between BMI, IL-6, depressive symptoms, and the measures of cognitive functioning across three timepoints. RESULTS: Across all timepoints, higher BMI was prospectively associated with higher levels of IL-6 and depressive symptoms, while higher levels of IL-6 were associated with worse performance on three behavioral and self-report measures of cognitive functioning. Higher depressive symptoms also were prospectively associated with elevated IL-6 and both higher depressive symptoms and a higher BMI predicted worse future executive functioning via increased IL-6. CONCLUSIONS: More severe depressive symptoms and increased BMI may disrupt executive functioning via elevated IL-6.

Longitudinal changes of inflammatory biomarkers moderate the relationship between recent stressful life events and prospective symptoms of depression in a diverse sample of urban adolescents.

This study investigated whether longitudinal changes in inflammatory physiology moderated the relationship between recent stressful life events and subsequent depressive symptoms in adolescence. A diverse sample of adolescents representative of an urban community (N = 129; Age at baseline = 12.5 years; 48.8% female; 55.0% African American) completed measures of stressful life events, depressive symptoms, and two annual blood draws (BD1 and BD2). Controlling for inflammatory activity at BD1, depression at BD1, demographics and the time between assessments, increases in interleukin-6 (IL-6; b = 0.878, p = .007) and C-reactive protein (CRP; b = 0.252, p = .024) from BD1 to BD2 interacted with recent stressful life events before BD1 to predict severity of depressive symptoms at BD2. Similar associations were evident for IL-6 (b = 2.074, p = .040) and CRP (b = 0.919, p = .050) when considering acute stressful life events that had occurred within the two weeks before the first blood collection. More frequent stressful life events before BD1 predicted significantly more severe depressive symptoms at BD2, but only for adolescents with moderate (50th percentile) and high (84th percentile) levels of IL-6 and CRP at BD2. In conclusion, adolescents who experienced both recent stressful life events and larger increases in inflammatory activity following these stressors were at increased risk for more severe depressive symptoms after approximately one year. The findings indicate that the interaction of stress and larger changes in inflammatory activity following these stressors are prognostic risk factors for depression severity in adolescents.

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

Background: Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Methods: Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Results: Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Conclusions: Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).

The role of perceived threat during emergency department cardiac evaluation and the age-posttraumatic stress disorder link.

Evaluation for acute coronary syndrome (ACS) can trigger posttraumatic stress symptoms (PSS). Research suggests that younger, versus older, individuals may be at elevated risk for PSS after ACS evaluation. It has been proposed that younger individuals may be at greater risk because they perceive the suspected ACS event as more threatening than their older counterparts; however, this has yet to be tested. We examined whether perceived threat during ACS evaluation mediated the association between age and PSS after ACS evaluation in an observational cohort study of patients presenting to the emergency department (ED) with suspected ACS. Demographics and perceived threat were assessed in the ED. PSS were measured upon inpatient transfer or by phone 3 days later. The analytic sample comprised 871 adult participants. Multiple linear regression was used to examine (1) associations of age and perceived threat with PSS and (2) whether perceived threat mediated the association. Bootstrapping with percentile-based confidence intervals (CIs) was used to test the indirect effect. Each year of age was associated with lower PSS (b = - 0.12, p < .001), independent of covariates. Older age was associated with lower perceived threat during ACS evaluation (b = - 0.05, p < .001). Greater threat perceptions predicted greater PSS (b = 0.94, p < .0001). The indirect effect (- 0.04) was statistically significant (95% CI - 0.07, - 0.02). Younger, versus older, individuals are at risk for greater PSS after ACS evaluation, and elevated perceived threat partially mediated this association. Understanding age differences in PSS development risk and the potential impact of age on threat perceptions may help inform ED treatment.

Posttraumatic stress disorder due to acute cardiac events and aversive cognitions towards cardiovascular medications.

Posttraumatic stress disorder (PTSD) after acute medical events is associated with medication nonadherence. The mechanisms of PTSD-related nonadherence are poorly understood. We tested whether patients with elevated PTSD symptoms induced by suspected acute coronary syndrome (ACS) were more likely to have aversive cognitions towards cardiovascular medications. We enrolled a consecutive cohort of patients who presented to the emergency department with suspected ACS. One month after discharge, ACS-induced PTSD symptoms were assessed using the PTSD Checklist (PCL-S), and patients were asked "how often did" (1) "you miss your heart medication because you did not want to be reminded about your heart problem"; (2) "thinking about your heart medication make you feel nervous or anxious"; and (3) "thinking about your heart medication make you think about your risk for future heart problems." Logistic regression was used to determine the association between elevated PTSD symptoms and each aversive cognition, adjusting for age, sex, race, ethnicity, education, depression, and ACS status. Of 424 patients included, 15.8% had elevated PTSD symptoms (PCL-S ≥ 34). In adjusted analyses, higher PCL-S scores were associated with missing medications to avoid reminders of heart disease (OR 1.22 per 5-point PCL-S increase, 95%CI 1.07-1.40), as well as anxiety (OR 1.34, 95%CI 1.19-1.51) and thoughts of future risk (OR 1.19, 95%CI 1.08-1.32) when thinking about cardiovascular medications. We concluded that patients with elevated PTSD symptoms following suspected ACS were more likely to report aversive cognitions about their cardiovascular medications, suggesting that medications can act as traumatic reminders of the cardiac event and ongoing risk in this group.

Chronic inflammation is associated with worsening working memory performance: Preliminary evidence from a diverse, longitudinal cohort of adolescents and young adults.

Many depressed individuals experience cognitive difficulties that persist when depression is in remission. Inflammation is hypothesized to play a role in cognitive dysfunction in depression; however, many aspects of this relationship are not well characterized. The current study examined whether inflammation is associated with specific cognitive deficits in individuals with a history of depression and with progressively worsening working memory over time. Adolescents who participated in a prospective, longitudinal study of adolescent-onset depression were recruited to complete a follow-up cognitive assessment. The sample was comprised of 82 participants (52.4% female; 37.8% white; 42.7% low socioeconomic status) who were aged 22.61 years (SD = 1.50) at the time of the follow-up cognitive assessment. Prior to the follow-up cognitive assessment, they had completed an average of 6.24 (SD = 1.80) prior annual assessments over 6.24 years (SD = 2.08) as part of the parent longitudinal study in which C-reactive protein (CRP), depressive symptoms, and working memory were assessed repeatedly. First, using linear regression, we tested whether individuals exhibiting inflammation (CRP ≥3 mg/L) at multiple timepoints and a history of likely depression (Children's Depression Inventory ≥19) exhibited differentially worse executive functioning, episodic memory, or psychomotor speed. Second, using hierarchical linear modeling, we tested whether the combination of inflammation and likely past depression was associated with poorer working memory over time. Chronic inflammation was associated with worsening working memory over time, but no significant associations were observed in cross-sectional analyses. These preliminary data indicate that chronic inflammation may lead to progressive decline in working memory over time.

Measures of Suicidal Thoughts and Behaviors in Children and Adolescents: A Systematic Review and Recommendations for Use in Clinical and Research Settings.

Empirically supported measures of suicidal thoughts and behaviors (STBs) are needed to serve as reference outcomes for suicide risk screening tools and to monitor severity and treatment progress in children and adolescents with STBs. The present paper systematically reviewed existing measures of STBs in youth and studies evaluating their psychometric properties and clinical utility. Measures were then evaluated on reliability, validity, and clinical utility. Sixteen articles (20 independent samples) were found with psychometric data with youth samples for eight measures. Interview-based measures were found to have the strongest psychometric support and clinical utility. Significant limitations exist for all self-report measures due to inherent characteristics of these measures that cannot be remedied through additional psychometric study. There is an urgent need for the development and validation of new self-report measures of STBs, particularly for preadolescent children, sexual and gender minority youth, and racial/ethnic minority youth.

The Impact of Early and Recent Life Stress on Trajectories of Inflammatory Biomarkers in a Diverse Sample of Adolescents.

Elevated inflammatory activity is one possible pathway through which exposure to childhood adversity engenders risk for physical and psychiatric illnesses. Limited research has investigated the compounding effects of childhood and adolescent stress exposure on changes in circulating levels of inflammatory biomarkers. This study assessed whether childhood adversity interacted with chronic or acute stress during adolescence to affect the temporal trajectories of five inflammatory biomarkers across at least three blood draws in a diverse sample of adolescents (N = 134; observations = 462). Using multilevel modeling, the interaction of childhood adversity, time, and within-person variance of acute stressors significantly predicted trajectories of higher interleukin-10 levels, controlling for demographics, medication use, and body mass index. Adolescents with high levels of childhood adversity who were exposed to a higher frequency of acute stressors compared to their own average rate of stress exposure consistently had higher levels of IL-10 as they got older, but those with average and below frequency of acute stressors had decreasing trajectories of log IL-10 as they matured. The results demonstrate how events early in life shape biological responses to the adolescent environment. This study also highlights the importance of developmental timing on the body's enhanced reactivity to acute and sustained stressors following childhood adversity.

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder.

Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures. Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.Reprinted from Am J Psychiatry 2021; 178:193-202, with permission from American Psychiatric Association Publishing. Copyright © 2021.

Stress-related reduction of hippocampal subfield volumes in major depressive disorder: A 7-Tesla study.

Background: Major depressive disorder (MDD) is a prevalent health problem with complex pathophysiology that is not clearly understood. Prior work has implicated the hippocampus in MDD, but how hippocampal subfields influence or are affected by MDD requires further characterization with high-resolution data. This will help ascertain the accuracy and reproducibility of previous subfield findings in depression as well as correlate subfield volumes with MDD symptom scores. The objective of this study was to assess volumetric differences in hippocampal subfields between MDD patients globally and healthy controls (HC) as well as between a subset of treatment-resistant depression (TRD) patients and HC using automatic segmentation of hippocampal subfields (ASHS) software and ultra-high field MRI. Methods: Thirty-five MDD patients and 28 HC underwent imaging using 7-Tesla MRI. ASHS software was applied to the imaging data to perform automated hippocampal segmentation and provide volumetrics for analysis. An exploratory analysis was also performed on associations between symptom scores for diagnostic testing and hippocampal subfield volumes. Results: Compared to HC, MDD and TRD patients showed reduced right-hemisphere CA2/3 subfield volume (p = 0.01, η 2 = 0.31 and p = 0.3, η 2 = 0.44, respectively). Additionally, negative associations were found between subfield volumes and life-stressor checklist scores, including left CA1 (p = 0.041, f 2 = 0.419), left CA4/DG (p = 0.010, f 2 = 0.584), right subiculum total (p = 0.038, f 2 = 0.354), left hippocampus total (p = 0.015, f 2 = 0.134), and right hippocampus total (p = 0.034, f 2 = 0.110). Caution should be exercised in interpreting these results due to the small sample size and low power. Conclusion: Determining biomarkers for MDD and TRD pathophysiology through segmentation on high-resolution MRI data and understanding the effects of stress on these regions can enable better assessment of biological response to treatment selection and may elucidate the underlying mechanisms of depression.

Examining momentary associations between behavioral approach system indices and nonsuicidal self-injury urges.

BACKGROUND: The current study aimed to examine the concurrent and prospective relationships between the three hypothesized components of behavioral approach system (BAS) sensitivity: drive, reflecting the motivation to pursue one's desired goals; reward responsiveness, reflecting sensitivity to reward or reinforcement; and fun-seeking, reflecting the motivation for pursuing novel rewards in a spontaneous manner, and NSSI urge severity. METHODS: A sample of 64 undergraduates with a history of repetitive NSSI completed an ecological momentary assessment protocol. During this period of time, participants reported on the BAS-constructs of drive, reward responsiveness, and fun-seeking, as well as NSSI urge severity on a momentary basis at three random intervals each day for a period of ten-days. RESULTS: Drive and reward responsiveness, but not fun-seeking, were concurrently positively associated with NSSI urge severity. However, no associations between BAS facets and prospective NSSI urges were found. LIMITATIONS: This study was limited by its use of single items to assess the BAS-constructs of drive, reward responsiveness, and fun-seeking. CONCLUSIONS: Our findings indicate that feeling strongly impacted by rewards and having a strong sense of drive toward goal attainment may represent cognitive risk states that are associated with increased within-person NSSI risk. However, their lack of prospective prediction may suggest that these cognitive states are associated only on a momentary basis with NSSI urges and may not confer risk.

Protocol for project MIME: Motivation, inflammation, and Mood in Emerging Adults.

Background: Atypical inflammatory biology is gaining evidence as a risk factor for mood psychopathology; however, little work has attempted to integrate inflammation into extant psychosocial frameworks of risk. Recent work using secondary data analysis has investigated the possibility of an immunocognitive model of mood disorders, in which cognitive vulnerabilities (i.e., rumination on positive or negative affect) increase the effect that arousal-related characteristics (e.g., reward sensitivity) have on inflammatory biology in ways that may confer risk for depression and hypo/mania symptoms. Project MIME (Motivation, Inflammation, and Mood in Emerging Adults) was designed to test this model in the context of a novel, reward-salient stressor (the Anger Incentive Delay Task, AIDT). Methods: This NIMH-funded study will result in a dataset of approximately 100 college undergraduates from a large university in Pennsylvania, United States of America. Eligible participants are recruited from an online screener, have to be 18-22 years old, fluent in English, and successfully answer several items designed to test whether participants randomly answer questions on the screener. Eligible participants are invited to an in-person visit in which they completed the AIDT, blood draws pre- and 50 minutes post-AIDT, and self-report questionnaires. Participants also complete a set of online questionnaires two weeks after the in-person visit. Discussion: Consistent with calls from the NIH director, this study seeks to diversify the tools used in stress research by validating a novel reward-salient stressor (in contrast to the field's reliance on social stressors) with respect to affective and immunological stress reactivity. In addition to this methodological goal, Project MIME is the first study specifically designed to test the immunocognitive model of mood psychopathology. Given the integration of several malleable treatment targets (approach behavior, emotion regulation, inflammation) into this model, results from this study could inform comprehensive, flexible intervention strategies for mood disorder prevention and treatment.

Sleep irregularity and nonsuicidal self-injurious urges and behaviors.

STUDY OBJECTIVES: The objectives of this study were to examine the relationships between sleep regularity and nonsuicidal self-injury (NSSI), including lifetime NSSI history and daily NSSI urges. METHODS: Undergraduate students (N = 119; 18-26 years), approximately half of whom endorsed a lifetime history of repetitive NSSI, completed a 10-day actigraphy and ecological momentary assessment (EMA) protocol. A Sleep Regularity Index was calculated for all participants using scored epoch by epoch data to capture rapid changes in sleep schedules. Participants responded to EMA prompts assessing NSSI urge severity and negative affect three times daily over the 10-day assessment period. RESULTS: Results indicate that individuals with a repetitive NSSI history were more likely to experience sleep irregularity than those without a history of NSSI. Findings also suggest that sleep irregularity was associated with more intense urges to engage in NSSI on a daily basis, even after accounting for average daily sleep duration, sleep timing, negative affect, and NSSI history. Neither sleep duration nor sleep timing was associated with NSSI history nor daily NSSI urge intensity. CONCLUSIONS: Findings suggest that sleep irregularity is linked with NSSI, including NSSI history and intensity of urges to engage in NSSI. The present study not only supports the growing evidence linking sleep disturbance with the risk for self-injury but also demonstrates this relationship using actigraphy and real-time assessments of NSSI urge severity. Findings highlight the importance of delineating the nuances in sleep irregularity that are proximally associated with NSSI risk and identifying targets for intervention.

Residence in High-Crime Neighborhoods Moderates the Association Between Interleukin 6 and Social and Nonsocial Reward Brain Responses.

BACKGROUND: Residence in high-crime neighborhoods, especially in childhood, is linked to mental health issues later. Detecting distinct neurobiological processes underlying the effects of this environmental stressor may be critical to identifying prevention and intervention targets. This study examined the relationships of levels of a circulating inflammatory protein with social and monetary reward-related brain function among adolescents who lived in high- versus low-crime neighborhoods during childhood. METHODS: A total of 70 participants (mean age = 16.3 years; 57% female) completed measures of inflammatory markers, depression history, and health and 2 functional magnetic resonance imaging tasks assessing responsivity to monetary and social rewards. Multivariate linear regression tested whether individuals with higher interleukin 6, an inflammatory cytokine, who also lived in neighborhoods with higher crime had distinct orbitofrontal cortex and nucleus accumbens activation to monetary reward and social acceptance. RESULTS: For adolescents who lived in neighborhoods with more crime, higher interleukin 6 was associated with higher nucleus accumbens responses to social acceptance. We did not detect significant moderating effects of neighborhood crime rates on the associations of interleukin 6 with orbitofrontal cortex responses to social acceptance or orbitofrontal cortex/nucleus accumbens activation during monetary reward anticipation or outcome. These results were obtained before and after adjusting for neighborhood income and other covariates. We did not detect significant moderating effects of neighborhood income. CONCLUSIONS: High-threat residence environment and specific demands of the social context in childhood may have shaped the effect of peripheral immune activation on reward-related neural function in adolescence. The prevailing view that inflammation-associated behaviors are characterized by blunted responsiveness to reward may be oversimplistic.

Applications of psychoneuroimmunology models of toxic stress in prevention and intervention efforts across early development.

Although evidence supporting psychoneuroimmunology (PNI) models of toxic stress have emerged over the past decade, the PNI field has struggled to integrate these important findings into real-world practical applications. There is great potential for these models to reduce the societal burden of childhood adversity by facilitating early detection and prevention with those children and adolescents at greatest risk for stress-related physical and psychological disorders. But further research is needed to validate and scale developmentally appropriate interventions with specific immune and endocrine mechanism-based targets that are developmentally sensitive. The allostatic load and additive PNI models of toxic stress exposure in youth are summarized. These models highlight the importance of integrating a standardized screening of environmental and interpersonal risk factors with stable and scalable cognitive and biological markers of risk. PNI models of toxic stress illustrate the need for intervention delivery as early as possible to prevent negative health outcomes in youth and comprehensive screening efforts would facilitate the deployment of community and family level interventions. This review discusses practical applications of toxic stress models that are currently under investigation, clarifies key obstacles, such as research gaps and scalability, and provides potential solutions, including cross-disciplinary partnerships.