The T-cell niche tunes immune function through modulation of the cytoskeleton and TCR-antigen forces.

Obesity is a major public health crisis given its rampant growth and association with an increased risk for cancer. Interestingly, patients with obesity tend to have an increased tumor burden and decreased T-cell function. It remains unclear how obesity compromises T-cell mediated immunity. To address this question, we modeled the adipocyte niche using the secretome released from adipocytes as well as the niche of stromal cells and investigated how these factors modulated T-cell function. We found that the secretomes altered antigen-specific T-cell receptor (TCR) triggering and activation. RNA-sequencing analysis identified thousands of gene targets modulated by the secretome including those associated with cytoskeletal regulation and actin polymerization. We next used molecular force probes to show that T-cells exposed to the adipocyte niche display dampened force transmission to the TCR-antigen complex and conversely, stromal cell secreted factors lead to significantly enhanced TCR forces. These results were then validated in diet-induced obese mice. Importantly, secretome-mediated TCR force modulation mirrored the changes in T-cell functional responses in human T-cells using the FDA-approved immunotherapy, blinatumomab. Thus, this work shows that the adipocyte niche contributes to T-cell dysfunction through cytoskeletal modulation and reduces TCR triggering by dampening TCR forces consistent with the mechanosensor model of T-cell activation.

Turn-key mapping of cell receptor force orientation and magnitude using a commercial structured illumination microscope.

Many cellular processes, including cell division, development, and cell migration require spatially and temporally coordinated forces transduced by cell-surface receptors. Nucleic acid-based molecular tension probes allow one to visualize the piconewton (pN) forces applied by these receptors. Building on this technology, we recently developed molecular force microscopy (MFM) which uses fluorescence polarization to map receptor force orientation with diffraction-limited resolution (~250 nm). Here, we show that structured illumination microscopy (SIM), a super-resolution technique, can be used to perform super-resolution MFM. Using SIM-MFM, we generate the highest resolution maps of both the magnitude and orientation of the pN traction forces applied by cells. We apply SIM-MFM to map platelet and fibroblast integrin forces, as well as T cell receptor forces. Using SIM-MFM, we show that platelet traction force alignment occurs on a longer timescale than adhesion. Importantly, SIM-MFM can be implemented on any standard SIM microscope without hardware modifications.

Live-cell super-resolved PAINT imaging of piconewton cellular traction forces.

Despite the vital role of mechanical forces in biology, it still remains a challenge to image cellular force with sub-100-nm resolution. Here, we present tension points accumulation for imaging in nanoscale topography (tPAINT), integrating molecular tension probes with the DNA points accumulation for imaging in nanoscale topography (DNA-PAINT) technique to map piconewton mechanical events with ~25-nm resolution. To perform live-cell dynamic tension imaging, we engineered reversible probes with a cryptic docking site revealed only when the probe experiences forces exceeding a defined mechanical threshold (~7-21 pN). Additionally, we report a second type of irreversible tPAINT probe that exposes its cryptic docking site permanently and thus integrates force history over time, offering improved spatial resolution in exchange for temporal dynamics. We applied both types of tPAINT probes to map integrin receptor forces in live human platelets and mouse embryonic fibroblasts. Importantly, tPAINT revealed a link between platelet forces at the leading edge of cells and the dynamic actin-rich ring nucleated by the Arp2/3 complex.

Stressful life events and depression symptoms: the effect of childhood emotional abuse on stress reactivity.

OBJECTIVE: Stressful life events are associated with an increase in depressive symptoms and the onset of major depression. Importantly, research has shown that the role of stress changes over the course of depression. The present study extends the current literature by examining the effects of early life stress on emotional reactivity to current stressors. METHOD: In a multiwave study (N = 281, mean age = 18.76; 68% female), we investigated the proximal changes that occur in depressive symptoms when individuals are faced with life stress and whether a history of childhood emotional abuse moderates this relationship. RESULTS: Results support the stress sensitivity hypothesis for early emotional abuse history. Individuals with greater childhood emotional abuse severity experienced greater increases in depressive symptoms when confronted with current dependent stressors, controlling for childhood physical and sexual abuse. CONCLUSIONS: This study highlights the importance of emotional abuse as an indicator for reactivity to stressful life events.

Aggression and impulsivity as predictors of stress generation in bipolar spectrum disorders.

BACKGROUND: Some evidence suggests that individuals with bipolar spectrum disorders (BSD) generate stressful life events, contributing to a more severe course of disorder. A recent update to the Behavioral Approach System (BAS) dysregulation theory of BSD highlights the need to investigate anger as approach motivation. Although research has shown that individuals with BSD generate stress, it is unclear whether personality traits characteristic of BSD, such as aggression and impulsivity, are related to this stress generation. METHODS: The current longitudinal study employed multilevel modeling to examine stress generation in a sample of 104 individuals with BSD and 96 healthy controls. We examined rates of BAS-deactivating, BAS-activating, and Anger-evoking life events over a period of up to 4.5 years as a function of levels of aggression and impulsivity. RESULTS: Individuals with BSD reported significantly higher numbers of dependent Anger-evoking events and BAS-deactivating events, but not dependent BAS-activating events, than controls. Trait levels of hostility and impulsivity predicted all types of events, although bipolar diagnosis remained a significant predictor of BAS-deactivating and Anger-evoking events. LIMITATIONS: The life events measures were not designed to assess Anger-evoking events; further research should replicate these findings and develop more finely tuned assessments of stressful anger events. In addition, the sample was not a clinical sample. CONCLUSIONS: This study adds to the literature on stress generation in BSD; trait level personality differences predict stress generation, beyond bipolar diagnosis. This also further establishes the importance of including anger-evoking events in the BAS model of BSDs and stress generation.

Life events and social rhythms in bipolar spectrum disorders: an examination of social rhythm sensitivity.

OBJECTIVES: To examine the presence of an underlying social rhythm sensitivity in individuals with bipolar spectrum disorders. METHODS: The present study examined the impact of life events on sleep loss and social rhythm disruption in 184 individuals with bipolar spectrum disorders (BSD) compared to 197 demographically similar normal controls (NC) drawn from the Longitudinal Investigation of Bipolar Spectrum Disorders (LIBS) project. Life events data were obtained at three time points, each spaced four months apart, and included information on the intensity of the event (high or low), valence (negative or positive), and levels of sleep loss and social rhythm disruption brought about the event. We hypothesized that BSD participants would exhibit higher levels of social rhythm disruption and sleep loss than normal controls as a consequence of the same life events. RESULTS: BSD participants experienced significantly more social rhythm disruption and sleep loss following all classes of life events. LIMITATIONS: The cross-sectional design of this study limits the strength of the conclusions that can be drawn, primarily cause and effect relationships between social rhythms and symptoms. CONCLUSIONS: Findings support the presence of an underlying social rhythm sensitivity in individuals with bipolar spectrum disorders. An additive effect of sleep loss and social rhythm disruption may contribute to subsequent mood symptomatology. Results from this study may inform early psychosocial interventions for at-risk individuals.

High Behavioral Approach System (BAS) sensitivity, reward responsiveness, and goal-striving predict first onset of bipolar spectrum disorders: a prospective behavioral high-risk design.

A prospective, behavioral high-risk design provided a theoretically guided examination of vulnerability to first onset of bipolar spectrum disorder based on the Behavioral Approach System (BAS) model. Adolescents (ages 14-19) at an "age of risk" for bipolar disorder onset were screened on BAS sensitivity by interviewers blind to current symptoms, lifetime history, and family history of psychopathology. Participants were selected with high versus moderate levels of BAS sensitivity and administered a lifetime diagnostic interview. Those with a bipolar spectrum disorder, psychosis, or hypomanic episode with onset prior to the BAS sensitivity assessment were excluded. High BAS (n = 171) and moderate BAS (n = 119) sensitivity participants in the final sample completed baseline measures of symptoms, goal-setting, and reward responsiveness and were followed prospectively with semistructured diagnostic interviews every 6 months. Consistent with the vulnerability hypothesis of the BAS model of bipolar disorder, high BAS participants had a greater likelihood, and shorter time to onset, of bipolar spectrum disorder than moderate BAS participants across an average of 12.8 months of follow-up (12.9% vs. 4.2%), controlling for baseline depressive and hypomanic symptoms, and family history of bipolar disorder. High reward responsiveness on a behavioral task and ambitious goal-striving for popular fame and financial success (but not impulsivity) also predicted first onset of bipolar spectrum disorder controlling for the covariates and BAS risk group, and ambitious goal-striving partially mediated the BAS risk group effect. We discuss implications of the findings for the BAS model of bipolar disorder and early intervention efforts.

Life stress and kindling in bipolar disorder: review of the evidence and integration with emerging biopsychosocial theories.

Most life stress literature in bipolar disorder (BD) fails to account for the possibility of a changing relationship between psychosocial context and episode initiation across the course of the disorder. According to Post's (1992) influential kindling hypothesis, major life stress is required to trigger initial onsets and recurrences of affective episodes, but successive episodes become progressively less tied to stressors and may eventually occur autonomously. Subsequent research on kindling has largely focused on unipolar depression (UD), and the model has been tested in imprecise and inconsistent ways. The aim of the present paper is to evaluate evidence for the kindling model as it applies to BD. We first outline the origins of the hypothesis, the evidence for the model in UD, and the issues needing further clarification. Next, we review the extant literature on the changing relationship between life stress and bipolar illness over time, and find that evidence from the methodologically strongest studies is inconsistent with the kindling hypothesis. We then integrate this existing body of research with two emerging biopsychosocial models of BD: the Behavioral Approach System dysregulation model, and the circadian and social rhythm theory. Finally, we present therapeutic implications and suggestions for future research.

Generation of life events in bipolar spectrum disorders: a re-examination and extension of the stress generation theory.

The extent to which stress generation occurs in bipolar spectrum disorders (BSD) is not well understood. The present study examined whether 75 BSD participants experienced elevated rates of behavior-dependent life events, as compared with 38 normal control participants. Within the BSD group, we also examined whether depressive or hypomanic symptoms prospectively predicted increases in various types of negative and positive life events. Results indicated that BSD participants experienced overall increases in behavior-dependent events over the follow-up, as compared with normal controls. At the symptom level, the event generation process occurred in more specific event domains. Results suggest that the stress generation theory of unipolar depression can be extended to BSD and that the type of generated events may be polarity-specific.

An experiential avoidance conceptualization of depressive rumination: three tests of the model.

This study examined an experiential avoidance conceptualization of depressive rumination in 3 ways: 1) associations among questionnaire measures of rumination, experiential avoidance, and fear of emotions; 2) performance on a dichotic listening task that highlights preferences for non-depressive material; and 3) psychophysiological reactivity in an avoidance paradigm modeled after the one used by Borkovec, Lyonfields, Wiser, and Deihl (1993) in their examination of worry. One hundred and thirty-eight undergraduates completed questionnaire measures and participated in a clinical interview to diagnose current and past episodes of depression. Of those, 100 were randomly assigned to a rumination or relaxation induction condition and participated in a dichotic listening task, rumination/relaxation induction, and depression induction. Questionnaire measures confirmed a relationship between rumination status and avoidance; however, no significant effects were found in the dichotic listening task. Psychophysiological measures indicated no difference in physiological response to a depression induction among high ruminators (HR). However, low ruminators (LR) in the relaxation condition exhibited a larger IBI response than LR in the rumination condition. Overall, these results provide partial support for an avoidance conceptualization of depressive rumination. Implications of these findings are discussed.

Increased rates of events that activate or deactivate the behavioral approach system, but not events related to goal attainment, in bipolar spectrum disorders.

Research indicates that life events involving goal attainment and goal striving trigger hypomania/mania and that negative life events trigger bipolar depression. These findings are consistent with the behavioral approach system (BAS) dysregulation model of bipolar disorders, which suggests that individuals with bipolar disorders are hypersensitive to cues signaling opportunity for reward and cues signaling failure and loss of rewards. However, no studies to date have investigated whether individuals with bipolar spectrum disorders experience increased rates of these BAS-relevant life events, which would place them at double risk for developing bipolar episodes. The present study found that individuals with bipolar II disorder and cyclothymia experience increased rates of BAS-activating and BAS-deactivating, but not goal-attainment, life events. Finally, for bipolar spectrum individuals only, BAS-activating events predicted BAS-deactivating events' rates.

Stress Generation Research in Depression: A Commentary.

The concept of stress generation is a powerful tool that is consistent with existing cognitive-behavioral theories of depression. In this brief commentary on the literature on stress generation in depression, we highlight several issues that we believe will help to advance the stress generation field. Specifically, we discuss important methodological considerations, issues related to generality and specificity, and theoretical and clinical implications of stress generation. We then address common misperceptions of the stress generation hypothesis. Finally, we end by posing several questions about the mechanisms driving stress generation that should be addressed in future research. Advancing the field's knowledge about stress generation will yield a tangible direction for theory-driven, targeted intervention. Our hope is that this commentary will help to stimulate and frame future research in this exciting area.

Bipolar spectrum-substance use co-occurrence: Behavioral approach system (BAS) sensitivity and impulsiveness as shared personality vulnerabilities.

Bipolar disorders and substance use disorders (SUDs) show high co-occurrence. One explanation for this co-occurrence may be common personality vulnerabilities involved in both. The authors tested whether high behavioral approach system (BAS) sensitivity and impulsiveness are shared personality vulnerabilities in bipolar spectrum disorders and substance use problems and their co-occurrence in a longitudinal study of 132 individuals on the bipolar spectrum and 153 control participants. At Time 1, participants completed the Behavioral Inhibition System/BAS Scales and the Impulsive Nonconformity Scale. Substance use problems were assessed via the Michigan Alcoholism Screening Test and the Drug Abuse Screening Test at 4-month intervals for 1 year. Participants with bipolar disorder had higher rates of lifetime SUDs and substance use problems during the follow-up, relative to control participants. In line with hypotheses, higher BAS sensitivity and impulsiveness predicted bipolar status and increased substance use problems prospectively. BAS total, BAS Fun Seeking, and impulsiveness mediated the association between bipolar spectrum status and prospective substance use problems, with impulsiveness as the most important mediator. High BAS sensitivity and impulsiveness may represent shared personality vulnerabilities for both disorders and may partially account for their co-occurrence.

A "community-friendly" version of integrated group therapy for patients with bipolar disorder and substance dependence: a randomized controlled trial.

BACKGROUND: Integrated group therapy, a new treatment for patients with bipolar disorder and substance use disorder, has previously been found to be efficacious in reducing substance use, but its length (20 sessions) and need for highly trained therapists may limit its adoption in substance use disorder community treatment programs. This paper compares a briefer (12 session) version of integrated group therapy, led by substance use disorder counselors without previous cognitive-behavioral training or bipolar disorder experience, to group drug counseling. METHODS: Sixty-one patients with bipolar disorder and substance dependence, taking mood stabilizers, were randomized to 12 sessions of integrated group therapy (n=31) or group drug counseling (n=30). RESULTS: Analyses of primary outcomes showed trends favoring integrated group therapy, with greater reduction in substance use during follow-up and a greater decline in risk of mood episodes during treatment. Secondary analyses favored integrated group therapy, with a significantly greater likelihood of achieving total abstinence, a significantly shorter time to the first abstinent month, and a significantly greater likelihood of achieving a "good clinical outcome" (a composite measure encompassing both substance use and mood simultaneously). CONCLUSIONS: A shortened version of integrated group therapy can be delivered successfully by substance use disorder counselors, with better overall outcomes than those achieved with group drug counseling.

Depression precipitated by alcohol use in patients with co-occurring bipolar and substance use disorders.

OBJECTIVE: Bipolar disorder and substance use disorder frequently co-occur. However, little is known about the near-term effects of substance use on bipolar disorder. Thus, the present study tests whether alcohol use precipitates depression among patients with co-occurring bipolar disorder and substance use disorder. METHOD: This study uses data collected as part of 2 clinical trials (the first study was conducted from March 1999 through March 2004 and the second study was conducted from August 2003 through May 2007) of a manualized group therapy for patients with co-occurring bipolar disorder and substance dependence. One hundred fifteen participants were assessed at baseline and each month through month 8. Baseline diagnoses were made using the Structured Clinical Interview for DSM-IV, and monthly substance use and mood data were collected using the Longitudinal Interval Follow-Up Evaluation and the Addiction Severity Index. Generalized estimating equation methodology was used to analyze these longitudinal data. RESULTS: Our primary hypotheses were supported: days of alcohol use and an increase in days of alcohol use each significantly predicted the presence of a depressive episode in the subsequent month when controlling for current depression and current drug use. CONCLUSION: These data suggest that alcohol use in patients with bipolar disorder and substance dependence increases the risk of a depressive episode in the near term. TRIAL REGISTRATION: This study draws on data generated during 2 clinical trials. One was exempt from trial registration; clinicaltrials.gov Identifier for other trial: NCT00227838.

Longitudinal Predictors of Bipolar Spectrum Disorders: A Behavioral Approach System (BAS) Perspective.

We review longitudinal predictors, primarily psychosocial, of the onset, course, and expression of bipolar spectrum disorders. We organize our review along a proximal - distal continuum, discussing the most proximal (i.e., prodromes) predictors of bipolar episodes first, then recent environmental (i.e., life events) predictors of bipolar symptoms and episodes next, followed by more distal psychological (i.e., cognitive styles) predictors, and ending with the most distal temperament (i.e., Behavioral Approach System sensitivity) predictors. We then present a theoretical model, the Behavioral Approach System (BAS) dysregulation model, for understanding and integrating the role of these predictors of bipolar spectrum disorders. Finally, we consider the implications of the reviewed longitudinal predictors for future research and psychosocial treatments of bipolar disorders.

Assessment of depressive symptom severity among patients with co-occurring bipolar disorder and substance dependence.

BACKGROUND: We examined a modified version of the Hamilton Depression Rating Scale (HDRS) among treatment-seeking patients with co-occurring bipolar disorder and substance dependence in order to elucidate key features of depression in this specific population of patients. METHODS: Patients with current bipolar disorder and substance dependence who were prescribed mood stabilizers (n=105) completed a 27-item version of the HDRS that was subjected to item and principal components analyses. Preliminary validity analysis consisted of comparing the derived total and component scores to the depressed mood indicators from the Addiction Severity Index (ASI). RESULTS: Eleven items representing two related components labeled "melancholia" and "anxiety" were retained. The 11-item HDRS total and component scores were higher for those who reported serious depression, serious anxiety, cognitive problems, and suicidal ideation on the ASI than for those who did not report these problems. LIMITATIONS: We conducted the analyses with a relatively small sample of patients who were primarily white and were diagnosed with bipolar I disorder, thus limiting the generalizability of findings. Moreover, we obtained limited data regarding construct validity of the 11-item scale. CONCLUSIONS: Our psychometric evaluation of the HDRS led us to retain 11 items representing primarily melancholic and neurovegetative symptoms of depression. These findings suggest that sample-specific item characteristics of the HDRS need to be evaluated prior to using this scale to assess depressive symptom severity among patients with complex diagnostic and treatment characteristics.

Assessing negative consequences in patients with substance use and bipolar disorders: psychometric properties of the short inventory of problems (SIP).

The Short Inventory of Problems (SIP), a questionnaire that measures negative consequences of alcohol use, has not been validated among substance users with co-occurring psychiatric illness. This study examined the psychometric properties of the SIP in 57 outpatients diagnosed with substance use disorder and bipolar disorder. We modified the items to assess drugs in addition to alcohol and, further, we added corresponding items to assess consequences of bipolar disorder. This modified version of the SIP was psychometrically sound, and may be useful in patients with both disorders. A greater understanding of perceived negative consequences may enhance outcome assessment in dually diagnosed populations.