Measuring morality: Analyzing the factor structure of the moral foundations questionnaire in veterans.

OBJECTIVES: Moral reasoning is an underexamined and potentially useful area of research relative to the care of moral injury in veterans. However, the most widely used measure of moral reasoning, the moral foundations questionnaire (MFQ), has not been validated in this population. METHODS: Post-9/11 veterans (N = 311) completed questionnaires which included the MFQ. Veterans' scores were compared to the general US population. Confirmatory factor analysis was used to test existing models of the MFQ in the sample. Exploratory factor analysis (EFA) was also used to examine potentially improved model fits. RESULTS: The two leading, preexisting MFQ models were both poor fits for the data. EFA results produced a four-factor model for the veteran sample using 25 of the original 30 items of the MFQ. CONCLUSIONS: Measuring moral reasoning among veterans may be important in understanding the experience of moral injury. However, the most widely used scale (MFQ) performs poorly among a sample of post-9/11 veterans, indicating that veterans may respond differently to the measure than the general US population. Military culture may uniquely influence veterans' moral reasoning, suggesting the need for military specific measures for this construct.

Exploring Potential Carcinogenic Activity of Per- and Polyfluorinated Alkyl Substances Utilizing High-Throughput Toxicity Screening Data.

Per- and polyfluorinated alkyl substances (PFAS) are ubiquitous, persistent, and toxic chemicals that pose public health risks. Recent carcinogenicity concerns have arisen based on epidemiological studies, animal tumor findings, and mechanistic data. Thousands of PFAS exist; however, current understanding of their toxicity is informed by studies of a select few, namely, perfluorooctanoic acid and perfluorooctanesulfonic acid. Hence, the computational, high-throughput screening tool, the US EPA CompTox Chemical Dashboard's ToxCast, was utilized to explore the carcinogenicity potential of PFAS. Twenty-three major PFAS that had sufficient in vitro ToxCast data and covered a range of structural subclasses were analyzed with the visual analytics software ToxPi, yielding a qualitative and quantitative assessment of PFAS activity in realms closely linked with carcinogenicity. A comprehensive literature search was also conducted to check the consistency of analyses with other mechanistic data streams. The PFAS were found to induce a vast range of biological perturbations, in line with several of the International Agency for Research on Cancer-defined key carcinogen characteristics. Patterns observed varied by length of fluorine-bonded chains and/or functional group within and between each key characteristic, suggesting some structure-based variability in activity. In general, the major conclusions drawn from the analysis, that is, the most notable activities being modulation of receptor-mediated effects and induction of oxidative stress, were supported by literature findings. The study helps enhance understanding of the mechanistic pathways that underlie the potential carcinogenicity of various PFAS and hence could assist in hazard identification and risk assessment for this emerging and relevant class of environmental toxicants.

Distress tolerance among substance users is associated with functional connectivity between prefrontal regions during a distress tolerance task.

Distress tolerance (DT), defined as the ability to persist in goal directed behavior while experiencing affective distress, is implicated in the development and maintenance of substance use disorders. While theory and evidence indicate that cortico-limbic neural dysfunction may account for deficits in goal directed behavior while experiencing distress, the neurobiological mechanisms of DT have yet to be examined. We modified a computerized DT task for use in functional magnetic resonance imaging (fMRI), the Paced Auditory Serial Addition Task (PASAT-M), and examined the neural correlates and functional connectivity of DT among a cohort of substance users (n = 21; regular cocaine and nicotine users) and healthy controls (n = 25). In response to distress during the PASAT-M, we found greater activation in a priori cortico-limbic network ROIs, namely the right insula, anterior cingulate cortex (ACC), bilateral medial frontal gyrus (MFG), right inferior frontal gyrus (IFG) and right ventromedial prefrontal cortex (vmPFC) significantly predicted higher DT among substance users, but not healthy controls. In addition, greater task-specific functional connectivity during distress between the right MFG and bilateral vmPFC/sgACC was associated with higher DT among substance users, but not healthy controls. The observed positive relationship between DT and neural activation in cortico-limbic structures, as well as functional connectivity between the rMFG and vmPFC/sgACC, is in line with theory and research suggesting the importance of these structures for persisting in goal directed behavior while experiencing affective distress.

Parametric modulation of neural activity during face emotion processing in unaffected youth at familial risk for bipolar disorder.

OBJECTIVES: Both patients with pediatric bipolar disorder (BD) and unaffected youth at familial risk (AR) for the illness show impairments in face emotion labeling. Few studies, however, have examined brain regions engaged in AR youth when processing emotional faces. Moreover, studies have yet to explore neural responsiveness to subtle changes in face emotion in AR youth. METHODS: Sixty-four unrelated youth, including 20 patients with BD, 15 unaffected AR youth, and 29 healthy comparisons (HC), completed functional magnetic resonance imaging. Neutral faces were morphed with angry or happy faces in 25% intervals. In specific phases of the task, youth alternatively made explicit (hostility) or implicit (nose width) ratings of the faces. The slope of blood oxygenated level-dependent activity was calculated across neutral to angry and neutral to happy face stimuli. RESULTS: Behaviorally, both subjects with BD (p ≤ 0.001) and AR youth (p ≤ 0.05) rated faces as less hostile relative to HC. Consistent with this, in response to increasing anger on the face, patients with BD and AR youth showed decreased modulation in the amygdala and inferior frontal gyrus (IFG; BA 46) compared to HC (all p ≤ 0.05). Amygdala dysfunction was present across both implicit and explicit rating conditions, but IFG modulation deficits were specific to the explicit condition. With increasing happiness, AR youth showed aberrant modulation in the IFG, which was also sensitive to task demands (all p ≤ 0.05). CONCLUSIONS: Decreased amygdala and IFG modulation in patients with BD and AR youth may be pathophysiological risk markers for BD, and may underlie the social cognition and face emotion labeling deficits observed in BD and AR youth.

Nerve Bundle Density and Expression of NGF and IL-1ß Are Intra-Individually Heterogenous in Subtypes of Endometriosis.

Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin-1ß (IL-1ß). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes of endometriosis (deep, superficial peritoneal, endometrioma) at surgery, with at least two surgically excised subtypes available for analysis. Immunolocalization for nerve bundle density around endometriosis using protein gene product 9.5 (PGP9.5), as well as NGF and IL-1ß histoscores in endometriosis epithelium/stroma, was performed to evaluate differences in scores between lesions and anatomic subtypes per patient. Intra-individual heterogeneity in scores across lesions was assessed using the coefficient of variation (CV). The degree of score variability between subtypes was evaluated using the percentage difference between mean scores from one subtype to another subtype for each marker. PGP9.5 nerve bundle density was heterogenous across multiple subtypes of endometriosis, ranging from 50.0% to 173.2%, where most patients (8/12) showed CV ≥ 100%. The percentage difference in scores showed that PGP9.5 nerve bundle density and NGF and IL-1ß expression were heterogenous between anatomic subtypes within the same patient. Based on these observations of intra-individual heterogeneity, we conclude that markers of neuroproliferation in endometriosis should be stratified by anatomic subtype in future studies of clinical correlation.

Characterizing the consensus residue specificity and surface of BCL-2 binding to BH3 ligands using the Knob-Socket model.

Cancer cells bypass cell death by changing the expression of the BCL-2 family of proteins, which are apoptotic pathway regulators. Upregulation of pro-survival BCL-2 proteins or downregulation of cell death effectors BAX and BAK interferes with the initiation of the intrinsic apoptotic pathway. In normal cells, apoptosis can occur through pro-apoptotic BH3-only proteins interacting and inhibiting pro-survival BCL-2 proteins. When cancer cells over-express pro-survival BCL-2 proteins, a potential remedy is the sequestration of these pro-survival proteins through a class of anti-cancer drugs called BH3 mimetics that bind in the hydrophobic groove of pro-survival BCL-2 proteins. To improve the design of these BH3 mimetics, the packing interface between BH3 domain ligands and pro-survival BCL-2 proteins was analyzed using the Knob-Socket model to identify the amino acid residues responsible for interaction affinity and specificity. A Knob-Socket analysis organizes all the residues in a binding interface into simple 4 residue units: 3-residue sockets defining surfaces on a protein that pack a 4th residue knob from the other protein. In this way, the position and composition of the knobs packing into sockets across the BH3/BCL-2 interface can be classified. A Knob-Socket analysis of 19 BCL-2 protein and BH3 helix co-crystals reveal multiple conserved binding patterns across protein paralogs. Conserved knob residues such as a Gly, Leu, Ala and Glu most likely define binding specificity in the BH3/BCL-2 interface, whereas other residues such as Asp, Asn, and Val are important for forming surface sockets that bind these knobs. These findings can be used to inform the design of BH3 mimetics that are specific to pro-survival BCL-2 proteins for cancer therapeutics.

Group behavioral activation with and without a smartphone app in intensive outpatient treatment for substance use disorder: A three-arm randomized controlled trial.

INTRODUCTION: Reward deficits negatively impact recovery from substance use disorder (SUD). LETS ACT, a behavioral activation treatment targeting substance-free reward, has demonstrated effectiveness in reducing post treatment substance use. There remains room for modifications to extend recovery gains, and LETS ACT remains largely untested in outpatient treatment. We tested the effect of LETS ACT when delivered alongside intensive outpatient SUD treatment, with and without a smartphone app designed to extend access to treatment content outside of clinician-administered sessions. METHODS: In this three-arm randomized controlled trial (N = 206; 54 % White, 67 % male), all participants received intensive outpatient SUD treatment as usual (TAU) and either LETS ACT (n = 56), smartphone-enhanced LETS ACT (n = 65), or assessments only (n = 61). Substance use days and substance related problems were assessed through 12 months posttreatment. RESULTS: Generalized estimating equations indicated a significant condition*time interaction for substance use days; Days of substance use significantly declined from pretreatment until 1-month for TAU, 3-months for LETS ACT-SE, and 6-months for LETS ACT. Decreases in substance-related problems were maintained across all conditions through 12 months. CONCLUSIONS: Adding LETS ACT to intensive outpatient treatment resulted in significant decreases in substance use through 6 months posttreatment, yet these gains were not sustained through 12 months posttreatment. A smartphone app did not facilitate superior treatment outcomes. Future studies should consider factors impacting treatment efficacy in outpatient settings and the utility of providing more than six sessions of behavioral activation.

Flavonoid-based inhibition of cyclin-dependent kinase 9 without concomitant inhibition of histone deacetylases durably reinforces HIV latency.

While combination antiretroviral therapy (cART) durably suppresses HIV replication, virus persists in CD4+ T-cells that harbor latent but spontaneously inducible and replication-competent provirus. One strategy to inactivate these viral reservoirs involves the use of agents that continue to reinforce HIV latency even after their withdrawal. To identify new chemical leads with such properties, we investigated a series of naturally-occurring flavones (chrysin, apigenin, luteolin, and luteolin-7-glucoside (L7G)) and functionally-related cyclin dependent kinase 9 (CDK9) inhibitors (flavopiridol and atuveciclib) which are reported or presumed to suppress HIV replication in vitro. We found that, while all compounds inhibit provirus expression induced by latency-reversing agents in vitro, only aglycone flavonoids (chrysin, apigenin, luteolin, flavopiridol) and atuveciclib, but not the glycosylated flavonoid L7G, inhibit spontaneous latency reversal. Aglycone flavonoids and atuveciclib, but not L7G, also inhibit CDK9 and the HIV Tat protein. Aglycone flavonoids do not reinforce HIV latency following their in vitro withdrawal, which corresponds with their ability to also inhibit class I/II histone deacetylases (HDAC), a well-established mechanism of latency reversal. In contrast, atuveciclib and flavopiridol, which exhibit little or no HDAC inhibition, continue to reinforce latency for 9 to 14+ days, respectively, following their withdrawal in vitro. Finally, we show that flavopiridol also inhibits spontaneous ex vivo viral RNA production in CD4+ T cells from donors with HIV. These results implicate CDK9 inhibition (in the absence of HDAC inhibition) as a potentially favorable property in the search for compounds that durably reinforce HIV latency.

Alpha-tACS effect on inhibitory control and feasibility of administration in community outpatient substance use treatment.

BACKGROUND: Deficits in inhibitory control (IC) and distress tolerance (DT) are associated with substance use disorders (SUD) and post-treatment return to substance use. Transcranial alternating current stimulation (tACS) modulates the neural oscillations that are associated with the cognitive and affective mechanisms contributing to IC and DT. The aims of the current study were to examine the feasibility and acceptability of administering tACS in a community-based SUD treatment setting, and to test the effect of alpha-tACS on IC and DT. METHOD: A double-blind, randomized, active sham-controlled trial of treatment-seeking adults with a SUD (N = 30, Meanage = 43.2 years, 70.0% male). Participants attended two sessions and completed computerized inhibitory control and distress tolerance tasks while receiving tACS targeting the bilateral dorsolateral prefrontal cortex (DLPFC). Participants received sham-tACS and were then randomized to receive sham-, alpha-, or gamma-tACS within 2-3 days. RESULTS: Treatment retention was 87%. Participant self-reported belief of having received tACS and mean side effect intensity ratings did not differ across conditions, with all side effect ratings in the absent to mild range. There was a large (d = 0.83) and significant effect of alpha-tACS on inhibitory control compared to sham-tACS (ß = 1.78, SE = 0.65, 95 % CI: 0.41, 3.14, p<0.01). There were no significant effects of condition on distress tolerance. CONCLUSIONS: To our knowledge, this is the first study of tACS in adults with a SUD. Our findings provide preliminary evidence for recruitment, retention, and administration feasibility of tACS in a community-based substance use treatment program and a beneficial effect of alpha-tACS on inhibitory control.

Triple Network Resting State Connectivity Predicts Distress Tolerance and Is Associated with Cocaine Use.

Distress tolerance (DT), a predictor of substance use treatment retention and post-treatment relapse, is associated with task based neural activation in regions located within the salience (SN), default mode (DMN), and executive control networks (ECN). The impact of network connectivity on DT has yet to be investigated. The aim of the present study was to test within and between network resting-state functional connectivity (rsFC) associations with DT, and the impact of cocaine use on this relationship. Twenty-nine adults reporting regular cocaine use (CU) and 28 matched healthy control individuals (HC), underwent resting-state functional magnetic resonance imaging followed by the completion of two counterbalanced, computerized DT tasks. Dual-regression analysis was used to derive within and between network rsFC of the SN, DMN, and lateralized (left and right) ECN. Cox proportional-hazards survival models were used to test the interactive effect of rsFC and group on DT. The association between cocaine use severity, rsFC, and DT was tested within the CU group. Lower LECN and higher DMN-SN rsFC were associated with DT impairment. Greater amount of cocaine use per using day was associated with greater DMN-SN rsFC. The findings emphasize the role of neural resource allocation within the ECN and between DMN-SN on distress tolerance.

Why do trauma survivors become depressed? Testing the behavioral model of depression in a nationally representative sample.

Despite accumulated evidence linking trauma exposure to major depressive disorder (MDD), there is limited understanding as to why some trauma survivors subsequently develop MDD. The behavioral model of depression points to a negative reinforcement cycle of trauma-related avoidance and depressed mood, but no study has evaluated this framework in trauma survivors. This study tested the hypothesis that traumatic stress symptom-related interference with daily activities and with relationships and self-medicating traumatic stress symptoms with alcohol and with drugs would predict MDD onset in a nationally representative sample after controlling for established risk factors. Data were drawn from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) using two samples: adults reporting lifetime trauma exposure but no history of MDD at Wave 1 (n = 8301) and a subset of those participants who met criteria for lifetime PTSD prior to Wave 1 (n = 1055). Younger age, female gender, a greater number of different trauma types, traumatic stress-related interference with daily activities, and self-medicating traumatic stress symptoms with alcohol significantly predicted MDD onset in both groups. Findings underscore the role of traumatic stress-related interference and self-medication in the development of MDD.

Neural reward response to substance-free activity images in opiate use disorder patients with depressive symptoms.

BACKGROUND: Deficits in the ability to experience reward from natural, substance-free activities and stimuli is a common mechanism contributing to both opiate use disorder and depressive symptoms, and is a target of behavioral-focused treatments for substance use and depression. Although the neural response to monetary, positive affect-eliciting and social images has been investigated, the neural response to images representing substance-free activity engagement remains untested. The current study tested the neural response to anticipation and receipt of substance-free activity engagement images and monetary reward in opiate use disorder patients with elevated depressive symptoms compared to healthy controls. METHODS: Sixteen male opiate use disorder detoxification patients with elevated depressive symptoms (Beck Depression Inventory (BDI-II) ≥ 14) (OUDD Mage = 32.19 years, SD = 8.17 years) and seventeen male healthy controls (BDI-II < 14) (HC: Mage = 26.82 years, SD = 5.29 years) completed the Monetary Incentive Delay (MID) and newly developed Activity Incentive Delay (AID) tasks. Within- and between-group whole-brain contrasts tested activation during anticipation ([reward]-[non-reward]) and receipt ([win]-[non-win]) of substance-free activity image, monetary, and substance-free activity relative to monetary (AID-MID), reward. RESULTS: OUDD demonstrated significantly lower activation in reward regions during anticipation and significantly greater activation during receipt of substance-free activity image reward compared to HC. OUDD demonstrated significantly lower activation during anticipation of substance-free activity reward relative to monetary reward, compared to HC. CONCLUSIONS: The observed reduction in frontostriatal response to reward anticipation of substance-free activity engagement images in OUDD, yet increased neural response to reward receipt, supports theory linking reductions in reward processing with deficits in motivation for substance-free activity engagement.

Brain Mechanisms of Attention Orienting Following Frustration: Associations With Irritability and Age in Youths.

OBJECTIVE: Childhood irritability is a common, impairing problem with changing age-related manifestations that predict long-term adverse outcomes. However, more investigation of overall and age-specific neural correlates is needed. Because youths with irritability exhibit exaggerated responses to frustrating stimuli, the authors used a frustration functional MRI (fMRI) paradigm to examine associations between irritability and neural activation and tested the moderating effect of age. METHOD: The authors studied a transdiagnostic sample of 195 youths with varying levels of irritability (disruptive mood dysregulation disorder, N=52; anxiety disorder, N=42; attention deficit hyperactivity disorder, N=40; and healthy volunteers, N=61). Irritability was measured by parent and child reports on the Affective Reactivity Index. The fMRI paradigm was a cued-attention task differentiating neural activity in response to frustration (rigged feedback) from activity during attention orienting in the trial following frustration. RESULTS: Whole-brain activation analyses revealed associations with irritability during attention orienting following frustration. Irritability was positively associated with frontal-striatal activation, specifically in the dorsolateral prefrontal cortex, inferior frontal gyrus, and caudate. Age moderated the association between irritability and activation in some frontal and posterior regions (the anterior cingulate cortex, medial frontal gyrus, cuneus, precuneus, and superior parietal lobule [F=19.04-28.51, df=1, 189, partial eta squared=0.09-0.13]). Specifically, higher irritability was more strongly related to increased activation in younger youths compared with older youths. CONCLUSIONS: Following frustration, levels of irritability correlated with activity in neural systems mediating attention orienting, top-down regulation of emotions, and motor execution. Although most associations were independent of age, dysfunction in the anterior cingulate cortex and posterior regions was more pronounced in young children with irritability.

Association of Irritability and Anxiety With the Neural Mechanisms of Implicit Face Emotion Processing in Youths With Psychopathology.

IMPORTANCE: Psychiatric comorbidity complicates clinical care and confounds efforts to elucidate the pathophysiology of commonly occurring symptoms in youths. To our knowledge, few studies have simultaneously assessed the effect of 2 continuously distributed traits on brain-behavior relationships in children with psychopathology. OBJECTIVE: To determine shared and unique effects of 2 major dimensions of child psychopathology, irritability and anxiety, on neural responses to facial emotions during functional magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional functional magnetic resonance imaging study in a large, well-characterized clinical sample at a research clinic at the National Institute of Mental Health. The referred sample included youths ages 8 to 17 years, 93 youths with anxiety, disruptive mood dysregulation, and/or attention-deficit/hyperactivity disorders and 22 healthy youths. MAIN OUTCOMES AND MEASURES: The child's irritability and anxiety were rated by both parent and child on the Affective Reactivity Index and Screen for Child Anxiety Related Disorders, respectively. Using functional magnetic resonance imaging, neural response was measured across the brain during gender labeling of varying intensities of angry, happy, or fearful face emotions. In mixed-effects analyses, the shared and unique effects of irritability and anxiety were tested on amygdala functional connectivity and activation to face emotions. RESULTS: The mean (SD) age of participants was 13.2 (2.6) years; of the 115 included, 64 were male. Irritability and/or anxiety influenced amygdala connectivity to the prefrontal and temporal cortex. Specifically, irritability and anxiety jointly influenced left amygdala to left medial prefrontal cortex connectivity during face emotion viewing (F4,888 = 9.20; P < .001 for mixed model term). During viewing of intensely angry faces, decreased connectivity was associated with high levels of both anxiety and irritability, whereas increased connectivity was associated with high levels of anxiety but low levels of irritability (Wald χ21 = 21.3; P < .001 for contrast). Irritability was associated with differences in neural response to face emotions in several areas (F2, 888 ≥ 13.45; all P < .001). This primarily occurred in the ventral visual areas, with a positive association to angry and happy faces relative to fearful faces. CONCLUSIONS AND RELEVANCE: These data extend prior work conducted in youths with irritability or anxiety alone and suggest that research may miss important findings if the pathophysiology of irritability and anxiety are studied in isolation. Decreased amygdala-medial prefrontal cortex connectivity may mediate emotion dysregulation when very anxious and irritable youth process threat-related faces. Activation in the ventral visual circuitry suggests a mechanism through which signals of social approach (ie, happy and angry expressions) may capture attention in irritable youth.

Evaluation of PAX8 Expression in Brain Tissue and Related Neoplasms.

Undifferentiated brain tumors represent a diagnostic challenge, particularly in small biopsies, with regards to their primary versus metastatic origin. The latter may show overlapping morphologic features with primary high-grade brain tumors. In recent years several new antibodies have entered the realm of daily pathology practice. PAX8 (mammalian paired box genes 1 to 9 protein encoding gene) is among these new markers and is recognized as a differentiating marker of the primary site in epithelial tumors outside of the central nervous system. A review of the literature shows lack of site-specific studies with regards to the expression of PAX8 in the central nervous system and its neoplasms. Using this marker we investigated its immunohistochemical expression in normal brain tissue and glial tumors. The immunostain was performed on tissue microarrays of 71 cores from 24 cases. We also performed PAX8 immunostain on sections from cerebellum, pons, periventricular ependymal layer, choroid plexus, pituitary, and meninges of 3 autopsy cases. Our results indicate lack of PAX8 expression by benign brain tissue. Only 1 glioblastoma core (1/9 cores) showed focal nuclear reactivity with the antibody. Our results indicate that presence of PAX8 immunoreactivity in an undifferentiated brain tumor lacking gliofibrillary acidic protein expression should prompt consideration of a metastatic tumor.

Cultural value orientations, internalized homophobia, and accommodation in romantic relationships.

In the present study, we examined the impact of cultural value orientations (i.e., the personally oriented value of individualism, and the socially oriented values of collectivism, familism, romanticism, and spiritualism) on accommodation (i.e., voice and loyalty, rather than exit and neglect, responses to partners' anger or criticism) in heterosexual and gay relationships; and we examined the impact of internalized homophobia (i.e., attitudes toward self, other, and disclosure) on accommodation specifically in gay relationships. A total of 262 heterosexuals (102 men and 162 women) and 857 gays (474 men and 383 women) participated in the present study. Consistent with hypotheses, among heterosexuals and gays, socially oriented values were significantly and positively related to accommodation (whereas the personally oriented value of individualism was unrelated to accommodation); and among gays in particular, internalized homophobia was significantly and negatively related to accommodation. Implications for the study of heterosexual and gay relationships are discussed.

Increased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder.

Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype.