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Emotion-related impulsivity (ERI) refers to chronically poor self-control during periods of strong emotion. ERI robustly predicts psychiatric disorders and related problems, yet its neuroanatomical correlates are largely unknown. We tested whether local brain morphometry in targeted brain regions that integrate emotion and control could explain ERI severity.One hundred twenty-two adults (ages 18-55 years) with internalizing or externalizing psychopathology completed a structural magnetic resonance imaging (MRI) scan, the Three-Factor Impulsivity Index, and the Structured Clinical Interview for DSM-5. The Three-Factor Impulsivity Index measures two types of ERI and a third type of impulsivity not linked to emotion. Cortical reconstruction yielded cortical thickness and local gyrification measurements. We evaluated whether morphometry in the orbitofrontal cortex (OFC), insula, amygdala, and nucleus accumbens was associated with ERI severity. Hypotheses and analyses were preregistered.Lower cortical gyrification in the right lateral OFC was associated with high ERI severity in a full, preregistered model. Separate examinations of local gyrification and cortical thickness also showed a positive association between gyrification in the left lateral OFC and ERI. An integrated measure of hemispheric imbalance in lateral OFC gyrification (rightleft) correlated with ERI severity. These findings were specific to ERI and did not appear with non-emotion-related impulsivity.Local gyrification in the lateral OFC is associated with ERI severity. The current findings fit with existing theories of OFC function, strengthen the connections between the transdiagnostic literature in psychiatry and neuroscience, and may guide future treatment development.

Background It remains unclear whether executive control (EC) deficits in autism spectrum disorder (ASD) represent a failure in proactive EC (engaged and maintained before a cognitively demanding event) or in reactive EC (engaged transiently as the event occurs). We addressed this question by administering a paradigm investigating components of EC in a sample of individuals with ASD and typically developing individuals during functional magnetic resonance imaging. Methods During functional magnetic resonance imaging, 141 participants (64 ASD, 77 typically developing) completed a rapid preparing to overcome prepotency task that required participants to respond to an arrow probe based on the color of an initially presented cue. We examined functional recruitment and connectivity in the frontoparietal task control, cingulo-opercular task control, salience, and default mode networks during cue and probe phases of the task. Results ASD participants showed evidence of behavioral EC impairment. Analyses of functional recruitment and connectivity revealed that ASD participants showed significantly greater activity during the cue in networks associated with proactive control processes, but on the less cognitively demanding trials. On the more cognitively demanding trials, cue activity was similar across groups. During the probe, connectivity between regions associated with reactive control processes was uniquely enhanced on more-demanding (relative to less-demanding) trials in individuals with ASD but not in typically developing individuals. Conclusions The current data suggest that rather than arising from a specific failure to engage proactive or reactive forms of EC, the deficits in EC commonly observed in ASD may be due to reduced proactive EC and a consequent overreliance on reactive EC on more cognitively demanding tasks.

Theory about the conceptual basis of psychiatric disorders has long emphasized negative emotionality. More recent ideas emphasize roles for positive emotionality and impulsivity as well. This article examines impulsive responses to positive and negative emotions, which have been labelled as urgency. Urgency is conceptually and empirically distinct from other forms of impulsivity. A large body of work indicates that Urgency is more robustly related to psychopathology than are other forms of impulsivity. Researchers have considered four neurocognitive models of urgency: excessive emotion generation, poor emotion regulation, risky decision-making, and poor cognitive control. Little evidence supports emotion generation or risky decision-making as the core issues driving urgency. Rather, urgency appears related to dysfunction in key hubs implicated in the integration of cognitive control and emotion regulation (e.g., the orbitofrontal cortex and anterior insula), expressed as response inhibition deficits that emerge most robustly in high arousal contexts. These neurocognitive processes appear remarkably parallel for positive and negative urgency. We provide methodological suggestions and theoretical hypotheses to guide future research.

Emotion-related impulsivity, the trait-like tendency toward regrettable behavior during states of high emotion, is a robust predictor of internalizing and externalizing psychopathology. Despite substantial evidence that emotion-related impulsivity is important transdiagnostically, relatively little is known about its cognitive correlates. This systematic review and meta-regression investigates one such candidate, risky decision-making. We analyzed 195 effect sizes from 51 studies of 14,957 total participants, including 105 newly calculated effect sizes that were not reported in the original publications. The meta-regression demonstrated evidence for a small, positive relationship of emotion-related impulsivity with behavioral indices of risky decision-making (ß = 0.086). Effects generalized across sample age, gender, Positive versus Negative Urgency, and clinical versus nonclinical samples. The average effect size varied by task type, with stronger effects for the Iowa Gambling Task and Delay Discounting Task. Experimental arousal manipulation was nearly a significant moderator, with stress and pharmacological manipulations yielding significant effect sizes. Analyses indicated that publication bias did not skew the current findings. Notwithstanding limitations, the data suggest that risky decision-making is a cognitive domain that relates to emotion-related impulsivity. We conclude with recommendations regarding the specific types of tasks and arousal inductions that will best capture emotion-related impulsivity in future experimental research.

Rationale: In pulmonary arterial hypertension (PAH), endothelial dysfunction and obliterative vascular disease are associated with DNA damage and impaired signaling of BMPR2 (bone morphogenetic protein type 2 receptor) via two downstream transcription factors, PPARγ (peroxisome proliferator-activated receptor gamma), and p53. Objective: We investigated the vasculoprotective and regenerative potential of a newly identified PPARγ-p53 transcription factor complex in the pulmonary endothelium. Methods and Results: In this study, we identified a pharmacologically inducible vasculoprotective mechanism in pulmonary arterial and lung MV (microvascular) endothelial cells in response to DNA damage and oxidant stress regulated in part by a BMPR2 dependent transcription factor complex between PPARγ and p53. Chromatin immunoprecipitation sequencing and RNA-sequencing established an inducible PPARγ-p53 mediated regenerative program regulating 19 genes involved in lung endothelial cell survival, angiogenesis and DNA repair including, EPHA2 ( ephrin type-A receptor 2 ), FHL2 ( four and a half LIM domains protein 2 ), JAG1 ( jagged 1 ), SULF2 ( extracellular sulfatase Sulf-2 ), and TIGAR ( TP53-inducible glycolysis and apoptosis regulator ). Expression of these genes was partially impaired when the PPARγ-p53 complex was pharmacologically disrupted or when BMPR2 was reduced in pulmonary artery endothelial cells (PAECs) subjected to oxidative stress. In endothelial cell-specific Bmpr2 -knockout mice unable to stabilize p53 in endothelial cells under oxidative stress, Nutlin-3 rescued endothelial p53 and PPARγ-p53 complex formation and induced target genes, such as APLN ( apelin ) and JAG1 , to regenerate pulmonary microvessels and reverse pulmonary hypertension. In PAECs from BMPR2 mutant PAH patients, pharmacological induction of p53 and PPARγ-p53 genes repaired damaged DNA utilizing genes from the nucleotide excision repair pathway without provoking PAEC apoptosis. Conclusions: We identified a novel therapeutic strategy that activates a vasculoprotective gene regulation program in PAECs downstream of dysfunctional BMPR2 to rehabilitate PAH PAECs, regenerate pulmonary microvessels, and reverse disease. Our studies pave the way for p53-based vasculoregenerative therapies for PAH by extending the therapeutic focus to PAEC dysfunction and to DNA damage associated with PAH progression.

Although autism spectrum disorder (ASD) is characterized by deficits in cognitive control, our previous work has shown that preparatory, goal-directed cognitive processing (proactive control) may be preserved in children with ASD. We investigated whether proactive control is intact in adolescents and young adults with ASD, as well as how symptoms of ASD (repetitive behaviors) and psychopathology (Depressive, Anxiety, and Attention-Deficit/Hyperactivity Problems) are related to proactive control. Participants were adolescents and young adults with ASD (N = 44) and typical development (TD; N = 44). Proactive control was assessed using a picture-word Stroop paradigm where participants named animals depicted in drawings while ignoring a superimposed written animal word. Interference effects (reaction time (RT) differences between more difficult incongruent trials, where animal pictures and words prompted different responses, and simpler congruent trials, where animal pictures and words prompted the same response) were calculated for two versions of the Stroop Task: a mostly congruent (MC) block, where the majority of trials were congruent, and a mostly incongruent (MI) block, where most trials were incongruent. Proactive control was calculated as the reduction in interference in the MI block in comparison to the MC block. Proactive control did not differ between groups, indicating that proactive control is not impaired in adolescents and young adults with ASD. In ASD, depression symptoms were associated with reduced proactive control. Future research should investigate the effects of interventions targeting depression as well as interventions targeting proactive control processes in individuals with ASD and comorbid depression. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Background Internalizing symptoms like anxiety and depression are common and impairing in autism spectrum disorder (ASD). Here, we test the hypothesis that aberrant functional connectivity among three brain networks (salience network [SN], default mode network [DMN], and frontoparietal network [FPN]) plays a role in the pathophysiology of internalizing in ASD. Methods We examined the association between resting-state functional connectivity and internalizing in 102 adolescents and young adults with ASD (n = 49) or typical development (n = 53). Seed-to-target functional connectivity was contrasted between adolescents and young adults with ASD and typically developing subjects using a recent parcellation of the human cerebral cortex, and connections that were aberrant in ASD were analyzed dimensionally as a function of parent-reported internalizing symptoms. Results Three connections demonstrated robust overconnectivity in ASD: 1) the anterior insula to the retrosplenial cortex (i.e., SN-DMN), 2) the anterior insula to the frontal pole (i.e., SN-FPN), and 3) the dorsolateral prefrontal cortex to the retrosplenial cortex (i.e., FPN-DMN). These differences remained significant after controlling for age, and no age-related effects survived correction. The SN-DMN connection was associated with greater internalizing in ASD, mediated by a bigger difference between self- and parent-reported internalizing. Control analyses found that the other two connections were not associated with internalizing, and SN-DMN connectivity was not associated with a well-matched control measure (externalizing symptoms). Conclusions The present findings provide novel evidence for a specific link between SN-DMN overconnectivity and internalizing in ASD. Further, the mediation results suggest that intact anterior insula-retrosplenial connectivity may play a role in an individual’s generating insight into his or her own psychopathology.

Proactive control refers to the active representation of contextual information to bias cognitive processing and facilitate goal-directed behavior. Despite research suggesting that proactive control may be impaired in autism spectrum disorder (ASD), the associations between proactive control and clinical symptoms of ASD remain underspecified. Here, we combined a children's version of the AX Continuous Performance Task (AX-CPT) with gold standard clinical assessments in children with ASD (N = 34) or typical development (TYP; N = 45). After controlling for full-scale IQ (FSIQ), measures of proactive control were similar between ASD and TYP. However, specifically within ASD we observed paradoxical relationships between proactive control and clinical symptoms. Increased reliance on proactive control was associated with reduced attention problems and increased restricted and repetitive behaviors in ASD. Therefore, proactive control appears to represent a double-edged sword in ASD: improved attentional control at the cost of heightened behavioral inflexibility. This represents a compelling and new characterization of the specific association between cognitive control processes isolated in computerized laboratory tasks and the multidimensional cognitive symptoms characteristic of ASD. (PsycINFO Database Record

Summary: Using proteomic approaches, we uncovered a DNA damage response (DDR) function for peroxisome proliferator activated receptor γ (PPARγ) through its interaction with the DNA damage sensor MRE11-RAD50-NBS1 (MRN) and the E3 ubiquitin ligase UBR5. We show that PPARγ promotes ATM signaling and is essential for UBR5 activity targeting ATM interactor (ATMIN). PPARγ depletion increases ATMIN protein independent of transcription and suppresses DDR-induced ATM signaling. Blocking ATMIN in this context restores ATM activation and DNA repair. We illustrate the physiological relevance of PPARγ DDR functions by using pulmonary arterial hypertension (PAH) as a model that has impaired PPARγ signaling related to endothelial cell (EC) dysfunction and unresolved DNA damage. In pulmonary arterial ECs (PAECs) from PAH patients, we observed disrupted PPARγ-UBR5 interaction, heightened ATMIN expression, and DNA lesions. Blocking ATMIN in PAH PAEC restores ATM activation. Thus, impaired PPARγ DDR functions may explain the genomic instability and loss of endothelial homeostasis in PAH. : Li et al. identify PPARγ interactions with MRN and UBR5. PPARγ promotes UBR5-mediated ATMIN degradation, necessary for ATM activation upon DNA damage. Pulmonary arterial hypertension (PAH) endothelial cells exhibit genomic instability and disrupted PPARγ-UBR5 interaction. Blocking ATMIN restores ATM signaling in these cells, highlighting the significance of the PPARγ-ATMIN axis. Keywords: PPARγ, DNA damage, vascular biology, pulmonary hypertension, endothelial cells, ATM, MRN

Pulmonary arterial (PA) hypertension (PAH) is a life-threatening disease characterized by loss of microvessels, the result of endothelial cell (EC) apoptosis associated with dysfunction or a mutation in BMPR2. We identified p53 as critical in the formation of a DNA damage-inducible transcriptionally active complex with PPARγ, an important downstream factor of BMPR2 signaling. The p53-PPARγ complex regulates genes promoting PAEC homeostasis. Upon reoxygenation after hypoxia, PAEC with defective BMPR2 fail to stabilize p53 leading to mitochondrial dysfunction, DNA damage, endothelial apoptosis and persistent pulmonary hypertension (PH) in mice. We therefore hypothesized that in PAEC, pharmacological activation of p53 by the small molecule compound Nutlin-3 would stabilize the PPARγ-p53 complex downstream of BMPR2 to reverse the PH phenotype. Indeed, we showed that in PAEC transfected with BMPR2 siRNA, disruption of the PPARγ-p53 complex upon reoxygenation was prevented by Nutlin-3 treatment. This was associated with a reduction in DNA damage as assessed by Histone 2AX phosphorylation. In PAEC isolated from PAH patients with a BMPR2 mutation, Nutlin-3 treatment induced repair of prevalent DNA damage as determined by the Comet assay, and improved PAEC survival as measured by Caspase 3/7 activity. In PAEC with a BMPR2 mutation, Nutlin treatment stabilized p53, and induced PPARγ-p53 complex formation and expression of target genes, i.e., apelin (a pro-angiogenic factor), GADD45A (a DNA repair enzyme) and p21 (a cell cycle inhibitor) as detected by quantitative PCR and western immunoblots. In EC-specific BMPR2 knockout mice, we have observed persistent chronic hypoxia induced PH even after a month of reoxygenation in room air. We now show that this can be reversed by daily i.p. treatment with Nutlin-3a (12 mg/kg) during reoxygenation. In conclusion, pharmacological stabilization of p53 by Nutlin-3 in PAEC with dysfunctional BMPR2 induces repair of DNA damage, improves PAEC survival and rescues persistent pulmonary hypertension. These results auger well for pursuing the use of Nutlin-3 in pulmonary hypertension and other vascular diseases associated with DNA damage such as atherosclerosis.