Absence of differential protection from extinction in human causal learning.

Elemental models of associative learning typically employ a common prediction-error term. Following a conditioning trial, they predict that the change in the strength of an association between a cue and an outcome is dependent upon how well the outcome was predicted. When multiple cues are present, they each contribute to that prediction. The same rule applies both to increases in associative strength during excitatory conditioning and the loss of associative strength during extinction. In five experiments using an allergy prediction task, we tested the involvement of a common error term in the extinction of causal learning. Two target cues were each paired with an outcome prior to undergoing extinction in compound either with a second excitatory cue or with a cue that had previously undergone extinction in isolation. At test, there was no difference in the causal ratings of the two target cues. Manipulations designed to bias participants toward elemental processing of cue compounds, to promote the acquisition of inhibitory associations, or to reduce generalization decrement between training and test were each without effect. These results are not consistent with common error term models of associative learning. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Hepatology consultation is associated with decreased early return to alcohol use after discharge from an inpatient alcohol use disorder treatment program.

BACKGROUND: Alcohol cessation is the only intervention that both prevents and halts the progressions of alcohol-associated liver disease. The aim of this study was to assess the relationship between a return to alcohol use and consultation with hepatology in treatment-seeking patients with alcohol use disorder (AUD). METHODS: Two hundred forty-two patients with AUD were enrolled in an inpatient treatment program, with hepatology consultation provided for 143 (59%) patients at the request of the primary team. Patients not seen by hepatology served as controls. The primary outcome was any alcohol use after discharge assessed using AUDIT-C at 26 weeks after discharge. RESULTS: For the primary endpoint, AUDIT at week 26, 61% of the hepatology group and 28% of the controls completed the questionnaire (p=0.07). For the secondary endpoint at week 52, these numbers were 22% and 11% (p = 0.6). At week 26, 39 (45%) patients in the hepatology group versus 31 (70%) controls (p = 0.006) returned to alcohol use. Patients evaluated by hepatology had decreased rates of hazardous alcohol use compared to controls, with 36 (41%) versus 29 (66%) (p = 0.008) of the patients, respectively, reporting hazardous use. There were no significant differences in baseline characteristics between groups and no difference in rates of prescribing AUD therapy. There was no difference in outcomes at 52 weeks. CONCLUSIONS: Patients evaluated by hepatology had significantly lower rates of return to alcohol use and lower rates of hazardous drinking at 26 weeks but not at 52 weeks. These findings suggest that hepatology evaluation during inpatient treatment of AUD may lead to decreased rates of early return to alcohol use.

Altering ß Cell Antigen Exposure to Exhausted CD8+ T Cells Prevents Autoimmune Diabetes in Mice.

Chronic destruction of insulin-producing pancreatic ß cells by T cells results in autoimmune diabetes. Similar to other chronic T cell-mediated pathologies, a role for T cell exhaustion has been identified in diabetes in humans and NOD mice. The development and differentiation of exhausted T cells depends on exposure to Ag. In this study, we manipulated ß cell Ag presentation to target exhausted autoreactive T cells by inhibiting IFN-γ-mediated MHC class I upregulation or by ectopically expressing the ß cell Ag IGRP under the MHC class II promotor in the NOD8.3 model. Islet PD-1+TIM3+CD8+ (terminally exhausted [TEX]) cells were primary producers of islet granzyme B and CD107a, suggestive of cells that have entered the exhaustion program yet maintained cytotoxic capacity. Loss of IFN-γ-mediated ß cell MHC class I upregulation correlated with a significant reduction in islet TEX cells and diabetes protection in NOD8.3 mice. In NOD.TII/8.3 mice with IGRP expression induced in APCs, IGRP-reactive T cells remained exposed to high levels of IGRP in the islets and periphery. Consequently, functionally exhausted TEX cells, with reduced granzyme B expression, were significantly increased in these mice and this correlated with diabetes protection. These results indicate that intermediate Ag exposure in wild-type NOD8.3 islets allows T cells to enter the exhaustion program without becoming functionally exhausted. Moreover, Ag exposure can be manipulated to target this key cytotoxic population either by limiting the generation of cytotoxic TIM3+ cells or by driving their functional exhaustion, with both resulting in diabetes protection.

TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes.

Introduction: Chronic activation of self-reactive T cells with beta cell antigens results in the upregulation of immune checkpoint molecules that keep self-reactive T cells under control and delay beta cell destruction in autoimmune diabetes. Inhibiting PD1/PD-L1 signaling results in autoimmune diabetes in mice and humans with pre-existing autoimmunity against beta cells. However, it is not known if other immune checkpoint molecules, such as TIGIT, can also negatively regulate self-reactive T cells. TIGIT negatively regulates the CD226 costimulatory pathway, T-cell receptor (TCR) signaling, and hence T-cell function. Methods: The phenotype and function of TIGIT expressing islet infiltrating T cells was studied in non-obese diabetic (NOD) mice using flow cytometry and single cell RNA sequencing. To determine if TIGIT restrains self-reactive T cells, we used a TIGIT blocking antibody alone or in combination with anti-PDL1 antibody. Results: We show that TIGIT is highly expressed on activated islet infiltrating T cells in NOD mice. We identified a subset of stem-like memory CD8+ T cells expressing multiple immune checkpoints including TIGIT, PD1 and the transcription factor EOMES, which is linked to dysfunctional CD8+ T cells. A known ligand for TIGIT, CD155 was expressed on beta cells and islet infiltrating dendritic cells. However, despite TIGIT and its ligand being expressed, islet infiltrating PD1+TIGIT+CD8+ T cells were functional. Inhibiting TIGIT in NOD mice did not result in exacerbated autoimmune diabetes while inhibiting PD1-PDL1 resulted in rapid autoimmune diabetes, indicating that TIGIT does not restrain islet infiltrating T cells in autoimmune diabetes to the same degree as PD1. Partial inhibition of PD1-PDL1 in combination with TIGIT inhibition resulted in rapid diabetes in NOD mice. Discussion: These results suggest that TIGIT and PD1 act in synergy as immune checkpoints when PD1 signaling is partially impaired. Beta cell specific stem-like memory T cells retain their functionality despite expressing multiple immune checkpoints and TIGIT is below PD1 in the hierarchy of immune checkpoints in autoimmune diabetes.

Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes.

Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.

Rhabdomyolysis Suspected to be Caused by Eravacycline Therapy: A Case Report.

Eravacycline is approved by the U.S. Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal infections. It is a novel, fully synthetic fluorocycline antibiotic belonging to the tetracycline class with a broad-spectrum of activity and an appealing side effect profile. This report describes a 74-year-old female who presented to the hospital with non-ST-elevation myocardial infarction (NSTEMI) requiring coronary artery bypass graft surgery. After surgery, she developed a sternal wound infection that grew multidrug resistant organisms, leading to a much longer than anticipated hospital stay. Eravacycline was eventually added to the antimicrobial regimen for the persistent infection. Shortly after therapy with eravacycline began, the patient started experiencing muscle pain and the creatine phosphokinase (CPK) level was noted to be elevated. Other causes, such as concomitant administration of an HMG-CoA reductase inhibitor, were explored in this case but not thought to be the cause of rhabdomyolysis. The patient's CPK dropped considerably upon discontinuation of the novel antibiotic, and symptoms resolved. The adverse drug event was reported to the drug manufacturer; however, there are no reports up until this time that address a possible relationship between eravacycline administration and the development of rhabdomyolysis.

Safety and feasibility clinical trial of nucleus accumbens deep brain stimulation for treatment-refractory opioid use disorder.

OBJECTIVE: There were more than 107,000 drug overdose deaths in the US in 2021, the most ever recorded. Despite advances in behavioral and pharmacological treatments, over 50% of those receiving treatment for opioid use disorder (OUD) experience drug use recurrence (relapse). Given the prevalence of OUD and other substance use disorders (SUDs), the high rate of drug use recurrence, and the number of drug overdose deaths, novel treatment strategies are desperately needed. The objective of this study was to evaluate the safety and feasibility of deep brain stimulation (DBS) targeting the nucleus accumbens (NAc)/ventral capsule (VC) and potential impact on outcomes in individuals with treatment-refractory OUD. METHODS: A prospective, open-label, single-arm study was conducted among participants with longstanding treatment-refractory OUD (along with other co-occurring SUDs) who underwent DBS in the NAc/VC. The primary study endpoint was safety; secondary/exploratory outcomes included opioid and other substance use, substance craving, and emotional symptoms throughout follow-up and 18FDG-PET neuroimaging. RESULTS: Four male participants were enrolled and all tolerated DBS surgery well with no serious adverse events (AEs) and no device- or stimulation-related AEs. Two participants sustained complete substance abstinence for > 1150 and > 520 days, respectively, with significant post-DBS reductions in substance craving, anxiety, and depression. One participant experienced post-DBS drug use recurrences with reduced frequency and severity. The DBS system was explanted in one participant due to noncompliance with treatment requirements and the study protocol. 18FDG-PET neuroimaging revealed increased glucose metabolism in the frontal regions for the participants with sustained abstinence only. CONCLUSIONS: DBS of the NAc/VC was safe, feasible, and can potentially reduce substance use, craving, and emotional symptoms in those with treatment-refractory OUD. A randomized, sham-controlled trial in a larger cohort of patients is being initiated.

Attentional bias in psoriasis: The role of processing time and emotional valence.

PURPOSE: The present study explored whether people with psoriasis display an attentional bias towards disease-related threat words and whether this bias occurs relatively early during the phase of stimulus disengagement, or during a later maintained attention phase dominated by controlled strategic processes. We also explored the degree to which attentional bias is dependent on the emotional valence of control words. METHODS: Individuals with psoriasis and matched controls took part in 4 online experiments. Participants completed a spatial cueing paradigm using disease-related threat words and control words as cues, in order to obtain reaction time estimates of attentional bias. RESULTS: We did not observe evidence for attentional bias when control words were matched with threat words for emotional valence, regardless of whether processing time for the cues was limited (Experiment 1: SOA = 250 ms) or extended (Experiment 2: SOA = 1050 ms). We also did not observe evidence for attentional bias when control words of positive valence were used, but processing time was limited (Experiment 3). An attentional bias was only observed (p = .012, Cohen's d = .37) when sufficient processing time was available and positively-valanced control words were used (Experiment 4). CONCLUSION: Rather than showing large and generalized AB effects as predicted by previous accounts, our results tentatively suggest that AB in psoriasis is restricted to situations where participants have ample processing time and threat words are easily distinguishable from control words on the basis of emotional valence. The pattern of results suggests that attentional bias in psoriasis is best characterized as a relatively slow strategic process.

Preliminary evidence for changes in frontoparietal network connectivity in the early abstinence period in alcohol use disorder: a longitudinal resting-state functional magnetic resonance imaging study.

The early abstinence period is a crucial phase in alcohol use disorder (AUD) in which patients have to find a new equilibrium and may start recovery, or conversely, relapse. However, the changes in brain functions during this key period are still largely unknown. We set out to study longitudinal changes in large-scale brain networks during the early abstinence period using resting-state scans. We scanned AUD patients twice in a well-controlled inpatient setting, with the first scan taking place shortly after admission and the second scan 4 weeks (±9 days) later near the end of the treatment period. We studied 37 AUD patients (22 males) and 27 healthy controls (16 males). We focused on three networks that are affected in AUD and underly core symptom dimensions in this disorder: the frontoparietal networks (left and right FPN) and default mode network (DMN). Both the whole brain and within network connectivity of these networks were studied using dual regression. Finally, we explored correlations between these brain networks and various neuropsychological and behavioral measures. In contrast to the controls (Z = -1.081, p = 0.280), the AUD patients showed a decrease in within left FPN connectivity (Z = -2.029, p = 0.042). However, these results did not survive a strict Bonferroni correction. The decrease in left FPN connectivity during the early abstinence period in AUD may reflect an initially upregulated FPN, which recovers to a lower resting-state connectivity level during subsequent weeks of abstinence. The AUD patients showed a trend for a positive association between the change in left FPN connectivity and trait anxiety (rs = 0.303, p = 0.068), and a trend for a negative association between the change in left FPN connectivity and delay discounting (rs = -0.283, p = 0.089) (uncorrected for multiple comparisons). This suggests that the FPN might be involved in top-down control of impulsivity and anxiety, which are important risk factors for relapse. Although there were no statistically significant results (after multiple comparison correction), our preliminary findings encourage further research into the dynamic neuroadaptations during the clinically crucial early abstinence period and could inform future study designs.

Review: Kirkwood-Riseman Model in Non-Dilute Polymeric Fluids.

In two prior articles, I demonstrated from extensive simulational studies by myself and others that the Rouse model of polymer dynamics is invalid in polymer melts and in dilute solution. However, the Rouse model is the foundational basis for most modern theories of polymeric fluid dynamics, such as reptation/scaling models. One therefore rationally asks whether there is a replacement. There is, namely by extending the Kirkwood-Riseman model. Here, I present a comprehensive review of one such set of extensions, namely the hydrodynamic scaling model. This model assumes that polymer dynamics in dilute and concentrated solution is dominated by solvent-mediated hydrodynamic interactions; chain crossing constraints are taken to create only secondary corrections. Many other models assume, contrariwise, that in concentrated solutions, the chain crossing constraints dominate the dynamics. An extended Kirkwood-Riseman model incorporating interchain hydrodynamic interactions is developed. It yields pseudovirial series for the concentration and molecular weight dependencies of the self-diffusion coefficient Ds and the low-shear viscosity η. To extrapolate to large concentrations, rationales based on self-similarity and on the Altenberger-Dahler positive-function renormalization group are presented. The rationales correctly predict how Ds and η depend on polymer concentration and molecular weight. The renormalization group approach leads to a two-parameter ansatz that correctly predicts the functional forms of the frequency dependencies of the storage and loss moduli. A short description is given of each of the papers that led to the hydrodynamic scaling model. Experiments supporting the aspects of the model are noted.

Inflammation versus regulation: how interferon-gamma contributes to type 1 diabetes pathogenesis.

Type 1 diabetes is an autoimmune disease with onset from early childhood. The insulin-producing pancreatic beta cells are destroyed by CD8+ cytotoxic T cells. The disease is challenging to study mechanistically in humans because it is not possible to biopsy the pancreatic islets and the disease is most active prior to the time of clinical diagnosis. The NOD mouse model, with many similarities to, but also some significant differences from human diabetes, provides an opportunity, in a single in-bred genotype, to explore pathogenic mechanisms in molecular detail. The pleiotropic cytokine IFN-γ is believed to contribute to pathogenesis of type 1 diabetes. Evidence of IFN-γ signaling in the islets, including activation of the JAK-STAT pathway and upregulation of MHC class I, are hallmarks of the disease. IFN-γ has a proinflammatory role that is important for homing of autoreactive T cells into islets and direct recognition of beta cells by CD8+ T cells. We recently showed that IFN-γ also controls proliferation of autoreactive T cells. Therefore, inhibition of IFN-γ does not prevent type 1 diabetes and is unlikely to be a good therapeutic target. In this manuscript we review the contrasting roles of IFN-γ in driving inflammation and regulating the number of antigen specific CD8+ T cells in type 1 diabetes. We also discuss the potential to use JAK inhibitors as therapy for type 1 diabetes, to inhibit both cytokine-mediated inflammation and proliferation of T cells.

Simulational Tests of the Rouse Model.

An extensive review of literature simulations of quiescent polymer melts is given, considering results that test aspects of the Rouse model in the melt. We focus on Rouse model predictions for the mean-square amplitudes ⟨(Xp(0))2⟩ and time correlation functions ⟨Xp(0)Xp(t)⟩ of the Rouse mode Xp(t). The simulations conclusively demonstrate that the Rouse model is invalid in polymer melts. In particular, and contrary to the Rouse model, (i) mean-square Rouse mode amplitudes ⟨(Xp(0))2⟩ do not scale as sin-2(pπ/2N), N being the number of beads in the polymer. For small p (say, p≤3) ⟨(Xp(0))2⟩ scales with p as p-2; for larger p, it scales as p-3. (ii) Rouse mode time correlation functions ⟨Xp(t)Xp(0)⟩ do not decay with time as exponentials; they instead decay as stretched exponentials exp(-αtß). ß depends on p, typically with a minimum near N/2 or N/4. (iii) Polymer bead displacements are not described by independent Gaussian random processes. (iv) For p≠q, ⟨Xp(t)Xq(0)⟩ is sometimes non-zero. (v) The response of a polymer coil to a shear flow is a rotation, not the affine deformation predicted by Rouse. We also briefly consider the Kirkwood-Riseman polymer model.

The Kirkwood-Riseman Model of Polymer Solution Dynamics Is Qualitatively Correct.

The Rouse model is the foundational basis of much of modern polymer physics. The period alternative, the Kirkwood-Riseman model, is rarely mentioned in modern monographs. The models are qualitatively different. The models do not agree as to how many internal modes a polymer molecule has. In the Kirkwood-Riseman model, polymers in a shear field perform whole-body rotation; in the Rouse model, polymers respond to shear with an affine deformation. We use Brownian dynamics to show that the Kirkwood-Riseman model for chain motion is qualitatively correct. Contrary to the Rouse model, in shear flow, polymer coils rotate. Rouse modes are cross-correlated. The amplitudes and relaxation rates of Rouse modes depend on the shear rate. Several alternatives to Rouse modes as collective coordinates are discussed.

Temporal distortion for angry faces: Testing visual attention and action preparation accounts.

When asked to judge the duration of a face people typically overestimate the duration of angry compared with neutral faces. A novel feature of the current research was the inclusion of secondary manipulations designed to distort timing performance namely the effects of visual cues (Experiment 1) and action preparedness (Experiment 2). Furthermore, to establish whether the effects are multiplicative with duration, the effects were examined across two duration ranges (200-800 and 400-1,600 ms). Visual cues and instructions to prepare to act increased the tendency to judge faces as lasting longer. Experiment 1 revealed an unexpected underestimation effect for angry faces presented for short durations (200-800 ms). However, the effect was not replicated in Experiment 2 where the results were generally consistent with either an increase the speed of a pacemaker mechanism that resides within an internal clock or the widening of an attentional gate-the temporal overestimation effect for angry faces grew in magnitude from the short to long duration. Experiment 2 also showed that the temporal overestimation for angry faces was reduced in magnitude when participants were asked to prepare to either push or pull a joystick.

First molecular confirmation of multiple zoonotic vector-borne diseases in pet dogs and cats of Hong Kong SAR.

In recent years, the incidence of vector-borne diseases (VBDs) has increased throughout the globe. In particular, tick-borne diseases (e.g., caused by Ehrlichia canis, E. ewingii, Anaplasma phagocytophilum, A. platys, Borrelia burgdorferi sensu stricto (s.s.) and Babesia gibsoni) and mosquito-borne diseases (e.g., caused by Dirofilaria immitis) diseases pose a burden on animal health. Nevertheless, there have been no studies undertaken on the occurrence of VBDs in pet dogs and cats in Hong Kong SAR. This study fills this gap, and is the first to determine the seroprevalence of major VBDs, such as those caused by D. immitis, E. canis, E. ewingii, A. phagocytophilum, A. platys and B. burgdorferi s.s, in dogs and cats through commercially available SNAP 4Dx plus testing. Infection by all these pathogens and Babesia sp. was further assessed through PCR and DNA sequencing. A total of 224 blood samples were collected from domestic dogs (n = 159) and cats (n = 65) in Hong Kong SAR during summer 2022. Hematocrit and platelet counts were determined in each blood sample and other hematological parameters were assessed using an automatic hematology analyzer and vortex the specimen for one to two minutes at or near the highest setting to minimize the clumping. All cat sera samples were negative for tested pathogens, but antibodies against some of the pathogens were detected in dog sera samples. Here, the highest figures were recorded for seroprevalence of E. canis/E. ewingii (10.7%), followed by D. immitis (5.7%), and A. phagocytophilum/A. platys (2.5%). No B. burgdorferi s.s. antibodies were detected in any of the dogs tested. Through molecular diagnostics, we detected the presence of B. gibsoni (3.7%), E. canis (3.1%), D. immitis (5.7%), and A. phagocytophilum (1.3%). Neighbor-Joining phylogenetic trees for vector-borne pathogens (i.e., genus Anaplasma sp.) showed 100% clustering to Japan, the USA and Germany, whereas genus Ehrlichia sp. showed 100% clustering to China, Turkey, Cuba, and Greece. Similarly, genus Babesia sp. clustered 100% to India, Sri Lanka and Austria, while D. immitis clustered in Iraq, South Korea, Portugal, France, the USA and Italy. This study provides the first evidence on the occurrence of tick-borne pathogens in pet dogs in Hong Kong SAR. Based on these findings, it is recommended that appropriate screening should be undertaken in domestic dogs to evaluate the prevalence of these pathogens and promote the timely control of VBDs.

WITHDRAWN: Cardiovascular disease in individuals with a history of out-of-home care: a Swedish national cohort study.

The authors have withdrawn their manuscript owing to errors apparent in the results. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Use of behavioural change taxonomies in systematic reviews and meta-analyses regarding obesity management.

We investigated the prevalence of behavioural change taxonomies in systematic reviews and meta-analyses related to obesity management. In addition, we analysed the funding sources, author conflicts of interest statements, risk of bias, and favorability of the results in such studies to determine if there was a relationship between methodological quality and taxonomy use. We searched several databases including MEDLINE, Epistemonikos, Cochrane EDSR, Pubmed and Embase for systematic reviews and meta-analyses regarding the behavioural treatment of obesity. Screening and data extraction was performed in a masked, duplicate fashion. We performed statistical analyses to determine any significant association between use of taxonomy and study characteristics. Fifteen (of 186; 8.06%) systematic reviews used a taxonomy-nine used the BCTTv1, three used OXFAB, two used the CALO-RE and one used "Taxonomy of choice architecture techniques." Most interventions that referenced a taxonomy were self-mediated (6/60, 10%). Behavioural change taxonomies were mentioned in 10 (of 87, 11.49%) studies with a public funding source. Of the studies with favourable results, 14 studies (of 181, 7.73%) referred to a taxonomy. We found no statistically significant relationships between use of taxonomy and study characteristics. We found that systematic reviews regarding the management of obesity rarely mention a behavioural change taxonomy. Given the global burden of obesity, it is crucial that behavioural change techniques are reproducible and translatable. We recommend that researchers look further into how taxonomies affect the quality and reproducibility of behavioural interventions in an effort to improve patient outcomes.

Corticotropin-Releasing Factor receptor 1 (CRF1) antagonism in patients with alcohol use disorder and high anxiety levels: effect on neural response during Trier Social Stress Test video feedback.

In preclinical models of alcohol use disorder, the corticotropin-releasing factor (CRF) receptor is upregulated, particularly in the extended amygdala. This upregulation is thought to play a role in stress-induced relapse to drinking by a mechanism that is independent of the hypothalamic-pituitary-adrenal axis. As part of a double-blind, placebo-controlled clinical study with pexacerfont, a selective, orally available, and brain-penetrant CRF1 receptor antagonist which has anti-anxiety effects in preclinical studies, we examined the effect of pexacerfont on the neural response to a social stress task adapted to fMRI. Subjects were 39 individuals (4 women) with high trait anxiety and moderate to severe alcohol use disorder randomized to receive pexacerfont or placebo. The task involved feedback of videoclips of an individual performing the Trier Social Stress Test. Pexacerfont had no effect on the neural response to self-observation under stress. The neural response to viewing oneself under stress vs an unknown other under stress activated prefrontal brain regions including insula, inferior frontal gyrus as well as medial, superior frontal gyri. These regions of activation overlap with those found in studies using similar paradigms. Potential applications of this task to probe neurocircuitry that is disrupted in addiction is discussed.

Competing contextual processes rely on the infralimbic and prelimbic medial prefrontal cortices in the rat.

Ambiguous relationships between events may be established using interference procedures such as latent inhibition, extinction or counterconditioning. Under these conditions, the retrieval of individual associations between a stimulus and outcome is affected by contextual cues. To examine the roles of the dorsal (prelimbic) and ventral (infralimbic) medial prefrontal cortex in the contextual modulation of such associations, we investigated the context specificity of latent inhibition. Male Lister hooded rats were pre-exposed to two separate stimuli, one in each of two distinct contexts. Both stimuli were then paired with the delivery of mild foot-shock in the same one of these contexts. Finally, the strength of the resultant conditioned emotional response (CER) to each stimulus was assessed in each context. For the sham-operated control rats, the CER was attenuated for each stimulus when it was tested in the context in which it had been pre-exposed. Rats who had received lesions to the infralimbic cortex showed this effect only in the conditioning context, whereas rats with lesions to the prelimbic cortex showed the effect only in the context in which conditioning had not taken place. These findings indicate that infralimbic and prelimbic cortices play distinct, and competing, roles in the contextual modulation of initial and later learning.

Multidimensional Quality of Life Across the Spectrum of Alcohol Use Behavior.

Objective: Quality of life (QoL) is inversely associated with alcohol misuse and is a key measure by which recovery from alcohol use disorder (AUD) might be assessed. Yet, the determinants of QoL are scarcely known. The authors examined three ways through which demographic characteristics, familial and early life factors, and psychopathology conferred risks for QoL, including unique direct effects, developmental pathways, and clinical risk Profiles. Methods: Cross-sectional data from 1095 adults (50.4% without AUD; 49.6% with AUD) who participated in the NIAAA Natural History Protocol from January 2015 to March 2022 were analyzed. Multivariable regressions, path analysis, and latent Profile analysis were conducted. Results: AUD was uniquely associated with lower QoL, and adverse effects of child maltreatment history and psychopathology symptoms on QoL were of similar or larger magnitudes. Mediation analysis indicated family history of AUD and child maltreatment history were indirectly associated with lower QoL through higher attention-deficit/hyperactivity disorder symptoms, higher depressive symptoms, and positive AUD diagnosis. Latent Profile analysis of an enriched set of clinical characteristics identified four latent Profiles capturing the full range of alcohol use behavior. Latent Profiles with greater severity of familial and early life factors, psychopathology, and problematic drinking showed dose-response associations with lower levels of physical, psychological, social, and environment QoL. Conclusions: A constellation of developmental and clinical characteristics disproportionately affects individuals with AUD and is negatively associated with QoL domains. To improve QoL, prevention and intervention need to target multiple factors, including history of child maltreatment, comorbid psychopathology, and problematic drinking itself.