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Opioid use disorder (OUD) is defined as a compulsion to seek and take opioids, loss of control over intake and the development of a negative emotional state when access to opioids is denied. Using functional magnetic resonance imaging (fMRI) data in a rat model of OUD, we demonstrate that the escalation of heroin self-administration (SA) and the increased heroin SA following an injection of an opioid receptor antagonist (naloxone) are associated with changes in distinct brain circuits, centered on the cingulate cortex (Cg). Here, SA escalation score was negatively associated with changes in resting state functional connectivity (rsFC) between the Cg and the dorsal striatum. Conversely, increased heroin SA following naloxone injection, was associated with increased connectivity between the Cg and the extended amygdala and hypothalamus. Naloxone-induced increased SA was also positively associated with changes in the amplitude of low frequency fluctuations within the Cg, a measure of spontaneous neuronal activity. Characterizing the distinct brain circuit and behavior changes associated with different facets of addiction increases our understanding of OUD and may provide insight into addiction prevention and treatment.

Introduction: Neuropsychiatric symptoms (NPS), such as depression and anxiety, are observed in 90% of Alzheimer's disease (AD) patients, two-thirds of whom are women. NPS usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brain-wide neuronal mechanisms., Methods: To gain mechanistic insight into how anxiety impacts AD progression, we performed a cross-sectional analysis on mood, cognition, and neural activity utilizing the ArcCreER T2 x enhanced yellow fluorescent protein (eYFP) x APP/PS1 (AD) mice. The ADNI dataset was used to determine the impact of anxiety on AD progression in human subjects., Results: Female APP/PS1 mice exhibited anxiety-like behavior and cognitive decline at an earlier age than control (Ctrl) mice and male mice. Brain-wide analysis of c-Fos + revealed changes in regional correlations and overall network connectivity in APP/PS1 mice. Sex-specific eYFP + /c-Fos + changes were observed; female APP/PS1 mice exhibited less eYFP + /c-Fos + cells in dorsal CA3 (dCA3), while male APP/PS1 mice exhibited less eYFP + /c-Fos + cells in the dorsal dentate gyrus (dDG). In the ADNI dataset, anxiety predicted transition to dementia. Female subjects positive for anxiety and amyloid transitioned more quickly to dementia than male subjects., Conclusions: While future studies are needed to understand whether anxiety is a predictor, a neuropsychiatric biomarker, or a comorbid symptom that occurs during disease onset, these results suggest that there are sex differences in AD network dysfunction, and that personalized medicine may benefit male and female AD patients rather than a one size fits all approach., (Copyright © 2024. Published by Elsevier Inc.)

Nicotine exposure is associated with regional changes in brain nicotinic acetylcholine receptors subtype expression patterns as a function of dose and age at the time of exposure. Moreover, nicotine dependence is associated with changes in brain circuit functional connectivity, but the relationship between such connectivity and concomitant regional distribution changes in nicotinic acetylcholine receptor subtypes following nicotine exposure is not understood. Although smoking typically begins in adolescence, developmental changes in brain circuits and nicotinic acetylcholine receptors following chronic nicotine exposure remain minimally investigated. Here, we combined in vitro nicotinic acetylcholine receptor autoradiography with resting state functional magnetic resonance imaging to measure changes in [ 3 H]nicotine binding and α4ß2 subtype nicotinic acetylcholine receptor binding and circuit connectivity across the brain in adolescent (postnatal Day 33) and adult (postnatal Day 68) rats exposed to 6 weeks of nicotine administration (0, 1.2 and 4.8 mg/kg/day). Chronic nicotine exposure increased nicotinic acetylcholine receptor levels and induced discrete, developmental stage changes in regional nicotinic acetylcholine receptor subtype distribution. These effects were most pronounced in striatal, thalamic and cortical regions when nicotine was administered during adolescence but not in adults. Using these regional receptor changes as seeds, resting state functional magnetic resonance imaging identified dysregulations in cortico-striatal-thalamic-cortical circuits that were also dysregulated following adolescent nicotine exposure. Thus, nicotine-induced increases in cortical, striatal and thalamic nicotinic acetylcholine receptors during adolescence modifies processing and brain circuits within cortico-striatal-thalamic-cortical loops, which are known to be crucial for multisensory integration, action selection and motor output, and may alter the developmental trajectory of the adolescent brain. This unique multimodal study significantly advances our understanding of nicotine dependence and its effects on the adolescent brain., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

After experiencing a traumatic event people often turn to alcohol to cope with symptoms. In those with post-traumatic stress disorder (PTSD) and a co-occurring alcohol use disorder (AUD), PTSD symptoms can worsen, suggesting that alcohol changes how traumatic memory is expressed. The objective of this series of experiments is to identify how alcohol drinking (EtOH), following cued fear conditioning and extinction, impacts fear expression in mice. Molecular (activity-regulated cytoskeleton-associated protein, Arc/arg3.1) and structural (dendrite and spine morphometry) markers of neuronal plasticity were measured following remote extinction retrieval. Mouse age (adolescent and adult) and sex were included as interacting variables in a full factorial design. Females drank more EtOH than males and adolescents drank more EtOH than adults. Adolescent females escalated EtOH intake across drinking days. Adolescent drinkers exhibited more conditioned freezing during extinction retrieval, an effect that persisted for at least 20 days. Heightened cued freezing in the adolescent group was associated with greater Arc/arg3.1 expression in layer (L) 2/3 prelimbic (PL) cortex, greater spine density, and reduced basal dendrite complexity. In adults, drinking was associated with reduced L2/3 infralimbic (IL) Arc expression but no behavioral differences. Few sex interactions were uncovered throughout. Overall, these data identify prolonged age-related differences in alcohol-induced fear extinction impairment and medial prefrontal cortex neuroadaptations., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Contemporary neuroscience aims to understand how neuronal activity produces internal processes and observable behavioral states. This aim crucially depends on systems-level, circuit-based analyses of the working brain, as behavioral states arise from information flow and connectivity within and between discrete and overlapping brain regions, forming circuits and networks. Functional magnetic resonance imaging (fMRI), offers a key to advance circuit neuroscience; fMRI measures inter and intra- regional circuits at behaviorally relevant spatial-temporal resolution. Herein, we argue that cross-sectional observations in human populations can be best understood via mechanistic and causal insights derived from brain circuitry obtained from preclinical fMRI models. Using nicotine addiction as an exemplar of a circuit-based substance use disorder, we review fMRI-based observations of a circuit that was first shown to be disrupted among human smokers and was recently replicated in rodent models of nicotine dependence. Next, we discuss circuits that predispose to nicotine dependence severity and their interaction with circuits that change as a result of chronic nicotine administration using a rodent model of dependence. Data from both clinical and preclinical fMRI experiments argue for the utility of fMRI studies in translation and reverse translation of a circuit-based understanding of brain disease states. We conclude by discussing the future of circuit neuroscience and functional neuroimaging as an essential bridge between animal models and human populations to the understanding of brain function in health and disease., (Published by Elsevier Inc.)

Doxorubicin remains an essential component of many cancer regimens, but its use is limited by lethal cardiomyopathy, which has been difficult to target, owing to pleiotropic mechanisms leading to apoptotic and necrotic cardiac cell death. Here we show that BAX is rate-limiting in doxorubicin-induced cardiomyopathy and identify a small-molecule BAX inhibitor that blocks both apoptosis and necrosis to prevent this syndrome. By allosterically inhibiting BAX conformational activation, this compound blocks BAX translocation to mitochondria, thereby abrogating both forms of cell death. When co-administered with doxorubicin, this BAX inhibitor prevents cardiomyopathy in zebrafish and mice. Notably, cardioprotection does not compromise the efficacy of doxorubicin in reducing leukemia or breast cancer burden in vivo, primarily due to increased priming of mitochondrial death mechanisms and higher BAX levels in cancer cells. This study identifies BAX as an actionable target for doxorubicin-induced cardiomyopathy and provides a prototype small-molecule therapeutic., Competing Interests: Competing interests R.N.K., E.G., D.A., T.P.G. and L.A.K. are inventors on a patent application PCT/US2018/021644 submitted by Albert Einstein College of Medicine that covers compounds, compositions and methods for BAX inhibition for the treatment of diseases and disorders.

Hypertrophic obstructive cardiomyopathy (HOCM) is the most frequently inherited cardiovascular disease (prevalence in the general population of 1/500) and is characterized by significant left ventricular hypertrophy, especially in the interventricular septum, combined with small-volume cardiac cavities. Transaortic surgical septal myectomy is the most commonly used technique to treat HOCM, and is associated with low operative morbidity and mortality and a reduction of the outflow gradients. The composite operative mortality of only 0.4% (17/3695 patients) from 5 major high-volume centers in North America highlights the role of dedicated HOCM units. The involvement of the mitral valve in the pathophysiology of HOCM has been addressed as systolic anterior motion (SAM)-related left ventricular outflow tract obstruction. Hypertrophic cardiomyopathy mitral malformations include leaflet elongation and a wide array of malformations of the papillary muscles and chordae that can be detected by transthoracic and transesophageal echocardiography and by cardiac magnetic resonance. Because they participate fundamentally in the predisposition to SAM, they have increasingly been repaired surgically.

Objective: There is increasing burnout incidence among medical disciplines, and physicians working in emergency settings seem at higher risk. Cardiac anesthesiology is a stressful anesthesiology subspecialty dealing with high-risk patients. The authors hypothesized a high risk of burnout in cardiac anesthesiologists., Design: National survey conducted on burnout., Setting: Italian cardiac centers., Participants: Cardiac anesthesiologists., Interventions: The authors administered via email an anonymous questionnaire divided into 3 parts. The first 2 parts evaluated workload and private life. The third part consisted of the Maslach Burnout Inventory test with its 3 constituents: high emotional exhaustion, high depersonalization, and low personal accomplishment., Measurements and Main Results: The authors measured the prevalence and risk of burnout through the Maslach Burnout Inventory questionnaire and analyzed factors influencing burnout. Among 670 contacts from 71 centers, 382 cardiac anesthesiologists completed the survey (57%). The authors found the following mean Maslach Burnout Inventory values: 14.5 ± 9.7 (emotional exhaustion), 9.1 ± 7.1 (depersonalization), and 33.7 ± 8.9 (personal accomplishment). A rate of 34%, 54%, and 66% of respondents scored in "high" or "moderate-high" risk of burnout (emotional exhaustion, depersonalization, and personal accomplishment, respectively). The authors found that, if offered to change subspecialty, 76% of respondents would prefer to remain in cardiac anesthesiology. This preference and parenthood were the only 2 investigated factors with a protective effect against all components of burnout. Significantly lower burnout scores were found in more experienced anesthesiologists., Conclusion: A relatively high incidence of burnout was found in cardiac anesthesiologists, especially regarding high depersonalization and low personal accomplishment. Nonetheless, most of the respondents would choose to remain in cardiac anesthesiology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The aims of this study were to test the hypotheses that in the postoperative period after coronary artery bypass graft surgery (1) atrio-right ventricular (RA-RV) pacing induces a decrease in cardiac output compared with RA pacing alone and (2) atrio-biventricular (RA-BiV) pacing improves CO compared with RA-RV pacing., Design: A prospective observational study., Setting: A single-center university hospital., Participants: Patients referred for coronary artery bypass graft surgery., Interventions: Patients were studied during atrial, RA-RV, and RA-BiV pacing. Cardiac output (echocardiography) and left ventricular dyssynchrony were assessed at each step., Measurements and Main Results: RA-RV pacing induced a significant decrease in cardiac output (4.3 +/- 1.0 to 3.7 +/- 0.8 L/min, p < 0.01) and a significant increase in left ventricular dyssynchrony (13 +/- 12 to 80 +/- 25 milliseconds, p < 0.01). Biventricular pacing induced a significant increase in cardiac output (3.7 +/- 0.8 to 4.5 +/- 1.0 L/min, p < 0.01) and a significant decrease in left ventricular dyssynchrony compared with right ventricular pacing (80 +/- 25 to 21 +/- 16 milliseconds, p < 0.05)., Conclusions: RA-BiV pacing improves cardiac output compared with RA-RV pacing in the postoperative period after coronary artery bypass graft surgery. This improvement is related to an improvement in left ventricular synchronicity.

Background: The purpose of this study was to determine the value of lymphoscintigraphy (LS) for internal mammary sentinel node (IMSN) identification, the metastatic rate, and the change in staging and treatment., Methods: Between 2001 and 2007 a prospective database was obtained of all patients undergoing IMSN biopsies using an open or thoracoscopic approach. Radiotracer injection was peritumoral., Results: Thirty-four patients were included. There was one man. Three had ductal carcinoma in situ. LS showed IMSN in 47.1%. The IMSN biopsy success rate was 91.2%. Seven of the 28 successfully biopsied invasive cancer patients had metastatic IMSNs (25%). Positive IMSNs were associated with positive axillary nodes in 71.4% (P = .036). All patients with positive IMSNs were upstaged and received radiation to the internal mammary chain. In 4 of 28 patients (14%) the chemotherapy plans were probably altered. In univariate and multivariate analyses tumor size, location, nuclear grade, estrogen receptors, progesterone receptors, Her-2, and histology were not significant predictors of positivity., Conclusions: IMSNs were positive in 25% of the invasive cancer patients. All had treatment changes. LS identified less than 50% of IMSNs. There are no good tumor-related predictors of IMSN positivity.