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Background: Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [ 18 F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition., Methods: A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [ 18 F]-VAT. Distribution volume (V T ) for [ 18 F]-VAT was derived for each region of interest, and group differences in V T were assessed with 2-sample t tests. Functional significance was explored through correlations between V T and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB)., Results: No group differences in [ 18 F]-VAT V T were observed. However, within the SCZ group, psychosis symptom severity was positively associated with V T in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with V T in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex., Conclusions: In this initial study, the severity of 2 important features of SCZ-psychosis and working memory deficit-was strongly associated with [ 18 F]-VAT V T in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The kappa opioid receptor (KOR) and its endogenous agonist dynorphin have been implicated in multiple psychiatric conditions including psychotic disorders. We tested the hypotheses that kappa expression is elevated and associated with psychotic symptoms in schizophrenia. We measured kappa expression in unmedicated patients with schizophrenia (7 female, 6 male) and matched controls (7 female, 6 male) with positron emission tomography (PET). We also acquired a measurement of cumulative dopamine activity over the life span in the same subjects using neuromelanin sensitive MRI. We hypothesized that neuromelanin accumulation would be higher in patients than controls and that in patients there would be a positive association between KOR availability and neuromelanin accumulation. Fourteen patients and thirteen controls were enrolled. Whole brain dynamic PET imaging data using the KOR selective tracer [ 18 F]LY245998 were acquired. Distribution volume (V T ) was measured with region of interest analysis in 14 brain regions. Neuromelanin accumulation in midbrain dopaminergic nuclei was assessed in the same subjects. Positive and negative symptoms were measured by a clinical psychologist. We did not observe group level differences in KOR expression, neuromelanin accumulation or relationships of these to positive symptoms. Unexpectedly, we did observe strong positive associations between KOR expression and symptoms of anhedonia in the patients (Pearson r > 0.7, uncorrected p < 0.01 in 8 cortical brain regions). We also observed moderate associations between KOR expression and neuromelanin levels in patients. In conclusion, we did not observe a relationship between kappa and symptoms of psychosis but the observed relationship to the negative symptom of anhedonia is in line with recent work testing kappa antagonism as a therapy for anhedonia in depression., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Individuals with substance use disorder show impaired self-awareness of ongoing behavior. This deficit suggests problems with metacognition, operationalized in the cognitive neuroscience literature as the ability to monitor and evaluate the success of one's own cognition and behavior. However, the neural mechanisms of metacognition have not been characterized in a drug-addicted population., Methods: Community samples of participants with opioid use disorder (OUD) (N=27) and healthy controls (N=29) performed a previously-validated fMRI metacognition task (perceptual decision-making task along with confidence ratings of performance). Measures of recent drug use and addiction severity were also acquired., Results: Individuals with OUD had lower metacognitive sensitivity than controls (i.e., disconnection between task performance and task-related confidence). Trial-by-trial analyses showed that this overall group difference was driven by (suboptimally) low confidence in OUD during correct trials. In fMRI analyses, the task engaged an expected network of brain regions (e.g., rostrolateral prefrontal cortex and dorsal anterior cingulate/supplementary motor area, both previously linked to metacognition); group differences emerged in a large ventral anterior cluster that included the medial and lateral orbitofrontal cortex and striatum (higher activation in OUD). Trial-by-trial fMRI analyses showed group differences in rostrolateral prefrontal cortex activation, which further correlated with metacognitive behavior across all participants. Exploratory analyses suggested that the behavioral and neural group differences were exacerbated by recent illicit opioid use and unexplained by general cognition., Conclusions: With confirmation and extension of these findings, metacognition and its associated neural circuits could become new, promising therapeutic targets in addiction., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Increased salience of drug-related cues over non-drug reinforcers can drive drug use and contribute to tobacco use disorder (TUD). An important scientific and clinical goal is to effectively measure this elevated drug-seeking behavior in TUD. However, most TUD assessments rely on self-reported cravings and cigarette consumption, not providing an objective measure of the impact of drug-cues on biasing behavior towards drugs. The probabilistic image choice (PIC) task investigates the choice of viewing drug-related pictures as compared to other salient pictures (e.g., pleasant and unpleasant). This study aimed to develop and validate the PIC task for TUD and evaluate the associations between behavioral choice and tobacco craving, daily cigarette consumption, quit attempts and motivation to quit, and nicotine dependence (the Fagerström score)., Methods: We recruited 468 smokers and 121 nonsmokers using the Prolific online platform. Participants performed the PIC task twice (at a one-month interval) and completed other measures relevant to TUD., Results: compared to nonsmokers, tobacco smokers selected to view significantly more tobacco images and less pleasant (non-drug reinforcer) images, a profile that remained stable at retest. Individual differences in choice of tobacco as compared to pleasant images on the PIC task were associated with craving but not with the other tobacco dependence measures, suggesting that the task may serve as a behavioral proxy measure of drug "wanting" rather than of cumulative nicotine exposure or physical dependence., Conclusions: these results suggest that the PIC task can be a valuable tool for objectively assessing craving-associated tobacco seeking in TUD., Implications Section: which should provide a brief description about what the study addsMost of the current measures of tobacco use disorder (TUD) rely on self-reports of consumption, dependence and craving and do not take into consideration the role of drug-related cues in driving tobacco seeking. This study shows that the probabilistic image choice (PIC) task provides an objective, reliable proxy measure of tobacco image seeking behavior in people who smoke cigarettes that is linked to craving (desire) for smoking but not to other measures of TUD. Therefore, the PIC task may be a useful complementary tool for the classification, diagnosis, and prognosis of TUD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Influential accounts of addiction posit alterations in adaptive behavior driven by deficient dopaminergic prediction errors (PEs), signaling the discrepancy between actual and expected reward. Dopamine neurons encode these error signals in subjective terms, calibrated by individual risk preferences, as "utility" PEs. It remains unclear, however, whether people with drug addiction have PE deficits or their computational source. Here, using an analogous task to prior single-unit studies with known expectancies, we show that fMRI-measured PEs similarly reflect utility PEs. Relative to control participants, people with chronic cocaine addiction demonstrate reduced utility PEs in the dopaminoceptive ventral striatum, with similar trends in orbitofrontal cortex. Dissecting this PE signal into its subcomponent terms attributed these reductions to weaker striatal responses to received reward/utility, whereas suppression of activity with reward expectation was unchanged. These findings support that addiction may fundamentally disrupt PE signaling and reveal an underappreciated role for perceived reward value in this mechanism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: Cannabis use disorder (CUD) prevalence has increased, while perceived risks of cannabis use and CUD treatment need have decreased. Chronic cannabis use may also impair the neural and behavioral mechanisms of insight, further hampering treatment-seeking. This study aimed to measure whether CUD is characterized by reduced self-monitoring in drug-related contexts (objectively-assessed insight), subserved by functional neural abnormalities in error-processing and manifested clinically as decreased awareness of the need to change., Design: Case-control laboratory study was used., Setting: University setting was in Alabama, USA., Participants: There were 42 CUD participants and 47 age-, sex-, and nicotine use-matched controls., Measurements: Participants completed a probabilistic choice task, adapted for the first time for CUD, in which they selected pleasant, unpleasant, neutral, and cannabis-related images according to their preference. Reduced versus accurate insight was operationalized as the correspondence between self-reported and actual most chosen image type. Neurophysiological error-processing during an inhibitory control task was recorded using electroencephalography. Participants with CUD completed measures of cannabis problem recognition and motivation to change., Findings: Compared with controls, the CUD group made significantly more cannabis selections on the choice task (mean difference [MD] = 8.11, 95% confidence interval [CI] [4.88 11.35], p < 0.001) and had significantly reduced insight into cannabis choice (odds ratio [OR] = 9.69, 95% CI [1.06 88.65], p = 0.04). CUD participants with reduced insight on the choice task had significantly decreased neurophysiological reactivity to errors on the inhibitory control task (error-related negativity) compared with CUD participants with accurate insight (MD = 2.64 μV, 95% CI [0.74 μV 4.54 μV], p = 0.008) and controls (MD = 4.05 μV, 95% CI [1.29 μV 6.80 μV], p = 0.005). Compared with CUD participants with accurate insight on the choice task, CUD participants with reduced insight reported significantly less agreement that they had a cannabis problem (MD = -5.06, 95% CI [-8.49-1.62], p = 0.003)., Conclusions: People with CUD who show reduced insight on a drug-related choice task may also have decreased early neural error-processing and less cannabis problem recognition., (© 2023 Society for the Study of Addiction.)

The U.S. pork supply chain is vulnerable to various internal and external threats and in need of prompt, comprehensive response plans. Under urgent circumstances, for example in the case of foreign disease incursions, swine farms will have to perform on-farm animal depopulation to prevent disease spread. Several animal depopulation methods including water-based foam (WBF) have been proposed and are under evaluation for feasibility in the field. However, the psychological/emotional impacts of applying depopulation methods for personnel managing and carrying on the tasks are not currently well understood. Thus, this study aimed to investigate WBF as an alternative for depopulation compared to existing methods approved by the American Veterinary Medical Association. Swine industry stakeholders were invited to voluntarily observe a WBF depopulation trial and to provide their self-reported perspectives before and after the observation. A survey was designed to explore key areas on expected and perceived method effectiveness, efficiency, and animal welfare considerations, as well as to evaluate short-term post-observation psychological impacts. Among 42 recruited stakeholders, 31.0% (13/42) were educators/researchers followed by animal health officials (26.2%, 11/42) and veterinarians (23.8%, 10/42), with an average of 11.7 ± 12.6 (n = 39) years of work experience. After the trial, respondents' positive perception of WBF depopulation increased specifically regarding the animal loading process being less stressful than restrained in-barn depopulation options (P = 0.003) and by the observation of fewer swine escape attempts and vocalizations than expected (P < 0.001). Respondents' positive perception of WBF also increased regarding to the time required to fill the trailer with foam, to stop hearing animal vocalization, and stop hearing animal movement, as the observed trial times were faster than their pre-observation estimates (P < 0.001). Additionally, 79.5% (31/39) of respondents agreed that the rapid destruction of animal populations had priority over animal welfare under urgent scenarios. Minor post-traumatic stress disorder-like (PTSD-like) symptoms from the observed trials were reported (26.7%, 4/15 respondents) one month after the observation. This study showed that the WBF depopulation process was perceived positively by swine stakeholders and may have limited short-term psychological impacts on personnel involved in animal depopulation., Competing Interests: The author(s) declare(s) that there are no conflicts of interest regarding the publication of this article., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Lapses in inhibitory control have been linked to relapse in human drug addiction. Evidence suggests differences in inhibitory control depending on abstinence duration, but the underlying neural mechanisms remain unknown. We hypothesized that early abstinence (2-5 days) would be characterized by the strongest impairments of inhibitory control and most wide-spread deviations in resting-state functional connectivity of brain networks, while longer-term abstinence (>30 days) would be characterized by weaker impairments as compared to healthy controls. In this laboratory-based cross-sectional study, we compared individuals with Cocaine Use Disorder (iCUD) during early (cocaine urine-positive: N = 19, iCUD+; 32% female; mean age: 46.8 years) and longer-term abstinence (cocaine urine-negative: N = 29, iCUD-; 15% female; mean age: 46.6 years) to healthy controls (N = 33; 24% female; mean age: 40.9 years). We compared the groups on inhibitory control performance (Stop-Signal Task) and, using a whole-brain graph theory analysis (638 region parcellation) of functional magnetic resonance imaging (fMRI) data, we tested for group differences in resting-state brain function (local/global efficiency). We characterized how resting-state brain function was associated with inhibitory control performance within iCUD. Inhibitory control performance was worst in the early abstinence group, and intermediate in the longer-term abstinence group, as compared to the healthy control group (P < 0.01). More recent use of cocaine (CUD+ > CUD- > healthy controls) was characterized by decreased efficiency in fronto-temporal and subcortical networks (primarily in the salience, semantic, and basal ganglia networks) and increased efficiency in visual networks. Importantly, a similar functional connectivity pattern characterized impaired inhibitory control performance within iCUD (all brain analyses P < 0.05, FWE-corrected). Together, we demonstrated that a similar pattern of systematic and widespread deviations in resting-state brain efficiency, extending beyond the networks commonly investigated in human drug addiction, is linked to both abstinence duration and inhibitory control deficits in iCUD., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Current options for depopulation of adult cattle are limited, have logistic constraints, and may not be practical on a large scale. Aspirated water-based foam ( WBF ) has been shown to be successful in depopulating poultry and swine but has yet to be tested in cattle. WBF is advantageous because necessary equipment can be readily available, easy to use, and presents minimal personnel risk. With the use of a modified rendering trailer in a field setting, we evaluated the efficacy of aspirated WBF for depopulation of adult cattle. Water-based medium-expansion foam was added to the trailer holding cattle to a depth of approximately 50 cm greater than head height. The study was conducted as a gated design and the initial trial was conducted using six anesthetized and six conscious animals for verification of the process and followed by four replicates each containing 18 conscious cattle. A total of 84 cattle were used, with a subset ( n  = 52) implanted with subcutaneous bio-loggers that recorded activity and electrocardiograms. Cattle were loaded onto the trailer and three gasoline-powered water pumps delivered foam into the trailer followed by a 15-min foam dwell period. Average (± SD) time to completely fill the trailer with foam was 84.8 ± 11.0 s. No animal vocalizations were heard during foam application or the dwell period, and all cattle were confirmed dead upon removal from the trailer after 15 min of immersion. Necropsies of a subset of cattle revealed foam extending to at least the tracheal bifurcation in all cattle and distal to this level in 67% (8/12) animals. Time to cessation of movement, which served as a proxy for loss of consciousness, was 2.5 ± 1.3 min and time to cardiac death was 8.5 ± 2.5 min as determined by data from animals carrying subcutaneous bio-loggers. The results of this study indicate that WBF is a rapid and effective method for depopulation of adult cattle with potential advantages in speed and carcass handling and disposal over current methods., Competing Interests: The authors report no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Society of Animal Science.)

The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post-traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety. This review highlights a critical gap in the biomarker validation process. An enormous societal investment over the past 50 years has identified numerous candidate biomarkers. However, to date, the overwhelming majority of these measures have not been proven sufficiently reliable, valid and useful to be adopted clinically. It is time to consider whether strategic investments might break this impasse, focusing on a limited number of promising candidates to advance through a process of definitive testing for a specific indication. Some promising candidates for definitive testing include the N170 signal, an event-related brain potential measured using electroencephalography, for subgroup identification within autism spectrum disorder; striatal resting-state functional magnetic resonance imaging (fMRI) measures, such as the striatal connectivity index (SCI) and the functional striatal abnormalities (FSA) index, for prediction of treatment response in schizophrenia; error-related negativity (ERN), an electrophysiological index, for prediction of first onset of generalized anxiety disorder, and resting-state and structural brain connectomic measures for prediction of treatment response in social anxiety disorder. Alternate forms of classification may be useful for conceptualizing and testing potential biomarkers. Collaborative efforts allowing the inclusion of biosystems beyond genetics and neuroimaging are needed, and online remote acquisition of selected measures in a naturalistic setting using mobile health tools may significantly advance the field. Setting specific benchmarks for well-defined target application, along with development of appropriate funding and partnership mechanisms, would also be crucial. Finally, it should never be forgotten that, for a biomarker to be actionable, it will need to be clinically predictive at the individual level and viable in clinical settings., (© 2023 World Psychiatric Association.)

The United States' swine industry is under constant threat of foreign animal diseases, which may emerge without warning due to the globalized transportation networks moving people, animals, and products. Therefore, having disease control and elimination protocols in place prior to pathogen introduction is paramount for business continuity and economic recovery. During extraordinary circumstances, it may become necessary to depopulate large populations of animals, including swine, as a disease containment measure. Currently approved depopulation methods for swine present significant logistical challenges when scaled to large populations or performed in field conditions. In the United States, water-based foam is currently approved for poultry depopulation, and recent field studies demonstrate water-based foam is an effective depopulation alternative for swine. While effective, the speed at which water-based foam induces loss of consciousness prior to death, a major welfare consideration, has not been adequately investigated. In this study, 12 nursery pigs were terminated using water-based medium-expansion foam to quantify the time to induce loss of consciousness and ultimately brain death. Each pig was implanted with subdermal electrodes to capture electroencephalographic data, placed in a body sling, and suspended in a plastic bulk container that was subsequently filled with water-based foam. Electroencephalographic data was recorded for 15 min, during which the pigs remained immersed in the water-based foam. Conservatively, average (± SD) time to unconsciousness and brain death was 1 min, 53 s ± 36 s and 3 min, 3 s ± 56 s, respectively. The relatively rapid loss of consciousness compared to other methods limits the amount of distress and is overall a positive finding for the welfare of the pigs that might be depopulated with water-based foam. The findings of this study add additional evidence supporting the use of water-based medium-expansion foam for an emergency depopulation of swine., (© 2022. The Author(s).)

Background: Modeling addictive behavior among individuals with, or at risk for, opioid use disorder (OUD) in a way that is accurate, ethical, and reproducible presents a pressing concern. OUD risk is elevated among people with chronic pain on long-term opioid therapy (LTOT). Objectives: To provide initial validation of a novel opioid preference task as an index of OUD and its symptomatology among veterans prescribed opioids for chronic pain, a population at high risk for poor opioid-related outcomes. The relative ease by which such a paradigm can be implemented and performed in clinical contexts, including enabling investigation of opioid reinforcement and drug-seeking behavior while avoiding ethical pitfalls associated with direct drug administration, could make this task an attractive approach for potentially tracking OUD symptoms. Methods: We studied 87 veterans (74 males, 13 females) on LTOT for chronic pain - 33 of whom had OUD diagnoses. Participants completed a picture-viewing choice task to assess preference for viewing opioid-related images in comparison with standardized pleasant, unpleasant, neutral, and blank images. Opioid-related choice, measured by vigor of button pressing, was tested for association with OUD severity (measured by symptom counts), as well as craving and anhedonia. Results: Choice for opioid-related images was positively correlated with OUD severity (i.e., number of DSM-5 measured OUD symptoms) (r = 0.38, p < .001), particularly among those meeting diagnostic criteria for OUD (r = 0.47, p = .006). Neither craving nor anhedonia correlated with opioid-related choice. Conclusions: Our results provide initial validation for a new opioid picture-choice paradigm in patients with chronic pain.

The threat of foreign animal disease introduction through contaminated animal products, feed ingredients, and wildlife vectors have highlighted the need for additional approved methods for mass depopulation of swine under emergency scenarios, especially methods that can be applied to pigs across all production phases. The market disruption within the swine industry due to the SARS-CoV-2 pandemic has demonstrated this lack of preparation. The objective of this study was to validate water-based foam as a mass depopulation method for suckling (18 to 24 days of age) and finisher stage (63 to 100 days of age) pigs. Finisher pigs ( n = 31, originally 32 but one finisher pig died prior to foaming), allocated as 9 triads and 1 set of 4 pigs, in 10 total replicates, and suckling pigs ( n = 32), randomly allocated to two replicates, were completely covered in water-based medium-expansion foam for a 15-min dwell time in a bulk container. Container fill time for the trials were 6.5 ± 0.68 s and 5.3 ± 0.03 s for finisher and suckling pig replicates, respectively. Average (± SD) time for cessation of movement was 105 ± 39.1 s (s) for finisher pigs and 79.5 ± 10.5 s for suckling pigs. After completion of the 15-min dwell time in the foam, all pigs were confirmed dead upon removal from the container. The results from the present study suggest that the use of water-based foam can be an effective means of mass depopulation for suckling and finisher stage pigs, supporting previous research on the application to adult swine.

Electrocution and the use of a penetrating captive bolt gun (PCBG) are both acceptable methods of euthanasia for market weight swine. Research has demonstrated that a PCBG is effective in both growing and mature swine. Given limited to no published research base on electrocution in mature swine, the objectives of the present study were to evaluate the efficacy of a two-stage (head only followed by head to heart, 10 s contact for each) mobile electric stunner (E-STUN, Hubert HAAS TBG 96N) and to assess euthanasia outcomes when comparing E-STUN with the frontal placement of a heavy-duty PCBG (Jarvis, In-line Cylinder Style) when applied to heavy-weight (>200 kg) mature boars and sows. Effectiveness of the E-STUN and PCBG was evaluated first in unconscious anesthetized mature swine (n = 7 boars and sows per treatment; average weight 282 ± 48 kg, n = 28) to reduce the risk of failure in a conscious animal and then in conscious mature swine (n = 3 boars and sows per treatment; average weight 282 ± 63 kg, n = 12). Data from both stages were combined for analyses. Treatment efficacy was defined as any pig that achieved cardiac and respiratory arrest within 10 min after treatment application. A three-point traumatic brain injury score (0 = normal; 1 = some abnormalities; and 2 = grossly abnormal, unrecognizable) was used to evaluate six neuroanatomical structures (cerebral cortex, cerebellum, hypothalamus, thalamus, pons, and brain stem), and the presence of intracranial hemorrhage was also noted. All animals were immediately rendered insensible with E-STUN and PCBG, and no difference was noted between treatments for the detection of corneal reflex following treatment application (P = 0.11). Rhythmic breathing was absent following the administration of either E-STUN or PCBG. When evaluating the time to last heartbeat, there was a significant interaction between sex and treatment. Boars euthanized via E-STUN had a 346.8-s decrease in time to last heartbeat compared with boars euthanized via PCBG (P < 0.001), and females euthanized via E-STUN had a 479.3-s decrease in time to last heartbeat compared with females euthanized via PCBG (P < 0.001). Intracranial hemorrhage was common for both methods, and visible disruption of neural tissue was evident due to the physical nature of the PCBG. This study demonstrated that a mobile E-STUN system is as effective as a heavy-duty PCBG in inducing insensibility and death and shows promise as an alternative method for euthanizing mature pigs on-farm., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia., (© 2022. The Author(s).)

Background: The majority of adolescents and young adults (AYA) who use cannabis also use alcohol. Although cannabis use is increasing in the United States (US), it is not known whether the increase contributes to either increased co-use of alcohol and cannabis (e.g., complementarity) or replacement of alcohol with cannabis (e.g., substitution). The current study estimated the prevalence of alcohol use by cannabis use status among US AYA ages 12 to 25 in 2018 and trends in alcohol use by cannabis use status from 2002 to 2018., Methods: Data were drawn from the 2002 to 2018 National Survey on Drug Use and Health public use data files. The analytic sample included AYA ages 12 to 25 (2018 sample, n = 26,924; total combined sample 2002 to 2018, n = 576,053). Linear and logistic regression models were used to estimate past-month alcohol use, daily alcohol use, and average quantity of alcohol consumed among AYA with and without past-month cannabis use from 2002 to 2018., Results: In 2018, any alcohol use and daily alcohol use were significantly more common among AYA who used cannabis use than those who did not use cannabis. Overall, any alcohol use, daily alcohol use, and average drinks per day declined from 2002 to 2018 among AYA irrespective of recent cannabis use. However, the decline in any alcohol use, daily alcohol use, and average alcohol drinks per day was more rapid among AYA who used cannabis (daily and nondaily) than those who did not use cannabis. The rate of decline in average alcohol drinks per day was also higher among AYA with daily compared to nondaily cannabis use., Conclusions: Even with declines in alcohol use over time, drinking is much more common among AYA who report cannabis than those without recent cannabis use, which is consistent with complementarity. Yet, because the decline in alcohol use has been more rapid among AYA who use cannabis, there is also evidence of substitution. Thus, the current data on alcohol and cannabis use are consistent with both complementarity and substitution. However, these relationships may change as cannabis legalization expands over time., (© 2021 by the Research Society on Alcoholism.)

Purpose of Review: Clinical insight is an emerging interest in substance use disorder research, but is difficult to study empirically. We reviewed recent research examining the behavioral and neural correlates of several psychological processes tapping into self-awareness that may in turn contribute to insight., Recent Findings: Individuals with substance use disorder exhibit deficits in self-monitoring (especially self-report / behavior dissociations), metacognition, alexithymia, readiness for behavior change, and interoception. Behavioral impairments have been further linked to neural abnormalities in a diverse network of brain regions encompassing cortical midline areas, insula, and frontal cortex, among others. Various treatment modalities may target these deficits, though corresponding effects on neural circuitry remain to be determined., Summary: Compromised insight in substance use disorder may be relevant to a constellation of behaviors that suggest a lack of behavioral awareness linked to drug use. Future work needs to refine and advance the measurements, continuing to investigate insight problems in addiction that may become important therapeutic targets., Competing Interests: Disclosure/Conflict of Interest The authors declare no competing financial interests.

The U.S. swine industry is currently inadequately prepared to counteract the increasing threat of high-consequence diseases. Although approved and preferred depopulation guidelines exist, ventilation shutdown (VSD+) is currently the only method being deployed during a state of emergency to depopulate large swine populations. However, the permitted use of VSD+ during constrained circumstances has been criticized due to raised swine welfare concerns. The objective of this study was to investigate the effectiveness of carbon dioxide gas (CO 2 ), nitrogen gas (N 2 ), compressed air foam (CAF), compressed nitrogen foam (CAF-N 2 ) and aspirated foam (AF) during a 15-min dwell time on adult swine in an emergency depopulation situation. A small-scale trial using 12 sows per depopulation method showed the highest efficiency to induce cessation of movement for AF and CO 2 (186.0 ± 48 vs. 202.0 ± 41, s ± SD). The ease of implementation and safety favored AF for further investigation. A large-scale field study using AF to depopulate 134 sows in modified rendering trailers showed a mean fill time of 103.8 s (SD: 5.0 s) and cessation of movement of 128.0 s (SD: 18.6 s) post filling. All sows were confirmed dead post-treatment for both trials. The implementation of AF in modified rendering trailers may allow for a safe and reliable method that allows for the expedient and mobile depopulation of both small and large numbers of sows during an emergency.

A relapse in addiction is often precipitated by heightened attention bias to drug-related cues, underpinned by a subcortically mediated transition to habitual/automatized responding and reduced prefrontal control. Modification of such automatized attention bias is a fundamental, albeit elusive, target for relapse reduction. Here, on a trial-by-trial basis, we used electroencephalography and eye tracking with a task that assessed, in this order, drug cue reactivity, its instructed self-regulation via reappraisal, and the immediate aftereffects on spontaneous (i.e., not instructed and automatized) attention bias. The results show that cognitive reappraisal, a facet of prefrontal control, decreased spontaneous attention bias to drug-related cues in cocaine-addicted individuals, more so in those with less frequent recent use. The results point to the mechanisms underlying the disruption of automatized maladaptive drug-related attention bias in cocaine addiction. These results pave the way for future studies to examine the role of such habit disruption in reducing compulsive drug seeking outside the controlled laboratory environment, with the ultimate goal of developing a readily deployable cognitive-behavioral and personalized intervention for drug addiction., Competing Interests: The authors declare no competing interest.

The present study used 48 lambs originating from three different locations in the Western United States (16 lambs per location; 8 ewes and 8 wethers per location). Each consisting of similar breed composition (Suffolk cross) that were selected to represent weight by age at harvest treatments: light weight carcasses at 5 mo ( LW5 , 31.81 ± 1.88 kg), light weight carcasses at 12 mo ( LW12 , 35.09 ± 4.45 kg), heavy weight carcasses at 12 mo ( HW12 , 57.89 ± 4.70 kg) with different carcass weight compositions. Older heavy weight lambs (HW12) had greater ( P ≤ 0.01) hot carcass weight, ribeye area, backfat and body wall thickness, and yield grade compared with light weight lamb carcasses (LW5 and LW12). The longissimus thoracis longissimus thoracis ( LT ) from older lamb carcasses (LW12 and HW12) had a greater ( P ≤ 0.01) total lipid percentage compared with younger lamb carcasses (LW5). Across harvest weight and age treatments, wether carcasses had greater ( P ≤ 0.05) total lipid percentage compared with ewe carcasses. Slice shear force values were greater ( P ≤ 0.01) for both the LT and semimembranosus from older lambs (LW12 and HW12) compared with LW5 lambs, with no differences between ewes and wethers. Lamb flavor intensity was greater ( P ≤ 0.05) for the LT of LW12 lambs and tended ( P = 0.08) to be greater for HW12 lambs, compared with the LT from LW5 lambs. The off-flavor intensity of the LT was greater ( P ≤ 0.01) for older lambs (LW12 and HW12) compared with LW5 lambs. Interestingly, the lamb flavor and off-flavor intensity scores of the ground shoulder exhibited a treatment × sex interaction. Lamb flavor intensity of LW12 lamb was greater ( P ≤ 0.05) from ewes compared with wethers, whereas wethers had a greater ( P ≤ 0.05) lamb flavor intensity compared with ewes for HW12 lambs, and LW12 ewe lambs had a greater ( P ≤ 0.05) off-flavor intensity compared with all other treatment × sex treatment combinations. Overall, lambs in the present study possessed a mild lamb flavor, typically with greater lamb flavor and off-flavor intensities for older animals; while slice shear force and LT lipid percentage increased as animal age increased at the time of harvest., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Euthanasia of mature swine is challenging. Temporal and behind-the-ear locations are two sites that have been identified as alternatives to the more commonly used frontal placement. In stage one, the effectiveness of two penetrating captive bolt gun styles (cylinder or pistol) was evaluated using frontal, temporal, and behind-the-ear placement in anesthetized mature swine (n = 36; weight: 267 ± 41 kg). For stage one, when evaluating treatment efficacy by sex, the cylinder-style equipment was 100% effective in achieving death when applied to all cranial locations (frontal, temporal, and behind-the-ear) for sows; however, the pistol-style equipment was only 100% effective when applied at the behind-the-ear location for sows. For boars, the cylinder-style equipment was 100% effective when applied to the frontal and behind-the-ear location, but the pistol-style equipment was not effective for any cranial location in boars. Therefore, the pistol-frontal, pistol-temporal, pistol-behind-the-ear, and cylinder-temporal were not included for boars, and pistol-frontal and pistol-temporal were not included for sows in stage two. In stage two, commercial, mixed-breed, mature swine (n = 42; weight: 292 +/- 56 kg) were randomly assigned to one of four treatments based on the inclusion criteria described in stage one. A three-point traumatic brain injury (TBI) score (0 = normal; 1 = some abnormalities; 2 = grossly abnormal, unrecognizable) was used to evaluate six neuroanatomical structures (cerebral cortex, cerebellum, hypothalamus, thalamus, pons, and brain stem), and the presence of hemorrhage was also noted. All treatments were 100% effective in stage two. A significant interaction between gun style and placement was determined on predicting total TBI as the cylinder style produced a higher total TBI score compared with the pistol type of the magnitude of +2.8 (P < 0.01). The cylinder style tended to produce a greater TBI score than the pistol in the temporal location (+1.2; P = 0.08). No difference was noted for TBI score behind-the-ear between the cylinder- and pistol-style gun (P > 0.05). TBI tended to be less in boars compared with sows (-0.6; P = 0.08). Hemorrhage was observed in frontal, parietal, occipital, and temporal lobes. This study demonstrated that the cylinder-style captive bolt gun more effectively resulted in brain trauma and death compared with a pistol-style gun and the behind-the-ear and temporal placement showed promise as an alternative placement site for euthanizing mature pigs on-farm., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Opioid/heroin use is an epidemic in the United States (US). Polysubstance use dramatically increases risk of adverse overdose outcomes, versus use of a single substance. Co-use of heroin and cocaine, known as "speedballing," is associated with higher risk of overdose than use of either alone. It is not known whether co-use relative to use of either alone has increased in the US in recent years at a national level. If so, this may be one contributing factor to the increasing fatality rate associated with the US opioid epidemic. This study investigated the prevalence of use of each and co-use of heroin and cocaine from 2002 to 2017 in the US., Methods: Data were drawn from the 2002 to 2017 National Survey on Drug Use and Health (NSDUH) to estimate prevalence of past-month heroin use, cocaine use, and co-use of heroin and cocaine among Americans ages 12 and older., Results: From 2002 to 2017, cocaine use (without heroin) (adjusted odds ratio (AOR) = 0.971, 95% confidence interval (0.963, 0.979)) declined overall, though a subsequent quadratic analysis suggested that it began increasing in 2011. In contrast, heroin and cocaine co-use (AOR = 1.062 (1.027, 1.099)) and heroin use (without cocaine) (AOR = 1.101 (1.070, 1.133)) linearly increased from 2002 to 2017., Conclusions: Screening, outreach, clinical treatment, and first responders should be aware of increasing patterns of polysubstance use and the potential implications of co-use of heroin and cocaine on first responders' intervention and the potential role of increasing exposure to multiple substances on overdose outcomes in the US., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The enzyme aromatase catalyzes the final step in estrogen biosynthesis, converting testosterone to estradiol, and is expressed in the brain of all mammals. Estrogens are thought to be important for maintenance of cognitive function in women, whereas testosterone is thought to modulate cognitive abilities in men. Here, we compare differences in cognitive performance in relation to brain aromatase availability in healthy men and women. Twenty-seven healthy participants were administered tests of verbal learning and memory and perceptual/abstract reasoning. In vivo images of brain aromatase availability were acquired in this sample using positron emission tomography (PET) with the validated aromatase radiotracer [ 11 C]vorozole. Regions of interest were placed bilaterally on the amygdala and thalamus where aromatase availability is highest in the human brain. Though cognitive performance and aromatase availability did not differ as a function of sex, higher availability of aromatase in the amygdala was associated with lower cognitive performance in men. No such relationship was found in women; and the corresponding regression slopes were significantly different between the sexes. Thalamic aromatase availability was not significantly correlated with cognitive performance in either sex. These findings suggest that the effects of brain aromatase on cognitive performance are both region- and sex-specific and may explain some of the normal variance seen in verbal and nonverbal cognitive abilities in men and women as well as sex differences in the trajectory of cognitive decline associated with Alzheimer's disease., (Copyright © 2020 Alia-Klein, Preston-Campbell, Kim, Pareto, Logan, Wang, Moeller, Fowler and Biegon.)

The effects of dietary energy source, energy level, sheep age, and sheep sex on flavor and off-flavor intensity were evaluated. Consumer panelists, with previous lamb-eating experience, assessed lamb flavor and off-flavor intensity on a 100-point, end-anchored scale (0 = very mild to 100 = very intense), with off-flavor being defined as anything different than lamb flavor. Lamb longissimus thoracis (LT) and whole, boneless ground shoulder (GS) formed into patties were evaluated. Trial 1 was a randomized complete block design with a 3 × 2 factorial arrangement of treatments. Sheep age (ewe lambs, yearling ewes, and mature ewes; n = 16/age) and ad libitum access to diets [alfalfa pellets (AP) or whole-shelled corn (WSC100)] were treatments. The LT from mature ewes had a greater ( P ≤ 0.02) off-flavor intensity when compared with yearling ewes and ewe lambs. Ground shoulder from sheep raised on AP had a greater lamb flavor ( P ≤ 0.04) and off-flavor ( P ≤ 0.04) intensity than GS from sheep consuming WSC100. Trial 2 was a randomized complete block design with a 3 × 2 × 2 factorial arrangement of treatments. Three dietary treatments [AP, WSC100, and restricted intake of whole-shelled corn to 85% of ad libitum (WSC85)], lamb sex (ewes and wethers; n = 48/sex), and lamb age [short fed, 177 ± 16.6 d of age and 93 ± 20.5 d on feed (DOF); long fed, 294 ± 7.0 d of age and 219 ± 3.8 DOF]. Flavor intensity of the LT was greater ( P ≤ 0.05) from lambs offered AP when compared with lambs offered WSC85, whereas lamb flavor of the LT from lambs fed WSC100 was intermediate and not different from the lamb flavor of the LT of lambs fed AP or WSC85. The LT of long-fed lambs had a greater ( P ≤ 0.01) lamb flavor and off-flavor intensity when compared with short-fed lambs. Lambs offered AP resulted in a GS with greater lamb flavor intensity ( P ≤ 0.01) when compared with lambs offered WSC85 and WSC100, with no diet influence on GS off-flavor intensity. Long-fed lambs produced GS with a greater lamb flavor ( P ≤ 0.01) and off-flavor ( P ≤ 0.01) intensity when compared with GS from short-fed lambs. Results from the two trials indicate lamb flavor and off-flavor intensity were greater from sheep offered a high-forage (AP) diet when compared with a high-concentrate (WSC) diet. Lamb flavor intensity increased as age of the sheep at harvest increased, suggesting dietary management and associated age-related effects at harvest will influence consumer perception of lamb flavor., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: Multiple psychopathologies feature impaired clinical insight. Emerging evidence suggests that insight problems may similarly characterize addiction, perhaps due to aberrant functioning of self-referential brain circuitry, including the rostral anterior cingulate and ventromedial prefrontal cortices (rACC/vmPFC). We developed a new fMRI task to probe whether rACC/vmPFC abnormalities in cocaine use disorder (CUD) constitute neural correlates of readiness to change, one facet of insight., Methods: Eighteen individuals with current CUD and 15 healthy controls responded about their own need to change their drug use and eating behavior (control condition) and the need for a named acquaintance to do the same (two additional control conditions). Measures of simulated drug-choice behavior, addiction severity, and neuropsychological function were collected outside the scanner., Results: CUD participants perceived a greater need for behavior change than controls (as expected, given their diagnosis), but fell short of "agreeing" to a need for change; in CUD, lower perceived need correlated with higher simulated drug-choice behavior, a proxy measure of drug-seeking. During drug-related insight judgments, CUD participants had higher activation than controls in an anatomically-defined region of interest (ROI) in the medial orbitofrontal cortex, part of the rACC/vmPFC. Although not showing group differences, activation in an anatomically-defined ACC ROI correlated with insight-related task behavior (in all participants) and memory performance (in CUD)., Conclusions: As a group, individuals with current CUD appear to show mild insight problems and rACC/vmPFC abnormalities vis-à-vis readiness to change behavior. With replication and extension of these results, insight-related circuitry may emerge as a novel therapeutic target., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Most individuals with substance use disorders (SUDs) do not seek treatment. Lack of perceived treatment need (PTN) is one contributing factor, but little is known about PTN over time. We estimated whether PTN changed over three years among those with SUDs in the United States and identified select variables, including sociodemographics and symptom burden, that predict malleability vs. stability of PTN., Methods: Data were from Waves 1 (collected 2001-2002) and 2 (collected 2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC); 1695 adults who met DSM criteria for alcohol or non-alcohol SUD at Wave 1 and maintained ≥1 diagnostic symptom at Wave 2 were included., Results: Most individuals with SUDs (77.2%) did not perceive a need for treatment at Wave 1 baseline. Only about 1 in 8 individuals not perceiving a need for treatment in Wave 1 came to perceive a need in Wave 2 (adjusted odds ratio = 0.18, 99% confidence interval = 0.11-0.29). In contrast, about half the individuals who perceived a need for treatment in Wave 1 no longer did so in Wave 2, despite maintaining ≥1 SUD symptom. Married respondents, and respondents with more SUD symptoms, were more likely to transition from low- to high-PTN status three years later. Respondents with incomes >$35,000 were less likely to transition to high-PTN status three years later., Conclusions: PTN was more likely to decline than increase over time. Low PTN appears to be stable among adults with SUDs in the United States, presenting a potentially enduring barrier to treatment-seeking., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2020. Published by Elsevier B.V.)

The objective of this study was to find a practical means of reducing pain associated with surgical castration by evaluating the effects of oral meloxicam and topical lidocaine, separately and in combination, on behavioral indicators of pain in piglets. Two hundred thirty-five piglets were surgically castrated between three and seven days of age. Immediately following castration, piglets received one of four treatments: (1) No pain mitigation (C; control; n = 58); (2) NSAID only (M; meloxicam; n = 59); (3) Topical anesthetic (L; lidocaine spray; n = 60); or (4) NSAID and topical anesthetic (X; meloxicam and lidocaine spray; n = 59). Behaviors were recorded by direct observation of individual piglets using five-minute scan samples over a five-hour period, for three days post-castration. Results of the experiment demonstrate the administration of oral meloxicam and topical lidocaine spray at the time of castration under the current methods did not mitigate pain associated with the procedure ( P  = 0.09; C: 2.1 ± 0.1, L: 2.4 ± 0.1, M: 2.1 ± 0.1 and X: 2.1 ± 0.1).

The U.S. Department of Agriculture (USDA) yield grade (YG) equation is used to predict the retail yield of beef carcasses, which facilitates a more accurate payment for cattle when they are sold on a grid pricing system that considers carcass composition instead of body weight alone. The current USDA YG equation was developed over 50 yr ago. Arguably, the population of cattle used to develop the YG equation is different than the current diverse U.S. beef cattle supply today. The objectives of this manuscript are to promote the adoption and use of precision agriculture technologies (i.e., camera grading and electronic animal identification) throughout the U.S. beef supply chain as a means to enhance the ability of the USDA YG equation to more accurately predict the retail yield across the population of cattle that contributes to the current U.S. beef supply. Camera grading has improved the accuracy of determining beef carcass retail yield; however, the use of electronic animal identification would allow for additional information to be passed back and forth between the packer, cattle feeder, and producer. Information, such as sex, genetics, medical treatment history, diets consumed, and growth promotant administration, as well as other information could be used to create additional variables for a new augmented USDA YG equation. Herein, fabrication yields demonstrated a 5.6 USDA YG and 12.8% boneless closely trimmed retail cut difference between actual cutout measurements and calculated values from the USDA YG equation for Jersey-influenced cattle. Evidence of such disparities between calculated and actual values warrants a reevaluation of the USDA YG system and consideration for implementing advancements in precision agriculture to improve the prediction of beef carcass retail yield to more accurately account for the large amount of variation in beef carcass retail yield from the cattle in the United States., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: The USA is currently enduring an opioid crisis. Identifying cost-effective, easy-to-implement behavioral measures that predict treatment outcomes in opioid misusers is a crucial scientific, therapeutic, and epidemiological goal., Methods: The current study used a mixed cross-sectional and longitudinal design to test whether a behavioral choice task, previously validated in stimulant users, was associated with increased opioid misuse severity at baseline, and whether it predicted change in opioid misuse severity at follow-up. At baseline, data from 100 prescription opioid-treated chronic pain patients were analyzed; at follow-up, data were analyzed in 34 of these participants who were non-misusers at baseline. During the choice task, participants chose under probabilistic contingencies whether to view opioid-related images in comparison with affectively pleasant, unpleasant, and neutral images. Following previous procedures, we also assessed insight into choice behavior, operationalized as whether (yes/no) participants correctly self-reported the image category they chose most often., Results: At baseline, the higher choice for viewing opioid images in direct comparison with pleasant images was associated with opioid misuse and impaired insight into choice behavior; the combination of these produced especially elevated opioid-related choice behavior. In longitudinal analyses of individuals who were initially non-misusers, higher baseline opioid v. pleasant choice behavior predicted more opioid misuse behaviors at follow-up., Conclusions: These results indicate that greater relative allocation of behavior toward opioid stimuli and away from stimuli depicting natural reinforcement is associated with concurrent opioid misuse and portends vulnerability toward future misuse. The choice task may provide important medical information to guide opioid-prescribing practices.

Although there is general consensus that altered brain structure and function underpins addictive disorders, clinicians working in addiction treatment rarely incorporate neuroscience-informed approaches into their practice. We recently launched the Neuroscience Interest Group within the International Society of Addiction Medicine (ISAM-NIG) to promote initiatives to bridge this gap. This article summarizes the ISAM-NIG key priorities and strategies to achieve implementation of addiction neuroscience knowledge and tools for the assessment and treatment of substance use disorders. We cover two assessment areas: cognitive assessment and neuroimaging, and two interventional areas: cognitive training/remediation and neuromodulation, where we identify key challenges and proposed solutions. We reason that incorporating cognitive assessment into clinical settings requires the identification of constructs that predict meaningful clinical outcomes. Other requirements are the development of measures that are easily-administered, reliable, and ecologically-valid. Translation of neuroimaging techniques requires the development of diagnostic and prognostic biomarkers and testing the cost-effectiveness of these biomarkers in individualized prediction algorithms for relapse prevention and treatment selection. Integration of cognitive assessments with neuroimaging can provide multilevel targets including neural, cognitive, and behavioral outcomes for neuroscience-informed interventions. Application of neuroscience-informed interventions including cognitive training/remediation and neuromodulation requires clear pathways to design treatments based on multilevel targets, additional evidence from randomized trials and subsequent clinical implementation, including evaluation of cost-effectiveness. We propose to address these challenges by promoting international collaboration between researchers and clinicians, developing harmonized protocols and data management systems, and prioritizing multi-site research that focuses on improving clinical outcomes., (Copyright © 2019 Verdejo-Garcia, Lorenzetti, Manning, Piercy, Bruno, Hester, Pennington, Tolomeo, Arunogiri, Bates, Bowden-Jones, Campanella, Daughters, Kouimtsidis, Lubman, Meyerhoff, Ralph, Rezapour, Tavakoli, Zare-Bidoky, Zilverstand, Steele, Moeller, Paulus, Baldacchino and Ekhtiari.)

Disproportionate anger and reactive aggression in response to provocation are core symptoms of intermittent-explosive disorder (IED). Previous research shows a link between the propensity for aggression in healthy individuals and altered functioning of prefrontal-limbic and default-mode networks (DMN) at rest when no provocation is present. In a pilot study, we used resting-state functional magnetic resonance imaging to investigate the effects of pronounced reactive aggression in men, exemplified by IED, on the functional organization of resting-state brain networks including subcortical nodes such as the habenula previously implicated in aggression in preclinical models. Graph theory was applied to resting-state networks to determine alterations in global efficiency and clustering in high reactive aggressive men compared to low reactive aggressive men (controls). Further, we computed within-group correlations between trait aggression and graph measures, as well as within-group whole-brain seed-to-voxel regression analyses between trait aggression and habenula resting-state functional connectivity (rsFC). Reactive aggressive men compared to controls showed higher global efficiency in the left habenula, the left pulvinar in the thalamus, the left dorso-lateral prefrontal cortex, and the right temporal pole, as well as a trend for decreased clustering in DMN nodes. In the reactive aggressive group, high levels of trait aggression were linked to lower global efficiency of the left habenula, and to lower rsFC between the left habenula and the left ventro-lateral prefrontal cortex, a core region involved in inhibitory control. Together with preclinical evidence, our findings in men underline the relevance of aberrant habenula-prefrontal connectivity for the severity of aggressive behavior. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Individual with substance use disorders have well-recognized impairments in cognitive control, including in behavioral adaptation after mistakes. One way in which this impairment manifests is via diminished post-error slowing, the increase in reaction time following a task-related error that is posited to reflect cautionary or corrective behavior. Yet, in the substance use disorder literature, findings with regard to post-error slowing have been inconsistent, and thus could benefit from quantitative integration. Here, we conducted a meta-analysis of case-control studies examining post-error slowing in addiction. Twelve studies with 15 unique comparisons were identified, comprising 567 substance users and 384 healthy controls across three broad types of inhibitory control paradigms (go-no/go, conflict resolution, and stop signal tasks, respectively). Results of the random-effects meta-analysis revealed a moderate group difference across all studies (Cohen's d = 0.31), such that the individuals with substance use disorder had diminished post-error slowing compared with controls. Despite this omnibus effect, there was also large variability in the magnitude of the effects, explained in part by differences between studies in task complexity. These findings suggest that post-error slowing may serve as a promising and easy-to-implement measure of cognitive control impairment in substance use disorder, with potential links to aberrant brain function in cognitive control areas such as the anterior cingulate cortex., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Feedlot performance, carcass yield, fatty acid composition, and tenderness of crossbred Jersey steers compared with purebred Jersey steers was investigated. Purebred Jersey ( n = 21) and crossbred Jersey steers sired by Angus ( n = 9), SimAngus ( n = 10), and Red Wagyu ( n = 15) bulls were assessed. Adjusted to a common initial body weight (BW), crossbred Jersey steers had a greater rate of BW gain ( P ≤ 0.01) compared with purebred Jersey steers. Angus sired steers had a greater daily dry matter intake ( P ≤ 0.01) compared with Wagyu and Jersey sired steers, whereas SimAngus sired steers had a greater daily dry matter intake compared with Jersey sired steers. Wagyu sired steers were more feed efficient ( P ≤ 0.03) compared with Jersey sired steers. Even with a greater ( P ≤ 0.01) number of days on feed, off-test BW of purebred Jersey steers was less ( P ≤ 0.01) compared with crossbred Jersey steers. Adjusted to a common hot carcass weight, Angus sired steers had a greater backfat thickness ( P ≤ 0.01) compared with steers from the other sire breeds. Kidney fat percentage ( P ≤ 0.01) was greatest for Jersey sired steers, with SimAngus and Wagyu sired steers being intermediate, and the lowest for Angus sired steers. Carcasses from Angus and Wagyu sired steers had a greater marbling score ( P ≤ 0.03) compared with carcasses from Jersey sired steers. Carcasses from Wagyu sired steers had a greater (P ≤ 0.01) total red meat yield compared with Angus and Jersey sired steers, whereas SimAngus sired steers had a greater total red meat yield compared with Jersey sired steers. Carcasses from Angus sired steers tended ( P = 0.07) to have a greater percentage of fat trim compared with Wagyu sired steer carcasses. There were no sire breed differences ( P = 0.38) for the percentage of total bone from the carcasses. Tenderness, measured by Warner-Bratzler shear force (WBSF), was improved (P ≤ 0.01) with 14 d of postmortem aging compared with 7 d. Wagyu and SimAngus sired steers produced steaks with a lesser (P ≤ 0.01) WBSF compared with steaks from Angus and Jersey sired steers. Steaks from Angus sired steers tended ( P = 0.10) to have a greater percentage of total lipid and had a greater (P ≤ 0.05) percentage of 16:0 compared with steaks from Jersey sired steers. Overall, crossbred Jersey steers improved economically relevant production parameters of feedlot performance, carcass quality, carcass yield, and instrumental predictors of eating quality compared with purebred Jersey steers., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science.)

The objective of this study was to describe the pharmacokinetics (PK) of flunixin in 12 nonlactating sows following transdermal (TD) flunixin (3.33 mg/kg) and intravenous (IV; 2.20 mg/kg) flunixin meglumine (FM) administration using a crossover design with a 10-day washout period. Blood samples were collected postadministration from sows receiving IV FM (3, 6, 10, 20, 40 min and 1, 3, 6, 12, 16, 24, 36, and 48 hr) and from sows receiving TD flunixin (10, 20, 40 min and 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, and 72 hr). Liquid chromatography and mass spectrometry were used to determine plasma flunixin concentrations, and noncompartmental methods were used for PK analysis. The geometric mean ± SD area under the plasma concentration-time curve (AUC) following IV injection was 26,820.59 ± 9,033.88 and 511.83 ± 213.98 hr ng/ml for TD route. Mean initial plasma concentration (C 0 ) was 26,279.70 ± 3,610.00 ng/ml, and peak concentration (C max ) was 14.61 ± 7.85 ng/ml for IV and TD administration, respectively. The percent mean bioavailability of TD flunixin was 1.55 ± 1.00. Our results demonstrate that topical administration is not an efficient route for delivering flunixin in mature sows., (© 2019 John Wiley & Sons Ltd.)

Background: The US National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal of improving diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions., Methods: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions., Results: Seven constructs were endorsed by ≥ 80% of experts as 'primary' to the understanding of addictive behaviour: five from the Positive Valence System (reward valuation, expectancy, action selection, reward learning, habit); one from the Cognitive Control System (response selection/inhibition); and one expert-initiated construct (compulsivity). These constructs were rated to be related differentially to stages of the addiction cycle, with some linked more closely to addiction onset and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions., Conclusions: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment., (© 2018 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Rationale: Attentional bias toward drug-related stimuli is a feature of drug addiction that is linked to craving and drug-seeking behavior., Objectives/method: An attentional bias modification (ABM) program was tested in 42 methamphetamine-dependent clients (DSM-IV criteria) receiving residential treatment for their drug use. Participants were randomly assigned to one of two groups (N = 21 each), receiving 12 sessions of either computerized ABM training (designed to train attention away from methamphetamine stimuli 100% of the time) or an attentional control condition (designed to train attention away from methamphetamine stimuli 50% of the time). Outcome measures included attentional bias to methamphetamine-related stimuli on a probe detection task, self-reported craving, and preferences to view methamphetamine-related images on a Simulated Drug Choice Task. A subset of participants (N = 17) also underwent fMRI in a cue-induced craving paradigm., Results: Poor split-half reliability was observed for the probe detection task. Using this task, attentional bias toward methamphetamine-related stimuli was greater after training than at baseline, irrespective of group (p = 0.037). Spontaneous and cue-induced methamphetamine craving diminished with time (ps < 0.01), but ABM training did not influence these effects (group by time interactions, ps > 0.05). ABM training did not influence selection of methamphetamine-related pictures in the Simulated Drug Choice task (p > 0.05). In the fMRI assessment, cue-induced activation in the ventromedial prefrontal cortex was reduced over time, without an effect of ABM training., Conclusions: ABM training did not improve several clinically relevant variables in treatment-seeking methamphetamine users. Additional research is needed to improve the measurement of attentional bias.

The neurobiological mechanisms that underlie the resistance of drug cue associations to extinction in addiction remain unknown. Fear extinction critically depends on the ventromedial prefrontal cortex (VMPFC). Here, we tested if this same region plays a role in extinction of non-fear, drug and pleasant cue associations. Eighteen chronic cocaine users and 15 matched controls completed three functional MRI scans. Participants first learned to associate an abstract cue (the conditioned stimulus, CS) with a drug-related (CS D+ ) or pleasant (CS P+ ) image. Extinction immediately followed where each CS was repeatedly presented without the corresponding image. Participants underwent a second identical session 24 hours later to assess retention of extinction learning. Results showed that like fear extinction, non-fear-based extinction relies on the VMPFC. However, extinction-related changes in the VMPFC differed by cue valence and diagnosis. In controls, VMPFC activation to the CS D+ (which was unpleasant for participants) gradually increased as in fear extinction, while it decreased to the CS P+ , consistent with a more general role of the VMPFC in flexible value updating. Supporting a specific role in extinction retention, we further observed a cross-day association between VMPFC activation and skin conductance, a classic index of conditioned responses. Finally, cocaine users showed VMPFC abnormalities for both CSs, which, in the case of the CS D+ , correlated with craving. These data suggest a global deficit in extinction learning in this group that may hinder extinction-based treatment efforts. More broadly, these data show that the VMPFC, when functionally intact, supports extinction learning in diverse contexts in humans., (© 2017 Society for the Study of Addiction.)

Background: Cannabis use is on the rise in the United States (US) and is disproportionately common among cigarette smokers. Cannabis use disorder (CUD) occurs among a small subset of cannabis users and may impact cigarette use. The objective of this study was to estimate trends in the prevalence of CUD among daily, non-daily, former, and never cigarette smokers from 2002 to 2016., Methods: Data were drawn from cross-sectional, nationally representative samples of individuals ages 12 and older in the US that were collected annually. The prevalence of past 12-month CUD was estimated each year from 2002 to 2016 among daily, non-daily, former, and never cigarette smokers (total analytic N = 837,326)., Results: Overall, the prevalence of CUD decreased from 2002 to 2016. Yet, trends differed by cigarette smoking status. Adjusting for demographics, the prevalence of CUD increased significantly among non-daily smokers (aOR = 1.02; 95% CI = 1.01-1.03) from 2002 to 2016 and did not change among daily, former, or never smokers. CUD was significantly more common among non-daily (4.32%) and daily cigarette smokers (2.92%) compared with former (0.99%) and never smokers (1.11%) in 2016. Approximately one in five (18.11%-22.87%) youth ages 12-17 who smoke cigarettes met criteria for CUD in 2016, compared with approximately 2% of non-smoking youth., Conclusions: Despite downward trends in CUD observed at the general population level, the prevalence of CUD significantly increased among non-daily cigarette smokers from 2002 to 2016. In the US, CUD remains significantly higher among cigarette smokers relative to non-cigarette smokers., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Cigarette smoking has declined in the United States. Still, identifying prevalent and modifiable barriers to quitting can help inform the next steps for tobacco control. Illicit drug use, which may be increasingly common in the United States, could be one such factor. We investigated the relationship between past-month illicit drug use and cigarette smoking status and estimated trends in the prevalence of past-month illicit drug use by cigarette smoking status from 2002 to 2014 in the United States., Methods: The 2002-2014 National Survey on Drug Use and Health was used to obtain nationally representative data on past-month illicit drug use., Results: From 2002 to 2014, past-month illicit drug use (for all drugs considered) was nearly 5 times more common among current smokers than among never smokers (adjusted odds ratio = 4.79) and nearly twice as prevalent in former smokers as in never smokers (adjusted odds ratio = 1.99). Illicit drug use increased linearly over time from 2002 to 2014 in the entire general population (ie, across and within current smokers, former smokers, and never smokers). This increasing trend in drug use was most rapid among former smokers (relative to current smokers and never smokers) and was largely, but not entirely, driven by increases in cannabis use., Conclusions: Illicit drug use is most prevalent among current cigarette smokers. Yet, the rate of increase in illicit drug use prevalence was most rapid among former smokers. Because former smokers outnumber current smokers in the general population, it may be important to monitor former smokers into the future for potential negative drug-related outcomes., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Background: The choice for drugs over alternative reinforcers is a translational hallmark feature of drug addiction. The neural basis of such drug-biased choice is not well understood, particularly in individuals with protracted drug abstinence who cannot ethically participate in studies that offer drug-using opportunities., Methods: We developed a functional magnetic resonance imaging drug-choice task to examine the choice for viewing drug-related images, rather than for actually consuming a drug. Actively using (n = 18) and abstaining (n = 19) individuals with a history of cocaine use disorder (CUD: dependence or abuse) and matched healthy control subjects (n = 26) participated., Results: Individuals with CUD, especially those actively using cocaine outside the laboratory, made more choices than control subjects to view images depicting cocaine (especially when directly compared against images depicting an alternative appetitive reinforcer [food]). Functional magnetic resonance imaging data revealed that in individuals with CUD, the act of making drug-related choices engaged brain regions implicated in choice difficulty or ambivalence (i.e., dorsal anterior cingulate cortex, which was higher in all individuals with CUD than control subjects). Drug-related choices in CUD also engaged brain regions implicated in reward (e.g., midbrain/ventral tegmental area, which was most activated in active users, although this region was not hypothesized a priori)., Conclusions: These results help clarify the neural mechanisms underlying drug-biased choice in human addiction, which, beyond mechanisms involved in value assignment or reward, may critically involve mechanisms that contribute to resolving difficult decisions. Future studies are needed to validate these behavioral and neural abnormalities as markers of drug seeking and relapse in treatment contexts., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Anger is considered a unique high-arousal and approach-related negative emotion. The influence of individual differences in trait anger on the processing of visual stimuli is relevant to questions about emotional processing and remains to be explored. Using functional magnetic resonance imaging (fMRI), we explored the neural responses to standardized images, selected based on valence and arousal ratings in a group of men with high trait anger compared to those with normative to low anger scores (controls). Results show increased activation in the left-lateralized ventral fronto-parietal attention network to unpleasant images by individuals with high trait anger. There was also a group by arousal interaction in the left thalamus/pulvinar such that individuals with high trait anger had increased pulvinar activation to the high-arousal (versus low arousal) unpleasant images as compared to controls. Thus, individual differences in trait anger in men are associated with brain regions subserving executive attentional and sensory integration during the processing of unpleasant emotional stimuli, particularly to high arousal images.

Individuals with drug use disorders seek drugs over other rewarding activities, and exhibit neurochemical deficits related to dopamine, which is involved in value-based learning and decision-making. Thus, a dopaminergic disturbance may underpin drug-biased choice in addiction. Classical drug-choice assessments, which offer drug-consumption opportunities, are inappropriate for addicted individuals seeking treatment or abstaining. Fifteen recently abstinent methamphetamine users and 15 healthy controls completed two laboratory paradigms of 'simulated' drug choice (choice for drug-related vs affectively pleasant, unpleasant, and neutral images), and underwent positron emission tomography measurements of dopamine D2-type receptor availability, indicated by binding potential (BP ND ) for [ 18 F]fallypride. Thirteen of the methamphetamine users and 10 controls also underwent [ 11 C]NNC112 PET scans to measure dopamine D1-type receptor availability. Group analyses showed that, compared with controls, methamphetamine users chose to view more methamphetamine-related images on one task, with a similar trend on the second task. Regression analyses showed that, on both tasks, the more methamphetamine users chose to view methamphetamine images, specifically vs pleasant images (the most frequently chosen images across all participants), the lower was their D2-type BP ND in the lateral orbitofrontal cortex, an important region in value-based choice. No associations were observed with D2-type BP ND in striatal regions, or with D1-type BP ND in any region. These results identify a neurochemical correlate for a laboratory drug-seeking paradigm that can be administered to treatment-seeking and abstaining drug-addicted individuals. More broadly, these results refine the central hypothesis that dopamine-system deficits contribute to drug-biased decision-making in addiction, here showing a role for the orbitofrontal cortex.