Anatomical and computational models of the role of phasic dopamine signaling in intracranial self-stimulation: psychophysical and electrochemical tests

Dopamine (DA) neurotransmission is heavily implicated in electrical intracranial self-stimulation (eICSS), operant performance aimed at triggering stimulation of certain brain regions. To study the underpinnings of reward seeking, we combined ICSS with fast-scan cyclic voltammetry (FSCV), a means of monitoring stimulation-induced DA transients. Chapter one examines the circuitry linking midbrain DA neurons to the non-DA neurons recruited at the tip of a medial forebrain bundle (MFB) eICSS electrode. We found that unilateral, electrical, MFB stimulation evoked bilateral DA transients and that DA activation occurred, in large part, through polysynaptic circuitry. The series-circuit hypothesis is the focus of chapter two. On that view, the signal representing the intensity of the stimulation-induced rewarding effect must pass obligatorily through midbrain DA neurons. We found that the the DAergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) cannot serve as a unique link that relays the reward signal underlying eICSS of the MFB to later stages of the circuitry underlying reward seeking. The last chapter addresses the dominant theory linking phasic DA signalling to learning. On that view, DA transients signal the discrepancy between expected and experienced rewards and adjust synaptic weights to update reward predictions and bias action selection. Several of our findings are difficult to reconcile with the DA-RPE hypothesis. Recent technological advances have provided tools for studying the neural bases of reward seeking that are unprecedented in their power and number. It is important to extend this level of sophistication to our electrochemical and behavioural methods

17β-estradiol locally increases phasic dopamine release in the dorsal striatum

Studies using in vivo microdialysis have shown that 17β-estradiol (E2) increases dopamine (DA) transmission in the dorsal striatum. Both systemic administration of E2 and local infusion into the dorsal striatum rapidly enhance amphetamine-induced DA release. However, it is not known to what degree these effects reflect tonic and/or phasic DA release. It was hypothesized that E2 acts directly within the DS to rapidly increase phasic DA transmission. In urethane-anaesthetized (1.5 mL/kg) female rats, we used fast-scan cyclic voltammetry to study the effects of E2 on phasic, electrically-evoked release of DA in the dorsal striatum. Rats were ovariectomized and implanted with a silastic tube containing 5% E2 in cholesterol, previously shown to mimic low physiological serum concentrations of ∼ 20–25 pg/ml. DA release was evoked every 1 min by delivering biphasic electrical stimulation in the substantia nigra. Local infusions of E2 (244.8 pg/μl) into the dorsal striatum increased the amplitude of the electrically evoked DA transients. Behaviorally significant stimuli and events trigger phasic release of DA. The present findings predict that E2 would boost such signaling in behaving subjects

Efficacy of adaptive e-learning for health professionals and students : a systematic review and meta-analysis

Objective Although adaptive e-learning environments (AEEs) can provide personalised instruction to health professional and students, their efficacy remains unclear. Therefore, this review aimed to identify, appraise and synthesise the evidence regarding the efficacy of AEEs in improving knowledge, skills and clinical behaviour in health professionals and students. Design Systematic review and meta-analysis. Data sources CINAHL, EMBASE, ERIC, PsycINFO, PubMed and Web of Science from the first year of records to February 2019. Eligibility criteria Controlled studies that evaluated the effect of an AEE on knowledge, skills or clinical behaviour in health professionals or students. Screening, data extraction and synthesis Two authors screened studies, extracted data, assessed risk of bias and coded quality of evidence independently. AEEs were reviewed with regard to their topic, theoretical framework and adaptivity process. Studies were included in the meta-analysis if they had a non-adaptive e-learning environment control group and had no missing data. Effect sizes (ES) were pooled using a random effects model. Results From a pool of 10 569 articles, we included 21 eligible studies enrolling 3684 health professionals and students. Clinical topics were mostly related to diagnostic testing, theoretical frameworks were varied and the adaptivity process was characterised by five subdomains: method, goals, timing, factors and types. The pooled ES was 0.70 for knowledge (95% CI −0.08 to 1.49; p.08) and 1.19 for skills (95% CI 0.59 to 1.79; p<0.00001). Risk of bias was generally high. Heterogeneity was large in all analyses. Conclusions AEEs appear particularly effective in improving skills in health professionals and students. The adaptivity process within AEEs may be more beneficial for learning skills rather than factual knowledge, which generates less cognitive load. Future research should report more clearly on the design and adaptivity process of AEEs, and target higher-level outcomes, such as clinical behaviour

Role of dopamine tone in the pursuit of brain stimulation reward

Dopaminergic neurons contribute to intracranial self-stimulation (ICSS) and other reward-seeking behaviors, but it is not yet known where dopaminergic neurons intervene in the neural circuitry underlying reward pursuit or which psychological processes are involved. In rats working for electrical stimulation of the medial forebrain bundle, we assessed the effect of GBR-12909, a specific blocker of the dopamine transporter. Operant performance was measured as a function of the strength and cost of electrical stimulation. GBR-12909 increased the opportunity cost most subjects were willing to pay for a reward of a given intensity. However, this effect was smaller than that produced by a regimen of cocaine administration that drove similar increases in nucleus accumbens (NAc) dopamine levels in unstimulated rats. Delivery of rewarding stimulation to drug-treated rats caused an additional increase in dopamine concentration in the NAc shell in cocaine-treated, but not GBR-treated, rats. These behavioral and neurochemical differences may reflect blockade of the norepinephrine transporter by cocaine but not by GBR-12909. Whereas the effect of psychomotor stimulants on ICSS has long been attributed to dopaminergic action at early stages of the reward pathway, the results reported here imply that increased dopamine tone boosts reward pursuit by acting at or beyond the output of the circuitry that temporally and spatially summates the output of the directly stimulated neurons underlying ICSS. The observed enhancement of reward seeking could be due to a decrease in the value of competing behaviors, a decrease in subjective effort costs, or an increase in reward-system gain. Video: The video reveals a fundamental source of ambiguity in two-dimensional measurements of operant performance for reward, such as those obtained in the curveshift and progressive-ratio paradigms. We show how the three-dimensional portrayal provided by the reward-mountain model resolves this ambiguity. The reward-mountain model is derived, described, discussed, and applied in the following papers: • Arvanitogiannis A, & Shizgal P (2008). The reinforcement mountain: allocation of behavior as a function of the rate and intensity of rewarding brain stimulation. Behav Neurosci 122:1126-1138. doi: 10.1037/a0012679 http://psycnet.apa.org/journals/bne/122/5/1126/ • Hernandez G, Breton YA, Conover K, & Shizgal P (2010). At what stage of neural processing does cocaine act to boost pursuit of rewards? PLoS One 5:e15081. doi: 10.1371/journal.pone.0015081 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015081 • Shizgal, P, & Hernandez, G (2010). Intracranial Self-Stimulation. Encyclopedia of Psychopharmacology, 653–660. doi:10.1007/978-3-540-68706-1_66 http://www.springerlink.com/content/w37074k2586301j6/?MUD=MP • Trujillo-Pisanty I, Hernandez G, Moreau-Debord I, Cossette MP, Conover K, Cheer JF, & Shizgal P (2011). Cannabinoid receptor blockade reduces the opportunity cost at which rats maintain operant performance for rewarding brain stimulation. J Neurosci 31:5426-5435. http://www.jneurosci.org/content/31/14/5426.long • Shizgal, P. (2012). Scarce means with alternative uses: Robbins' definition of economics and its extension to the behavioral and neurobiological study of animal decision making. Frontiers in Neuroscience, 6, 20. doi:10.3389/fnins.2012.00020 http://www.frontiersin.org/Decision_Neuroscience/10.3389/fnins.2012.00020/abstract • Hernandez, G., Trujillo-Pisanty, I., Cossette, M-P., Conover, K., & Shizgal, P. (2012). Role of dopamine tone in the pursuit of brain stimulation reward. Journal of Neuroscience, 2012, in press

Cannabinoid receptor blockade reduces the opportunity cost at which rats maintain operant performance for rewarding brain stimulation

There is ample evidence that blockade of CB1 receptors reduces reward seeking. However, the reported effects of CB1 blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we show that AM-251, a CB1 receptor antagonist, does indeed decrease performance for rewarding electrical stimulation of the medial forebrain bundle in rats. Reward-seeking depends on multiple sets of variables, including the intensity of the reward, its cost, and the value of competing rewards. In turn, reward intensity depends both on the sensitivity and gain of brain reward circuitry. We show that drug-induced changes in sensitivity cannot account for the suppressive effect of AM-251 on reward seeking. Therefore, the role of CB1 receptors must be sought among the remaining determinants of performance. Our analysis provides an explanation of the inconsistencies between prior reports, which likely arose from: a) the averaging of data across subjects showing heterogeneous effects and b) the use of methods that cannot distinguish between the different determinants of reward pursuit. By means of microdialysis, we demonstrate that blockade of CB1 receptors attenuates nucleus accumbens dopamine release in response to rewarding medial forebrain bundle stimulation, and we propose that this action is responsible for the ability of the drug to decrease performance for the electrical reward

Effects of implementation strategies on nursing practice and patient outcomes : a comprehensive systematic review and meta-analysis

Acknowledgements The authors wish to acknowledge the contribution of Jérémie Blondin for the development of search strategies and the search in bibliographical databases. We thank Ariane Ballard for contributing to study selection. We thank the individuals who responded to requests for additional data, including Jens Abraham, Patrick Akande, Marvin J. Bittner, Ian Blanco Mavillard, Nicolle P. G. Boumans, Marian C. Brady, Diane L. Carroll, Andrea Chaplin, Lorena Charrier, Francine M. Cheater, Lynn Chenoweth, Yeu-Hui Chuang, Lorenzo Cohen, Kelly Jo Cone, Susan Cortez, J. Randall Curtis, Barbara Davies, Tina Day, Marlies de Rond, Dennis de Ruijter, Helen Edwards, Mohamed Elzeky, Ruth Engelberg, David Evans, Valeria Fabre, Tobias Filmer, Christopher R. Friese, Marjorie Funk, Matthew Bidwell Goetz, Salla Grommi, Mary Beth Happ, Michael Hendryx, Manuela Hödl, Anita Huis, Alison Hutchinson, Yueh-Juan Hwu, Ali Khani Jeihooni, Céleste Johnston, Eileen F. S. Kaner, Zahra Karimian, Kristina H. Karvinen, Sedigheh Khanjari, Mahnaz Khatiban, Serena Koh, Sascha Köpke, Ruth Kleinpell, Una Kyriacos, Jan van Lieshout, Li-Chan Lin, Elizabeth Manias, Edward R. Marcantonio, Gabriele Meyer, Sandy Middleton, Tatsuya Morita, Janneke Noordman, Mary Patricia Nowalk, Jane Ogden, Christine Paul, James A. Rankin, Marilyn Rantz, Susan M. Ray, Staci S. Reynolds, Young Sook Roh, Jeffrey M. Rothschild, Reza Sadeghi, Trygve Johannes Lereim Sævareid, Parvin Mangolian Shahrbabaki, Davide Sisti, Wilma ten Ham-Baoyi, Sousan Valizadeh, Maritta Välimäki, Ayse Kacaroglu Vicdan, Thomas von Lengerke, Laura Wagner, Timothy Walsh, Marcia Weaver, Chistopher Weir, and Carla Zotti.Peer reviewe

Pharmacogenomics of the efficacy and safety of Colchicine in COLCOT

© 2021 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. Results: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.info:eu-repo/semantics/publishedVersio

Pregnancy and Maternal Behavior Induce Changes in Glia, Glutamate and Its Metabolism within the Cingulate Cortex

An upregulation of the astrocytic proteins GFAP and bFGF within area 2 of the cingulate cortex (Cg2) occurs within 3 hours of parturition in rats. These changes are the result of an interaction between hormonal state and maternal experience and are associated with increased dendritic spine density in this area. Here, we examined whether this upregulation of astrocytic proteins generalized to other glial markers and, in particular those associated with glutamate metabolism. We chose glial markers commonly used to reflect different aspects of glial function: vimentin, like GFAP, is a marker of intermediate filaments; glutamine synthetase (GS), and S-100beta, are used as markers for mature astrocytes and GS has also been used as a specific marker for glutamatergic enzymatic activity. In addition, we examined levels of proteins associated with glutamine synthetase, glutamate, glutamine and two excitatory amino acid transporters found in astrocytes, glt-1 and glast. S100beta immunoreactivity did not vary with reproductive state in either Cg2 or MPOA suggesting no change in the number of mature astrocytes across these conditions. Vimentin-ir did not differ across groups in Cg2, but expression of this protein decreased from Day 1 postpartum onwards in the MPOA. By contrast, GS-ir was increased within 24 h postpartum in Cg2 but not MPOA and similarly to GFAP and bFGF this upregulation of GS resulted from an interaction between hormonal state and maternal experience. Within Cg2, upregulation of GS was not accompanied by changes in the astrocytic glutamatergic transporters, glt-1 and glast, however, an increase in both glutamate and glutamine proteins were observed within the Cg2 of postpartum animals. Together, these changes suggest postpartum upregulation of glutamatergic activity and metabolism within Cg2 that is stimulated by pregnancy hormones and maternal experience

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population