A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque

[EN] Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves specific attention and learning mechanisms beyond working memory, and whether the drug effects can be formalized computationally to allow single subject predictions. We tested and confirmed these suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased distractibility and improved learning. In a second experimental phase using only that dose we examined the faster feature-based reversal learning with Guanfacine with single-subject computational modeling. Parameter estimation suggested that improved learning is not accounted for by varying a single reinforcement learning mechanism, but by changing the set of parameter values to higher learning rates and stronger suppression of non-chosen over chosen feature information. These findings provide an important starting point for developing nonhuman primate models to discern the synaptic mechanisms of attention and learning functions within the context of a computational neuropsychiatry framework.This research was supported by grants from the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Ontario Ministry of Economic Development and Innovation (MEDI). We thank Dr. Hongying Wang for invaluable help with drug administration and animal careHassani, SA.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid-Ramírez, JS.; Van Der Meer, MA.; Tiesinga, P.... (2017). A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque. Scientific Reports. 7:1-19. https://doi.org/10.1038/srep40606S1197Arnsten, A. F., Wang, M. J. & Paspalas, C. D. Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76, 223–239 (2012).Arnsten, A. F. & Dudley, A. G. Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct 1, 2 (2005).Clark, K. L. & Noudoost, B. The role of prefrontal catecholamines in attention and working memory. Front Neural Circuits 8, 33 (2014).Wang, M. et al. Neuronal basis of age-related working memory decline. Nature 476, 210–213 (2011).Wang, M. et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129, 397–410 (2007).Aston-Jones, G. & Cohen, J. D. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28, 403–450 (2005).Yu, A. J. & Dayan, P. Uncertainty, neuromodulation, and attention. Neuron 46, 681–692 (2005).Mather, M., Clewett, D., Sakaki, M. & Harley, C. W. Norepinephrine ignites local hot spots of neuronal excitation: How arousal amplifies selectivity in perception and memory. Behav Brain Sci, 1–100, doi: 10.1017/S0140525X15000667 (2015).Amemiya, S. & Redish, A. D. Manipulating Decisiveness in Decision Making: Effects of Clonidine on Hippocampal Search Strategies. J Neurosci 36, 814–827 (2016).Doya, K. Metalearning and neuromodulation. Neural Netw 15, 495–506 (2002).Uhlen, S., Muceniece, R., Rangel, N., Tiger, G. & Wikberg, J. E. Comparison of the binding activities of some drugs on alpha 2A, alpha 2B and alpha 2C-adrenoceptors and non-adrenergic imidazoline sites in the guinea pig. Pharmacology & toxicology 76, 353–364 (1995).Mao, Z. M., Arnsten, A. F. & Li, B. M. Local infusion of an alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biological psychiatry 46, 1259–1265 (1999).Arnsten, A. F. & Goldman-Rakic, P. S. Analysis of alpha-2 adrenergic agonist effects on the delayed nonmatch-to-sample performance of aged rhesus monkeys. Neurobiol Aging 11, 583–590 (1990).Franowicz, J. S. & Arnsten, A. F. The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 136, 8–14 (1998).Caetano, M. S. et al. Noradrenergic control of error perseveration in medial prefrontal cortex. Frontiers in Integrative Neuroscience 6, 125 (2012).Kim, S., Bobeica, I., Gamo, N. J., Arnsten, A. F. & Lee, D. Effects of alpha-2A adrenergic receptor agonist on time and risk preference in primates. Psychopharmacology 219, 363–375 (2012).Seu, E., Lang, A., Rivera, R. J. & Jentsch, J. D. Inhibition of the norepinephrine transporter improves behavioral flexibility in rats and monkeys. Psychopharmacology 202, 505–519 (2009).Kawaura, K., Karasawa, J., Chaki, S. & Hikichi, H. Stimulation of postsynapse adrenergic alpha2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder. Behav Brain Res 270, 349–356 (2014).Aoki, C., Go, C. G., Venkatesan, C. & Kurose, H. Perikaryal and synaptic localization of alpha 2A-adrenergic receptor-like immunoreactivity. Brain Res 650, 181–204 (1994).Barth, A. M., Vizi, E. S., Zelles, T. & Lendvai, B. Alpha2-adrenergic receptors modify dendritic spike generation via HCN channels in the prefrontal cortex. J Neurophysiol 99, 394–401 (2008).Ji, X. H., Ji, J. Z., Zhang, H. & Li, B. M. Stimulation of alpha2-adrenoceptors suppresses excitatory synaptic transmission in the medial prefrontal cortex of rat. Neuropsychopharmacology 33, 2263–2271 (2008).Yi, F., Liu, S. S., Luo, F., Zhang, X. H. & Li, B. M. Signaling mechanism underlying alpha2A -adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats. Eur J Neurosci 38, 2364–2373 (2013).Engberg, G. & Eriksson, E. Effects of alpha 2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Naunyn-Schmiedeberg’s archives of pharmacology 343, 472–477 (1991).Jakala, P. et al. Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 20, 460–470 (1999).Jakala, P. et al. Guanfacine and clonidine, alpha 2-agonists, improve paired associates learning, but not delayed matching to sample, in humans. Neuropsychopharmacology 20, 119–130 (1999).Muller, U. et al. Lack of effects of guanfacine on executive and memory functions in healthy male volunteers. Psychopharmacology 182, 205–213 (2005).Scahill, L. et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. The American journal of psychiatry 158, 1067–1074 (2001).Huys, Q. J. M., Maia, T. V. & Frank, M. J. Computational psychiatry as a bridge from neuroscience to clinical applications. Nat Neurosci 19, 404–413 (2016).Stephan, K. E. et al. Computational neuroimaging strategies for single patient predictions. NeuroImage in press (2015).Arnsten, A. F., Cai, J. X. & Goldman-Rakic, P. S. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 8, 4287–4298 (1988).Callado, L. F. & Stamford, J. A. Alpha2A- but not alpha2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus: voltammetric data. Eur J Pharmacol 366, 35–39 (1999).Millan, M. J. et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nature reviews. Drug discovery 11, 141–168 (2012).Niv, Y. et al. Reinforcement learning in multidimensional environments relies on attention mechanisms. J Neurosci 35, 8145–8157 (2015).Balcarras, M., Ardid, S., Kaping, D., Everling, S. & Womelsdorf, T. Attentional Selection Can Be Predicted by Reinforcement Learning of Task-relevant Stimulus Features Weighted by Value-independent Stickiness. J Cogn Neurosci 28, 333–349 (2016).Redish, A. D., Jensen, S., Johnson, A. & Kurth-Nelson, Z. Reconciling reinforcement learning models with behavioral extinction and renewal: implications for addiction, relapse, and problem gambling. Psychol Rev 114, 784–805 (2007).Nassar, M. R. et al. Rational regulation of learning dynamics by pupil-linked arousal systems. Nat Neurosci 15, 1040–1046 (2012).O’Reilly, J. X. et al. Dissociable effects of surprise and model update in parietal and anterior cingulate cortex. Proc Natl Acad Sci USA 110, 3660–3669 (2013).Shenhav, A., Botvinick, M. M. & Cohen, J. D. The expected value of control: an integrative theory of anterior cingulate cortex function. Neuron 79, 217–240 (2013).Womelsdorf, T. & Everling, S. Long-Range Attention Networks: Circuit Motifs Underlying Endogenously Controlled Stimulus Selection. Trends Neurosci 38, 682–700 (2015).Yang, Y. et al. Nicotinic alpha7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci USA 110, 12078–12083 (2013).Aston-Jones, G., Rajkowski, J. & Cohen, J. Role of locus coeruleus in attention and behavioral flexibility. Biological psychiatry 46, 1309–1320 (1999).Cole, B. J. & Robbins, T. W. Forebrain norepinephrine: role in controlled information processing in the rat. Neuropsychopharmacology 7, 129–142 (1992).Dalley, J. W., Cardinal, R. N. & Robbins, T. W. Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neuroscience and biobehavioral reviews 28, 771–784 (2004).Devauges, V. & Sara, S. J. Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav Brain Res 39, 19–28 (1990).Connor, D. F., Arnsten, A. F., Pearson, G. S. & Greco, G. F. Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. Expert opinion on pharmacotherapy 15, 1601–1610 (2014).Sallee, F. R. et al. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 48, 155–165 (2009).Steere, J. C. & Arnsten, A. F. The alpha-2A noradrenergic receptor agonist guanfacine improves visual object discrimination reversal performance in aged rhesus monkeys. Behav Neurosci 111, 883–891 (1997).Doya, K. Modulators of decision making. Nat Neurosci 11, 410–416 (2008).Wang, X. J. & Krystal, J. H. Computational psychiatry. Neuron 84, 638–654 (2014).Wiecki, T. V. et al. A Computational Cognitive Biomarker for Early-Stage Huntington’s Disease. PLoS One 11, e0148409, doi: 10.1371/journal.pone.0148409 (2016).Huys, Q. J., Pizzagalli, D. A., Bogdan, R. & Dayan, P. Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis. Biol Mood Anxiety Disord 3, 12 (2013).Gershman, S. J. & Niv, Y. Learning latent structure: carving nature at its joints. Curr Opin Neurobiol 20, 251–256 (2010).Voon, V. et al. Disorders of compulsivity: a common bias towards learning habits. Mol Psychiatry 20, 345–352 (2015).Maia, T. V. & Frank, M. J. From reinforcement learning models to psychiatric and neurological disorders. Nature Neuroscience 14, 154–162 (2011).Adams, R. A., Huys, Q. J. M. & Roiser, J. P. Computational Psychiatry: towards a mathematically informed understanding of mental illness. Journal of Neurology, Neurosurgery, and Psychiatry 87, 53–63 (2015).Schlagenhauf, F. et al. Striatal dysfunction during reversal learning in unmedicated schizophrenia patients. NeuroImage 89, 171–180 (2014).Harlé, K. M. et al. Bayesian neural adjustment of inhibitory control predicts emergence of problem stimulant use. Brain 138, 3413–3426 (2015).Zhang, J. et al. Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson’s disease. Brain 139, 161–173 (2016).Frank, M. J. et al. fMRI and EEG Predictors of Dynamic Decision Parameters during Human Reinforcement Learning. Journal of Neuroscience 35, 485–494 (2015).Smith, A. C. & Brown, E. N. Estimating a state-space model from point process observations. Neural Comput 15, 965–991 (2003).Wilson, R. C. & Niv, Y. Inferring relevance in a changing world. Frontiers in human neuroscience 5, 189 (2011).Rämä, P. et al. Medetomidine, atipamezole, and guanfacine in delayed response performance of aged monkeys. Pharmacology Biochemistry and Behavior 55, 415–422 (1996).Arnsten, A. F. T. & Contant, T. A. Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task. Psychopharmacology 108, 159–169 (1992).O’Neill, J. et al. Effects of guanfacine on three forms of distraction in the aging macaque. Life Sciences 67, 877–885 (2000).Wang, M., Ji, J.-Z. & Li, B.-M. The α2A-Adrenergic Agonist Guanfacine Improves Visuomotor Associative Learning in Monkeys. Neuropsychopharmacology 29, 86–92 (2004).Witte, E. a. & Marrocco, R. T. Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert orienting. Psychopharmacology 132, 315–323 (1997).Decamp, E., Clark, K. & Schneider, J. S. Effects of the alpha-2 adrenoceptor agonist guanfacine on attention and working memory in aged non-human primates. European Journal of Neuroscience 34, 1018–1022 (2011)

Pattern Classification of Working Memory Networks Reveals Differential Effects of Methylphenidate, Atomoxetine, and Placebo in Healthy Volunteers

Stimulant and non-stimulant drugs can reduce symptoms of attention deficit/hyperactivity disorder (ADHD). The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for ADHD treatment, but their differential effects on human brain function remain unclear. We combined event-related fMRI with multivariate pattern recognition to characterize the effects of MPH and ATX in healthy volunteers performing a rewarded working memory (WM) task. The effects of MPH and ATX on WM were strongly dependent on their behavioral context. During non-rewarded trials, only MPH could be discriminated from placebo (PLC), with MPH producing a similar activation pattern to reward. During rewarded trials both drugs produced the opposite effect to reward, that is, attenuating WM networks and enhancing task-related deactivations (TRDs) in regions consistent with the default mode network (DMN). The drugs could be directly discriminated during the delay component of rewarded trials: MPH produced greater activity in WM networks and ATX produced greater activity in the DMN. Our data provide evidence that: (1) MPH and ATX have prominent effects during rewarded WM in task-activated and -deactivated networks; (2) during the delay component of rewarded trials, MPH and ATX have opposing effects on activated and deactivated networks: MPH enhances TRDs more than ATX, whereas ATX attenuates WM networks more than MPH; and (3) MPH mimics reward during encoding. Thus, interactions between drug effects and motivational state are crucial in defining the effects of MPH and ATX

Preliminary Evidence of the Association between Time on Buprenorphine and Cognitive Performance among Individuals with Opioid Use Disorder Maintained on Buprenorphine: A Pilot Study

People on buprenorphine maintenance treatment (BMT) commonly present cognitive deficits that have been associated with illicit drug use and dropout from buprenorphine treatment. This study has compared cognitive responses to the Stroop Task and the Continuous Performance Task (CPT) among individuals on BMT, with recent drug use, and healthy controls and explored the associations between cognitive responses and drug use, craving, and buprenorphine use among participants on BMT. The participants were 16 individuals on BMT and 23 healthy controls. All participants completed a 60 min laboratory session in which they completed the Stroop Task and the CPT, a saliva drug test, a brief clinical history that collected substance-use- and treatment-related information, and the Opioid Craving Scale. The results showed that the BMT participants presented more commission errors (MBMT participants = 2.49; Mhealthy controls = 1.38; p = 0.048) and longer reaction times (MBMT participants = 798.09; Mhealthy controls = 699.09; p = 0.047) in the Stroop Task than did the healthy controls. More days on buprenorphine were negatively associated with reaction time in the CPT (−0.52) and the number of commission errors (−0.53), simple reaction time (−0.54), and reaction time correct (−0.57) in the Stroop Task. Neither drug use nor craving was significantly associated with the results for the cognitive tasks. Relative to the control participants, the BMT individuals performed worse in terms of longer reaction times and more commission errors in the Stroop Task. Within the BMT participants, longer times on buprenorphine were associated with better cognitive results in terms of faster reaction times for both tasks and lower commission errors for the Stroop Task

Mindfulness-based interventions for young offenders: a scoping review

Youth offending is a problem worldwide. Young people in the criminal justice system have frequently experienced adverse childhood circumstances, mental health problems, difficulties regulating emotions and poor quality of life. Mindfulness-based interventions can help people manage problems resulting from these experiences, but their usefulness for youth offending populations is not clear. This review evaluated existing evidence for mindfulness-based interventions among such populations. To be included, each study used an intervention with at least one of the three core components of mindfulness-based stress reduction (breath awareness, body awareness, mindful movement) that was delivered to young people in prison or community rehabilitation programs. No restrictions were placed on methods used. Thirteen studies were included: three randomized controlled trials, one controlled trial, three pre-post study designs, three mixed-methods approaches and three qualitative studies. Pooled numbers (n = 842) comprised 99% males aged between 14 and 23. Interventions varied so it was not possible to identify an optimal approach in terms of content, dose or intensity. Studies found some improvement in various measures of mental health, self-regulation, problematic behaviour, substance use, quality of life and criminal propensity. In those studies measuring mindfulness, changes did not reach statistical significance. Qualitative studies reported participants feeling less stressed, better able to concentrate, manage emotions and behaviour, improved social skills and that the interventions were acceptable. Generally low study quality limits the generalizability of these findings. Greater clarity on intervention components and robust mixed-methods evaluation would improve clarity of reporting and better guide future youth offending prevention programs

Relationship between CD4 count and quality of life over time among HIV patients in Uganda: A cohort study

© 2015 Mwesigire et al. Background: Immunological markers (CD4 count) are used in developing countries to decide on initiation of antiretroviral therapy and monitor HIV/AIDS disease progression. HIV is an incurable chronic illness, making quality of life paramount. The direct relationship between quality of life and CD4 count is unclear. The purpose of this study is to determine the relationship between change in CD4 count and quality of life measures in a Ugandan cohort of people living with HIV. Methods: We prospectively assessed quality of life among 1274 HIV patients attending an HIV clinic within a national referral hospital over a period of 6months. Quality of life was measured using an objective measure, the Medical Outcomes Study HIV health survey summarized as Physical Health Score and Mental Health Score and a subjective measure, the Global Person Generated Index. Generalized estimating equations were used to analyze the data. The primary predictor variable was change in CD4 count, and the outcome was quality of life scores. We controlled for sociodemographic characteristics, clinical factors and behavioral factors. Twenty in-depth interviews were conducted to assess patient perception of quality of life and factors influencing quality of life. Results: Of the 1274 patients enrolled 1159 had CD4 count at baseline and six months and 586 (51%) received antiretroviral therapy. There was no association found between change in CD4 count and quality of life scores at univariate and multivariate analysis among the study participants whether on or not on antiretroviral therapy. Participants perceived quality of life as happiness and well-being, influenced by economic status, psychosocial factors, and health status. Conclusions: Clinicians and policy makers cannot rely on change in immunological markers to predict quality of life in this era of initiating antiretroviral therapy among relatively healthy patients. In addition to monitoring immunological markers, socioeconomic and psychosocial factors should be underscored in management of HIV patients

Quality of life in patients treated with first-line antiretroviral therapy containing nevirapine or efavirenz in Uganda: A prospective non-randomized study

© 2015 Mwesigire et al. Background: The goal of antiretroviral therapy (ART) is to suppress viral replication, reduce morbidity and mortality, and improve quality of life (QoL). For resource-limited settings, the World Health Organization recommends a first-line regimen of two-nucleoside reverse-transcriptase inhibitors and one non-nucleoside transcriptase inhibitor (nevirapine (NVP) or efavirenz (EFV)). There are few data comparing the QoL impact of NVP versus EFV. This study assessed the change in QoL and factors associated with QoL among HIV patients receiving ART regimens based on EFV or NVP. Methods: We enrolled 640 people with HIV eligible for ART who received regimens including either NVP or EFV. QoL was assessed at baseline, three months and six months using Physical Health Summary (PHS) and Mental Health Summary (MHS) scores and the Global Person Generated Index (GPGI). Data were analyzed using generalized estimating equations, with ART regimen as the primary exposure, to identify associations between patient and disease factors and QoL. Results: QoL increased on ART. The mean QoL scores did not differ significantly for regimens based on NVP versus EFV during follow-up for MHS and GPGI regardless of CD4 stratum and for PHS among patients with a CD4 count >250 cells/μL. The PHS-adjusted β coefficients for ART regimens based on EFV versus NVP by CD4 count strata were as follows: -1.61 (95 % CI -2.74, -0.49) for CD4 count 250 cells/μL. The corresponding MHS-adjusted β coefficients were as follows: -0.39 (-1.40, 0.62) for CD4∈250 cells/μL. The GPGI-adjusted odds ratios for EFV versus NVP were 0.51 (0.25, 1.04) for CD4 count ∈250 cells/μL. QoL improved among patients on EFV over the 6-month follow-up period (MHS p

Long-Term Continuous Corticosterone Treatment Decreases VEGF Receptor-2 Expression in Frontal Cortex

Objective: Stress and increased glucocorticoid levels are associated with many neuropsychiatric disorders including schizophrenia and depression. Recently, the role of vascular endothelial factor receptor-2 (VEGFR2/Flk1) signaling has been implicated in stress-mediated neuroplasticity. However, the mechanism of regulation of VEGF/Flk1 signaling under longterm continuous glucocorticoid exposure has not been elucidated. Material and Methods: We examined the possible effects of long-term continuous glucocorticoid exposure on VEGF/Flk1 signaling in cultured cortical neurons in vitro, mouse frontal cortex in vivo, and in post mortem human prefrontal cortex of both control and schizophrenia subjects. Results: We found that long-term continuous exposure to corticosterone (CORT, a natural glucocorticoid) reduced Flk1 protein levels both in vitro and in vivo. CORT treatment resulted in alterations in signaling molecules downstream to Flk1 such as PTEN, Akt and mTOR. We demonstrated that CORT-induced changes in Flk1 levels are mediated through glucocorticoid receptor (GR) and calcium. A significant reduction in Flk1-GR interaction was observed following CORT exposure. Interestingly, VEGF levels were increased in cortex, but decreased in serum following CORT treatment. Moreover, significant reductions in Flk1 and GR protein levels were found in postmortem prefrontal cortex samples from schizophrenia subjects. Conclusions: The alterations in VEGF/Flk1 signaling following long-term continuous CORT exposure represents a molecula

Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.This research work was funded by a Core Award from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). Also supported by a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) awarded to TWR. CE was supported by the Swiss National Science Foundation (PA00P1_134135) and the Vienna Science and Technology Fund (WWTF VRG13-007)

Increased Risk of Fragility Fractures among HIV Infected Compared to Uninfected Male Veterans

BACKGROUND: HIV infection has been associated with an increased risk of fragility fracture. We explored whether or not this increased risk persisted in HIV infected and uninfected men when controlling for traditional fragility fracture risk factors. METHODOLOGY/PRINCIPAL FINDINGS: Cox regression models were used to assess the association of HIV infection with the risk for incident hip, vertebral, or upper arm fracture in male Veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC). We calculated adjusted hazard ratios comparing HIV status and controlling for demographics and other established risk factors. The sample consisted of 119,318 men, 33% of whom were HIV infected (34% aged 50 years or older at baseline, and 55% black or Hispanic). Median body mass index (BMI) was lower in HIV infected compared with uninfected men (25 vs. 28 kg/m²; p<0.0001). Unadjusted risk for fracture was higher among HIV infected compared with uninfected men [HR: 1.32 (95% CI: 1.20, 1.47)]. After adjusting for demographics, comorbid disease, smoking and alcohol abuse, HIV infection remained associated with an increased fracture risk [HR: 1.24 (95% CI: 1.11, 1.39)]. However, adjusting for BMI attenuated this association [HR: 1.10 (95% CI: 0.97, 1.25)]. The only HIV-specific factor associated with fragility fracture was current protease inhibitor use [HR: 1.41 (95% CI: 1.16, 1.70)]. CONCLUSIONS/SIGNIFICANCE: HIV infection is associated with fragility fracture risk. This risk is attenuated by BMI