Showing papers by "Trevor W. Robbins published in 2011"

Disruption in the balance between goal-directed behavior and habit learning in obsessive-compulsive disorder

Abstract: Objective:Obsessive-compulsive disorder (OCD) is characterized by repetitive, ritualistic behaviors and thought patterns. Although patients with OCD report that these compulsive behaviors are unproductive and often senseless, they are unable to desist. This study investigated whether the urge to perform compulsive acts is mediated by a disruption in the balance between flexible, goal-directed action control and habitual behavior. Method:A total of 21 patients with OCD and 30 healthy comparison subjects participated in a set of tasks designed to assess relative goal-directed versus habitual behavioral control. In the training stage, participants were asked to respond to different pictured stimuli in order to gain rewarding outcomes. In the subsequent (instructed) outcome devaluation test and in a novel “slips-of-action” test, the authors assessed whether participants were able to flexibly adjust their behavior to changes in the desirability of the outcomes. The authors also used a questionnaire to test exp...

Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence

Abstract: A growing body of preclinical evidence indicates that addiction to cocaine is associated with neuroadaptive changes in frontostriatal brain systems. Human studies in cocaine-dependent individuals have shown alterations in brain structure, but it is less clear how these changes may be related to the clinical phenotype of cocaine dependence characterized by impulsive behaviours and compulsive drug-taking. Here we compared self-report, behavioural and structural magnetic resonance imaging data on a relatively large sample of cocaine-dependent individuals (n = 60) with data on healthy volunteers (n = 60); and we investigated the relationships between grey matter volume variation, duration of cocaine use, and measures of impulsivity and compulsivity in the cocaine-dependent group. Cocaine dependence was associated with an extensive system of abnormally decreased grey matter volume in orbitofrontal, cingulate, insular, temporoparietal and cerebellar cortex, and with a more localized increase in grey matter volume in the basal ganglia. Greater duration of cocaine dependence was correlated with greater grey matter volume reduction in orbitofrontal, cingulate and insular cortex. Greater impairment of attentional control was associated with reduced volume in insular cortex and increased volume of caudate nucleus. Greater compulsivity of drug use was associated with reduced volume in orbitofrontal cortex. Cocaine-dependent individuals had abnormal structure of corticostriatal systems, and variability in the extent of anatomical changes in orbitofrontal, insular and striatal structures was related to individual differences in duration of dependence, inattention and compulsivity of cocaine consumption.

Dissociating Inhibition, Attention, and Response Control in the Frontoparietal Network Using Functional Magnetic Resonance Imaging

Abstract: Evidence suggests that the right inferior frontal cortex (IFC) plays a specialized role in response inhibition. However, more recent findings indicate a broader role for this region in attentional control. Here, we used functional magnetic resonance imaging to examine the functional role of the right IFC in attention, inhibition, and response control in 2 experiments that employed novel variations of the go/no-go task. Across the 2 experiments, we observed a graded response in the right insula/IFC, whereby increasing response control demands led to an increase in activation. The results are consistent with the hypothesis that this region plays a key role in the integration of bottom-up, sensory information with top-down, response-related information to facilitate flexible, goal-directed behavior.

The natural history of treated Parkinson's disease in an incident, community based cohort

Abstract: Background Our understanding of the natural history of idiopathic Parkinson’s disease (PD) remains limited. In the era of potential disease modifying therapies, there is an urgent need for studies assessing the natural evolution of treated PD from onset so that relevant outcome measures can be identified for clinical trials. No previous studies have charted progression in unselected patients followed from the point of diagnosis. Methods A representative cohort of 132 PD patients was followed from diagnosis for up to 7.9 years (mean 5.2 years). Comprehensive clinical and neuropsychological evaluations were performed every 18 months. Disease progression was evaluated using well validated clinical measures (motor progression and development of dyskinesia on the Unified PD Rating Scale and HoehneYahr scale, dementia onset according to DSM-IV criteria). Multi-level linear modelling was used to chart the nature and rate of progression in parkinsonian symptoms and signs over time. The prognostic importance of baseline demogr‘aphic, clinical and genetic variables was evaluated using survival analysis. Results Axial (gait and postural) symptoms evolve more rapidly than other motor features of PD and appear to be the best index of disease progression. Conversely, conventional outcome measures are relatively insensitive to change over time. Earlier onset of postural instability (HoehneYahr stage 3) is strongly associated with increased age at disease onset and has a significant impact on quality of life. Conclusions Dementia risk is associated with increased age, impaired baseline semantic fluency and the MAPT H1/H1 genotype. The efficacy of disease modifying therapies may be more meaningfully assessed in terms of their effects in delaying the major milestones of PD, such as postural instability and dementia, since it is these that have the greatest impact on patients.

Lower Ventral Striatal Activation During Reward Anticipation in Adolescent Smokers

Abstract: Objective:Adolescents are particularly vulnerable to addiction, and in the case of smoking, this often leads to long-lasting nicotine dependence. The authors investigated a possible neural mechanism underlying this vulnerability. Method:Functional MRI was performed during reward anticipation in 43 adolescent smokers and 43 subjects matched on age, gender, and IQ. The authors also assessed group differences in novelty seeking, impulsivity, and reward delay discounting. Results:In relation to the comparison subjects, the adolescent smokers showed greater reward delay discounting and higher scores for novelty seeking. Neural responses in the ventral striatum during reward anticipation were significantly lower in the smokers than in the comparison subjects, and in the smokers this response was correlated with smoking frequency. Notably, the lower response to reward anticipation in the ventral striatum was also observed in smokers (N=14) who had smoked on fewer than 10 occasions. Conclusions:The present findin...

Dissociable effects of lesions to orbitofrontal cortex subregions on impulsive choice in the rat.

Abstract: The orbitofrontal cortex (OFC) is implicated in a variety of adaptive decision-making processes. Human studies suggest that there is a functional dissociation between medial and lateral OFC (mOFC and lOFC, respectively) subregions when performing certain choice procedures. However, little work has examined the functional consequences of manipulations of OFC subregions on decision making in rodents. In the present experiments, impulsive choice was assessed by evaluating intolerance to delayed, but economically optimal, reward options using a delay-discounting paradigm. Following initial delay-discounting training, rats received bilateral neurotoxic or sham lesions targeting whole OFC (wOFC) or restricted to either mOFC or lOFC subregions. A transient flattening of delay-discounting curves was observed in wOFC-lesioned animals relative to shams--differences that disappeared with further training. Stable, dissociable effects were found when lesions were restricted to OFC subregions; mOFC-lesioned rats showed increased, whereas lOFC-lesioned rats showed decreased, preference for the larger-delayed reward relative to sham-controls--a pattern that remained significant during retraining after all delays were removed. When locations of levers leading to small-immediate versus large-delayed rewards were reversed, wOFC- and lOFC-lesioned rats showed retarded, whereas mOFC-lesioned rats showed accelerated, trajectories for reversal of lever preference. These results provide the first direct evidence for dissociable functional roles of the mOFC and lOFC for impulsive choice in rodents. The findings are consistent with recent human functional imaging studies and suggest that functions of mOFC and lOFC subregions may be evolutionarily conserved and contribute differentially to decision-making processes.

Decision Making, Affect, and Learning: Attention and Performance XXIII

Abstract: SECTION 1: PSYCHOLOGICAL PROCESSES UNDERLYING DECISION MAKING 1. Trial-by-trial data analysis using computational models 2. Psychological influences on economic choice: Pavlovian cuing and emotional regulation 3. The psychology of common value auctions 4. The instability of value 5. Do intransitive choices reflect genuinely context-dependent preferences? SECTION 2: NEURAL SUSTEMS OF DECISION MAKING 6. On the difficulties of integrating evidence from fMRI and electrophysiology in cognitive neuroscience (TUTORIAL REVIEW) 7. Neuroeconomics of risky decisions: from variables to strategies 8. Multiple neural circuits in value-based decision making 9. Model-based analysis of decision variables 10. Reversal learning in fronto-striatal circuits: a functional, autonomic, and neurochemical analysis 11. Cingulate and orbitofrontal contributions to valuing knowns and unknowns in a changeble world SECTION 3: NEURAL SYSTEMS OF EMOTION, REWARD, AND LEARNING 12. Dissociating encoding of attention, errors, and value in outcome-related neural activity (Tutorial Review) 13. The striatum and beyond: contributions of the hippocampus decision making 14. The neural basis of positive and negative emotion regulation: implications for decision making 15. Reward processing and conscious awareness 16. Role of striatal dopamine in the fast adaption of outcome-based decisions 17. Investigating the role of the noradrenergic system in human cognition 18. Interoception and decision making SECTION 4: NEURODEVELOPMENTAL AND CLINICAL ASPECTS 19. A neural systems model of decision making in adolescents 20. Risky and impulsive components of adolescent decision making 21. Abnormalities in monetary and other non-drug reward processing in drug addiction 22. The neuropsychology of stimulant and opiate dependence: neuroimaging and neuropsychological studies 23. Depression and resilience: insights from cognitive, neuroimaging, and psychopharmacological studies

Prefrontal and Monoaminergic Contributions to Stop-Signal Task Performance in Rats

Abstract: Defining the neural and neurochemical substrates of response inhibition is of crucial importance for the study and treatment of pathologies characterized by impulsivity such as attention-deficit/hyperactivity disorder and addiction. The stop-signal task (SST) is one of the most popular paradigms used to study the speed and efficacy of inhibitory processes in humans and other animals. Here we investigated the effect of temporarily inactivating different prefrontal subregions in the rat by means of muscimol microinfusions on SST performance. We found that dorsomedial prefrontal cortical areas are important for inhibiting an already initiated response. We also investigated the possible neural substrates of the selective noradrenaline reuptake inhibitor atomoxetine via its local microinfusion into different subregions of the rat prefrontal cortex. Our results show that both orbitofrontal and dorsal prelimbic cortices mediate the beneficial effects of atomoxetine on SST performance. To assess the neurochemical specificity of these effects, we infused the α2-adrenergic agonist guanfacine and the D1/D2 antagonist α-flupenthixol in dorsal prelimbic cortex to interfere with noradrenergic and dopaminergic neurotransmission, respectively. Guanfacine, which modulates noradrenergic neurotransmission, selectively impaired stopping, whereas blocking dopaminergic receptors by α-flupenthixol infusion prolonged go reaction time only, confirming the important role of noradrenergic neurotransmission in response inhibition. These results show that, similar to humans, distinct networks play important roles during SST performance in the rat and that they are differentially modulated by noradrenergic and dopaminergic neurotransmission. This study advances our understanding of the neuroanatomical and neurochemical determinants of impulsivity, which are relevant for a range of psychiatric disorders.

Contrasting roles for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats.

Abstract: Dopamine and dopamine-receptor function are often implicated in behavioral inhibition, and deficiencies within behavioral inhibition processes linked to attention deficit/hyperactivity disorder (ADHD), schizophrenia, obsessive-compulsive disorder, and drug addiction. In the stop-signal task, which measures the speed of the process of inhibition [stop-signal reaction time (SSRT)], psychostimulant-related improvement of SSRT in ADHD is linked with dopamine function. However, the precise nature of dopaminergic control over SSRT remains unclear. This study examined region- and receptor-specific modulation of SSRT in the rat using direct infusions of the dopamine D1 receptor (DRD1) antagonist SCH 23390 or dopamine D2 receptor (DRD2) antagonist sulpiride into the dorsomedial striatum (DMStr) or nucleus accumbens core (NAcbC). DRD1 and DRD2 antagonists had contrasting effects on SSRT that were specific to the DMStr. SCH 23390 decreased SSRT with little effect on the go response. Conversely, sulpiride increased SSRT but also increased go-trial reaction time and reduced trial completion at the highest doses. These results suggest that DRD1 and DRD2 function within the DMStr, but not the NAcbC, may act to balance behavioral inhibition in a manner that is independent of behavioral activation.

Dopamine, But Not Serotonin, Regulates Reversal Learning in the Marmoset Caudate Nucleus

Abstract: Studies of visual discrimination reversal learning have revealed striking neurochemical dissociations at the level of the orbitofrontal cortex (OFC) with serotoninergic, but not dopaminergic, integrity being important for successful reversal learning These findings have considerable implications for disorders such as obsessive compulsive disorder and schizophrenia, in which reversal learning is impaired, and which are primarily treated with drugs targeting the dopaminergic and serotoninergic systems Dysfunction in such disorders however, is not limited to the OFC and extends subcortically to other structures implicated in reversal learning, such as the medial caudate nucleus Therefore, because the roles of the serotonin and dopamine within the caudate nucleus are poorly understood, this study compared the effects of selective serotoninergic or selective dopaminergic depletions of the marmoset medial caudate nucleus on serial discrimination reversal learning All monkeys were able to learn novel stimulus–reward associations but, unlike control monkeys and monkeys with selective serotoninergic medial caudate depletions, dopamine-depleted monkeys were markedly impaired in their ability to reverse this association This impairment was not perseverative in nature These findings are the opposite of those seen in the OFC and provide evidence for a neurochemical double dissociation between the OFC and medial caudate in the regulation of reversal learning Although the specific contributions of these monoamines within the OFC–striatal circuit remain to be elucidated, these findings have profound implications for the development of drugs designed to remediate some of the cognitive processes underlying impaired reversal learning

Animal Models of Neuropsychiatric Disorders

Abstract: We survey the utility of animal models of mental illness, based on the identification of possible neurocognitive or neurobehavioral endophenotypes. Three broad clusters of neuropsychiatric disorder are discussed: (a) impulsive-compulsive syndromes, comprising drug addiction, attention deficit/hyperactivity disorder, gambling, obsessive-compulsive disorder, and compulsive eating; (b) disorders at the cognitive-emotional interface, comprising anxiety, depression, and schizophrenia; and (c) disorders purely of cognition, which contribute to the third cluster, cognitive disorders. The emphasis is thus on modeling symptoms rather than disorders per se. We also distinguish between two main aspects of any validated model: the precise neurobehavioral or neurocognitive processes implicated from detailed study of the clinical phenotype, and the perturbations, whether typically genetic, environmental, pharmacological, or neurodevelopmental, that are designed to simulate relevant neural, neurochemical, or molecular aspects of particular neuropsychiatric disorders.

High impulsivity predicting vulnerability to cocaine addiction in rats: some relationship with novelty preference but not novelty reactivity, anxiety or stress

Abstract: Impulsivity is a vulnerability marker for drug addiction in which other behavioural traits such as anxiety and novelty seeking (‘sensation seeking’) are also widely present However, inter-relationships between impulsivity, novelty seeking and anxiety traits are poorly understood The objective of this paper was to investigate the contribution of novelty seeking and anxiety traits to the expression of behavioural impulsivity in rats Rats were screened on the five-choice serial reaction time task (5-CSRTT) for spontaneously high impulsivity (SHI) and low impulsivity (SLI) and subsequently tested for novelty reactivity and preference, assessed by open-field locomotor activity (OF), novelty place preference (NPP), and novel object recognition (OR) Anxiety was assessed on the elevated plus maze (EPM) both prior to and following the administration of the anxiolytic drug diazepam, and by blood corticosterone levels following forced novelty exposure Finally, the effects of diazepam on impulsivity and visual attention were assessed in SHI and SLI rats SHI rats were significantly faster to enter an open arm on the EPM and exhibited preference for novelty in the OR and NPP tests, unlike SLI rats However, there was no dimensional relationship between impulsivity and either novelty-seeking behaviour, anxiety levels, OF activity or novelty-induced changes in blood corticosterone levels By contrast, diazepam (03–3 mg/kg), whilst not significantly increasing or decreasing impulsivity in SHI and SLI rats, did reduce the contrast in impulsivity between these two groups of animals This investigation indicates that behavioural impulsivity in rats on the 5-CSRTT, which predicts vulnerability for cocaine addiction, is distinct from anxiety, novelty reactivity and novelty-induced stress responses, and thus has relevance for the aetiology of drug addiction

Translational approaches to obsessive-compulsive disorder: From animal models to clinical treatment

Abstract: Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts) and compulsions (repetitive ritualistic behaviours) leading to functional impairment. Accumulating evidence links these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. However, the brain bases of these conditions and treatment mechanisms are still not fully elucidated. Animal models simulating the behavioural and clinical manifestations of the disorder show great potential for augmenting our understanding of the pathophysiology and treatment of OCD. This paper provides an overview of what is known about OCD from several perspectives. We begin by describing the clinical features of OCD and the criteria used to assess the validity of animal models of symptomatology; namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) neurobehavioural models. We also discuss their advantages and shortcomings in relation to their capacity to identify potentially efficacious new compounds. It is of interest that there has been rather little evidence of 'false alarms' for therapeutic drug effects in OCD models which actually fail in the clinic. While it is more difficult to model obsessive cognition than compulsive behaviour in experimental animals, it is feasible to infer cognitive inflexibility in certain animal paradigms. Finally, key future neurobiological and treatment research areas are highlighted.

Effects of two dopamine-modulating genes (DAT1 9/10 and COMT Val/Met) on n-back working memory performance in healthy volunteers

Abstract: Background. Impairments in working memory are present in many psychiatric illnesses such as attention-deficit hyperactivity disorder (ADHD) and schizophrenia. The dopamine transporter and catechol-O-methyltransferase (COMT) are proteins involved in dopamine clearance and the dopamine system is implicated in the modulation of working memory (WM) processes and neurochemical models of psychiatric diseases. The effects of functional polymorphisms of the dopamine transporter gene (DAT1) and the COMT gene were investigated using a visuospatial and numerical n-back working memory paradigm. Our n-back task was designed to reflect WM alone, and made no demands on higher executive functioning. Method. A total of 291 healthy volunteers (aged 18-45 years) were genotyped and matched for age, sex, and Barratt Impulsivity Scale (BIS) and National Adult Reading Test (NART) scores. To assess individual gene effects on WM, factorial mixed model analysis of variances (ANOVAs) were conducted with the between-subjects factor as genotype and difficulty level (0-, 1-, 2- and 3-back) entered as the within-subjects factor. Results. The analysis revealed that the DAT1 or COMT genotype alone or in combination did not predict performance on the n-back task in our sample of healthy volunteers. Conclusions. Behavioral effects of DAT1 and COMT polymorphisms on WM in healthy volunteers may be non- existent, or too subtle to identify without exceedingly large sample sizes. It is proposed that neuroimaging may provide more powerful means of elucidating the modulatory influences of these polymorphisms. Received 15 July 2009 ; Revised 7 April 2010 ; Accepted 10 April 2010 ; First published online 19 May 2010

Peripheral biomarkers of cognitive response to dopamine receptor agonist treatment

Abstract: Rationale Using biological markers to objectively measure addiction severity or to identify individuals who might benefit most from pro-cognitive treatment could potentially revolutionize neuropsychopharmacology. We investigated the use of dopamine receptor mRNA levels in circulating blood cells as predictors of cognitive response following dopamine agonist treatment, and as biomarkers of the severity of stimulant drug dependence.

Decision Making, Affect, and Learning: Attention and Performance XXIII

Abstract: This latest volume in the critically acclaimed and highly influential Attention and Performance series focuses on two of the fastest moving research areas in cognitive and affective neuroscience - decision making and emotional processing. Decision Making, Affect, and Learning investigates the psychological and neural systems underlying decision making, and the relationship with reward, affect, and learning. In addition, it considers neurodevelopmental and clinical aspects of these issues - for example the role of decision making and reward in drug addiction. It also looks at the applied aspects of this knowledge to other disciplines, including the growing field of Neuroeconomics. After an introductory chapter from the Volume editors, the book is then arranged according to the following themes: Psychological Processes underlying decision-making. Neural systems of decision-making Neural systems of emotion, reward and learning Neurodevelopmental and clinical aspects Superbly written and edited, the book highlights the complex interplay between emotional and decision-making processes and their relationship with learning. Contributors to this volume - Trevor W. Robbins, University of Cambridge, UK Mauricio Delgado, Rutgers University, USA Elizabeth A. Phelps, New York University, USA Colin F. Camerer, California Institute of Technology, USA Nathaniel D. Daw, New York University, USA Monique Ernst, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health Rita Z. Goldstein, Brookhaven National Laboratory Scott Huettel, Duke University, USA John W. Payne, Duke University, USA Vinod Venkatraman, Duke University, USA Samuel McClure, Stanford University, USA Wouter van den Bos, Leiden University, Germany G. Elliott Wimmer, Columbia University, USA Daphna Shohamy, Columbia University, USA B.J. Casey, Weill Medical College of Cornell University, UK Todd Hare, California Institute of Technology, USA Adriana Galvan, University of California, USA Nick Chater, University College London, UK Ivaylo Vlaev, Imperial College London, UK Laura N. Martin, Rutgers University, USA Tobias Kalenscher, University of Amsterdam, The Netherlands Cyriel M. A. Pennartz, University of Amsterdam, The Netherlands Sander T. Nieuwenhuis, Leiden University, Germany Marieke Jepma, Leiden University, Germany Mathias Pessiglione, Institut du Cerveau et de la Moelle epiniere (ICM), INSERM Paris, France Liane Schmidt, Institut du Cerveau et de la Moelle epiniere (ICM), INSERM Paris, France Stefano Palminteri, Institut du Cerveau et de la Moelle epiniere (ICM), INSERM Paris, France Chris D. Frith, University College London, UK and University of Aarhus, Denmark Michael Platt, Duke University, USA Barbara Sahakian, University of Cambridge, UK Sharon Morein-Zamir, University of Cambridge, UK Manami Yamamoto, Brain Science Research Center Tamagawa University Brain Science Institute, Tokyo, Japan Xiochuan Pan, Brain Science Research Center Tamagawa University Brain Science Institute, Tokyo, Japan Kensaku Nomoto, Brain Science Research Center Tamagawa University Brain Science Institute, Tokyo, Japan Masamichi Sakagami, Brain Science Research Center Tamagawa University Brain Science Institute, Tokyo, Japan Roshan Cools, Donders Institute for Brain, Cognition and Behaviour, The Netherlands Kenji Doya, Okinawa Institute of Science and Technology, Japan Makoto Ito Okinawa Institute of Science and Technology, Japan Kazuyuki Samejima Okinawa Institute of Science and Technology, Japan Karen D. Ersche, University of Cambridge, UK Martin Paulus, University of California, USA H. F. Clarke, University of Cambridge, UK Angela C. Roberts, University of Cambridge, UK Matthew R. Roesch, University of Maryland School of Medicine, USA Geoffrey Schoenbaum, University of Maryland, USA Mark E. Walton, University of Oxford, UK Peter H. Rudebeck, University of Oxford, UK Timothy E. J. Behrens, University of Oxford, UK Matthew F. S. Rushworth University of Oxford, UK

Animal models of ADHD.

Abstract: Studies employing animal models of attention-deficit/hyperactivity disorder (ADHD) present clear inherent advantages over human studies. Animal models are invaluable tools for the study of underlying neurochemical, neuropathological and genetic alterations that cause ADHD, because they allow relatively fast, rigorous hypothesis testing and invasive manipulations as well as selective breeding. Moreover, especially for ADHD, animal models with good predictive validity would allow the assessment of potential new therapeutics. In this chapter, we describe and comment on the most frequently used animal models of ADHD that have been created by genetic, neurochemical and physical alterations in rodents. We then discuss that an emerging and promising direction of the field is the analysis of individual behavioural differences among a normal population of animals. Subjects presenting extreme characteristics related to ADHD can be studied, thereby avoiding some of the problems that are found in other models, such as functional recovery and unnecessary assumptions about aetiology. This approach is justified by the theoretical need to consider human ADHD as the extreme part of a spectrum of characteristics that are distributed normally in the general population, as opposed to the predominant view of ADHD as a separate pathological category.

Differential Cognitive Deterioration in Dementia: A Two Year Longitudinal Study

Abstract: The ability to predict cognitive deterioration in patients with dementia holds valuable potential for clinical trials and early intervention. This study identified cognitive domains deteriorating differentially over time as well as baseline predictors of subsequent cognitive decline in patients referred to a memory clinic. Twenty-six subjects with Alzheimer's disease (AD) and 43 subjects with Subjective Memory Impairment (SMI) were entered into a longitudinal study in which cognitive function was assessed at baseline and at 8-monthly intervals for 2 years, using a range of well-validated measures. Thirty-seven patients with depression and 39 healthy controls were also longitudinally assessed. AD was associated with disproportionate deterioration over time on general measures of cognitive function, multiple measures of mnemonic processing, mental fluency (letter and category), and aspects of motor speed. SMI showed restricted relative cognitive deterioration on general measures of cognitive function, on a subset of memory measures, and on letter but not category fluency. Secondary analysis showed that earliest detectable ADAS-cog and MMSE decline in AD was at 16 months, while several specific neuropsychological indices were sensitive as early as 8 months (graded naming test, semantic naming, and the category/letter fluency tests). In combination, baseline/early changes in cognitive performance, alongside clinical measures, predicted 48% of disease progression over two years in memory impaired patients as a whole. These findings have implications for identifying patients likely to benefit from disease modifying agents, and for designing, powering, enriching, and implementing future clinical trials. Follow-up studies in independent populations are needed to validate predictive algorithms identified.

Differences in self-reported decision-making styles in stimulant-dependent and opiate-dependent individuals.

Abstract: In light of the growing evidence of altered decision-making in addiction we assessed decision-making styles in drug-dependent individuals using the Melbourne Decision-Making Questionnaire (MDMQ). Consistent with the literature on laboratory tests of decision-making, we found that stimulant users reported less competent and more maladaptive decision-making styles compared with controls.

5-HT modulation by acute tryptophan depletion of human instrumental contingency judgements.

Abstract: Introduction The concept of ‘depressive realism’, that depression leads to more accurate perception of causal control, has been influential in the field of depression research, but remains controversial. Recent work testing contingency learning has suggested that contextual processing might determine realism-like effects. Serotonin (5-hydroxytryptamine, (5-HT)), which is implicated in the pathophysiology of depression, might also influence contextual processing. Using acute tryptophan depletion (ATD), we tested the hypothesis that dysfunctional serotoninergic neurotransmission influences contingency judgements in dysphoric subjects via an effect on contextual processing.