Showing papers by "Trevor W. Robbins published in 2010"

Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease

Abstract: Cognitive impairment in patients with Parkinson's disease is gaining increased clinical significance owing to the relative success of therapeutic approaches to the motor symptoms of this disorder. Early investigations contributed to the concept of subcortical dementia associated with bradyphrenia and cognitive rigidity. For cognition in parkinsonian disorders, this notion developed into the concept of mild cognitive impairment and fronto-executive dysfunction in particular, driven mainly by dopaminergic dysmodulation and manifesting as deficits in flexibility, planning, working memory, and reinforcement learning. However, patients with Parkinson's disease could also develop a syndrome of dementia that might depend on non-dopaminergic, cholinergic cortical dysfunction. Recent findings, supplemented by advances in neuroimaging and genetic research, reveal substantial heterogeneity in the range of cognitive deficits in patients with Parkinson's disease. Remediation and management prospects for these cognitive deficits are based on neuropharmacological and cognitive rehabilitation approaches.

The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology.

Abstract: The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology

Serotonin selectively influences moral judgment and behavior through effects on harm aversion

Abstract: Aversive emotional reactions to real or imagined social harms infuse moral judgment and motivate prosocial behavior. Here, we show that the neurotransmitter serotonin directly alters both moral judgment and behavior through increasing subjects’ aversion to personally harming others. We enhanced serotonin in healthy volunteers with citalopram (a selective serotonin reuptake inhibitor) and contrasted its effects with both a pharmacological control treatment and a placebo on tests of moral judgment and behavior. We measured the drugs' effects on moral judgment in a set of moral 'dilemmas' pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person). Enhancing serotonin made subjects more likely to judge harmful actions as forbidden, but only in cases where harms were emotionally salient. This harm-avoidant bias after citalopram was also evident in behavior during the ultimatum game, in which subjects decide to accept or reject fair or unfair monetary offers from another player. Rejecting unfair offers enforces a fairness norm but also harms the other player financially. Enhancing serotonin made subjects less likely to reject unfair offers. Furthermore, the prosocial effects of citalopram varied as a function of trait empathy. Individuals high in trait empathy showed stronger effects of citalopram on moral judgment and behavior than individuals low in trait empathy. Together, these findings provide unique evidence that serotonin could promote prosocial behavior by enhancing harm aversion, a prosocial sentiment that directly affects both moral judgment and moral behavior.

Approach and avoidance learning in patients with major depression and healthy controls: relation to anhedonia.

Abstract: BackgroundCentral to understanding of the behavioural consequences of depression has been the theory that the disorder is accompanied by an increased sensitivity to negative compared with positive reinforcement (negative bias), whereas other theorists have emphasized a global reduction in sensitivity to reinforcement in depression (blunting).MethodIn this study, we used a probabilistic selection task that was designed to examine independently rates of learning to predict both positive and negative reinforcement. Twenty-three depressed out-patients and 23 healthy controls from the local population participated in the study.ResultsNo evidence for a negative bias was observed on the task, either during acquisition of the task or during generalization of the learned information. Depressed patients responded slower on the task than controls but showed a similar modulation of reaction times (RTs) as controls following reinforcement. Evidence for blunting was observed on the training phase, as reflected in reduced trial-by-trial adjustment during this phase. However, this effect was related specifically to the severity of anhedonia, as measured by the Snaith–Hamilton Pleasure Scale (SHAPS), and was independent of overall depression severity.ConclusionsWe argue that the observation of a negative bias or blunting in a group of depressed patients may be dependent on the neuropsychological task and the symptoms of the patients tested. Our results provide insight into how these theories might be further tested.

Impulsive choice and altruistic punishment are correlated and increase in tandem with serotonin depletion.

Abstract: Human cooperation may partly depend on the presence of individuals willing to incur personal costs to punish noncooperators. The psychological factors that motivate such 'altruistic punishment' are not fully understood; some have argued that altruistic punishment is a deliberate act of norm enforcement that requires self-control, while others claim that it is an impulsive act driven primarily by emotion. In the current study, we addressed this question by examining the relationship between impulsive choice and altruistic punishment in the ultimatum game. As the neurotransmitter serotonin has been implicated in both impulsive choice and altruistic punishment, we investigated the effects of manipulating serotonin on both measures. Across individuals, impulsive choice and altruistic punishment were correlated and increased following serotonin depletion. These findings imply that altruistic punishment reflects the absence rather than the presence of self control, and suggest that impulsive choice and altruistic punishment share common neural mechanisms.

Enhancement of spatial reversal learning by 5-HT2C receptor antagonism is neuroanatomically specific.

Abstract: We have recently demonstrated that systemic administration of 5-HT2C and 5-HT2A receptor antagonists significantly enhanced and impaired spatial reversal learning, respectively. In this study, the role of 5-HT2C and 5-HT2A receptor subtypes in the mediation of these opposing effects was further investigated with respect to neuroanatomical specificity. The roles of 5-HT2C and 5-HT2A receptors were examined within some of the brain regions implicated in cognitive flexibility, namely the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), by means of targeted infusions of selective 5-HT2C and 5-HT2A receptor antagonists (SB 242084 and M100907, respectively). Intra-OFC 5-HT2C receptor antagonism produced dose-dependent effects similar to those of systemic administration, i.e., improved spatial reversal learning by reducing the number of trials (all doses: 0.1, 0.3, and 1.0 μg) and perseverative errors to criterion (0.3 and 1.0 μg) compared with controls. However, the highest dose (1.0 μg) showed a nonselective effect, as it also affected retention preceding the reversal phase and decreased learning errors. Intracerebral infusions of SB 242084 into the mPFC or NAc produced no significant effects on any behavioral measures. Similarly, no significant differences were observed with intra-OFC, -mPFC, or -NAc infusions of M100907. These data suggest that the improved performance in reversal learning observed after 5-HT2C receptor antagonism is mediated within the OFC. These data also bear on the issue of whether 5-HT2C receptor antagonism within the OFC might help elucidate the biological substrate of obsessive-compulsive disorder, offering the potential for therapeutic application.

Differential Contributions of the Primate Ventrolateral Prefrontal and Orbitofrontal Cortex to Serial Reversal Learning

Abstract: The discrimination reversal paradigm is commonly used to measure a subject's ability to adapt their behavior according to changes in stimulus–reward contingencies. Human functional neuroimaging studies have demonstrated activations in the lateral orbitofrontal cortex (OFC) and the inferior frontal gyrus (IFG) in subjects performing this task. Excitotoxic lesions of analogous regions in marmosets have revealed, however, that although the OFC is indeed critical for reversal learning, ventrolateral prefrontal cortex (VLPFC) (analogous to IFG) is not, contributing instead to higher order processing, such as that required in attentional set-shifting and strategy transfer. One major difference between the marmoset and human studies has been the level of training subjects received in reversal learning, being far greater in the latter. Since exposure to repeated contingency changes, as occurs in serial reversal learning, is likely to trigger the development of higher order, rule-based strategies, we hypothesized a critical role of the marmoset VLPFC in performance of a serial reversal learning paradigm. After extensive training in reversal learning, marmosets received an excitotoxic lesion of the VLPFC, OFC, or a sham control procedure. In agreement with our prediction, postsurgery, VLPFC lesioned animals were impaired in performing a series of discrimination reversals, but only when novel visual stimuli were introduced. In contrast, OFC lesioned animals were impaired regardless of whether the visual stimuli were the same or different from those used during presurgery training. Together, these data demonstrate the heterogeneous but interrelated involvement of primate OFC and VLPFC in the performance of serial reversal learning.

Influence of Compulsivity of Drug Abuse on Dopaminergic Modulation of Attentional Bias in Stimulant Dependence

Abstract: Context There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. Objective To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D 2 /D 3 receptor antagonist and agonist challenges. Design Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. Setting Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. Participants S timulant-dependent individuals (n = 18) and healthy volunteers (n = 18). Interventions Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. Main Outcome Measures Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. Results Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. Conclusions Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.

Trait-like impulsivity does not predict escalation of heroin self-administration in the rat

Abstract: Rationale The neural and psychological mechanisms underlying vulnerability to drug addiction are poorly understood. Although a number of animal models have been developed to investigate vulnerability to stimulant addiction, few have considered how vulnerability traits such as impulsivity predict hallmark features of heroin addiction including the escalation of drug intake and increased propensity for relapse following protracted abstinence.

Inhibition of thoughts and actions in obsessive-compulsive disorder: extending the endophenotype?

Abstract: Original article can be found at: http://journals.cambridge.org/ Copyright © Cambridge University Press 2009 The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence .

Top-down attentional control in parkinson's disease: Salient considerations

Abstract: Cognitive dysfunction in Parkinson's disease (PD) has been hypothesized to reflect a failure of cortical control. In keeping with this hypothesis, some of the cognitive deficits in PD resemble those seen in patients with lesions in the lateral pFC, which has been associated with top-down attentional control. However, there is no direct evidence for a failure of top-down control mechanisms in PD. Here we fill this gap by demonstrating disproportionate control by bottom-up attention to dimensional salience during attentional set shifting. Patients needed significantly more trials to criterion than did controls when shifting to a low-salient dimension while, remarkably, needing significantly fewer trials to criterion than did controls when shifting to a high-salient dimension. Thus, attention was captured by bottom-up attention to salient information to a greater extent in patients than in controls. The results provide a striking reinterpretation of prior set-shifting data and provide the first direct evidence for a failure of top-down attentional control, resembling that seen after catecholamine depletion in the pFC.

Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers.

Abstract: Previous research has demonstrated cognitive-enhancing effects of modafinil in humans and generated evidence for its therapeutic potential in psychiatric disorders. The neurochemical basis of these effects remains unresolved although a role for α1-adrenoceptors has been hypothesised. In this within-subject, double-blind, placebo-controlled study, 12 healthy male adults received modafinil (300 mg), the α1-adrenoceptor antagonist prazosin (3 mg), both together and placebo on separate occasions at least 5 days apart. Cognitive effects were assessed using a well-validated testing battery focusing on executive and working memory functions. Blood pressure, heart rate and salivary α-amylase (sAA) were measured at hourly intervals. Cognitive effects of modafinil and prazosin were identified at the difficult levels of the One-Touch Stockings of Cambridge (OTSOC) planning task. Prazosin antagonized the error-reducing effect of modafinil when the agents were given together. In contrast, the combined agents acted synergistically to increase time taken to complete OTSOC problems compared with placebo. The tachycardic and sAA-elevating effects of prazosin were also potentiated by concurrent modafinil administration. The current data suggest that the cognitive effects of modafinil on performance accuracy and latency are dissociable in terms of their neurochemical mechanisms. Our findings support the hypothesised involvement of α1-adrenoceptors in some of the cognitive-enhancing effects of modafinil and warrant further investigation.

Methylphenidate-induced impulsivity: pharmacological antagonism by β-adrenoreceptor blockade

Abstract: Noradrenaline-dopamine interactions mediate increases in locomotor activity, development of sensitisation and subjective effects of psychostimulant drugs. However, the modulatory effects of noradrenaline on psychostimulant-induced impulsivity are less clear. This article examined the relative roles of noradrenaline and dopamine in the modulation of methylphenidate-induced impulsive responding in rats performing the 5-choice serial reaction time task. Experiment 1 examined the systemic antagonism of methylphenidate-induced impulsivity with either propranolol, a beta-adrenoreceptor blocker, or prazosin, an alpha1-adrenoreceptor antagonist, which antagonises the locomotor activating effects of amphetamine. Propranolol completely abolished methylphenidate-induced impulsivity. This effect was centrally rather than peripherally mediated, as nadolol, a peripheral beta-blocker failed to affect methylphenidate-induced premature responding. Prazosin partially attenuated the methylphenidate-mediated increase in premature responding. A second experiment examined the effects of selective anti-D beta H saporin-induced cortical noradrenaline depletion on methylphenidate-induced impulsivity. Contrary to the effects of beta-adrenoreceptor blockade, cortical noradrenergic depletion did not alter methylphenidate-induced impulsivity. Other experiments examined the comparative effects of selective dopamine and serotonin receptor blockade. D4 dopamine receptor blockade with systemically administered L-745,870 also attenuated methylphenidate-induced impulsivity. The other antagonists had no effect on methylphenidate-induced impulsivity. Taken together, these studies provide evidence for a modulatory role of beta-adrenoreceptors on methylphenidate-induced impulsive responding.

Impaired visuospatial associative memory and attention in obsessive compulsive disorder but no evidence for differential dopaminergic modulation

Abstract: Patients with obsessive compulsive disorder (OCD) demonstrate impaired cognition in some selected domains. Although serotoninergic dysfunction has been implicated in OCD, recent evidence suggests that dopamine may play a role as well. The aim of the study was to evaluate learning and working memory in OCD and to determine the effects of dopaminergic manipulations on these capacities. Visuospatial associative memory and spatial and verbal working memory were examined in 18 nondepressed patients with OCD and 18 matched healthy controls. The study further investigated whether acute administration of dopamine D2/D3 receptor agonist and antagonist would differentially modulate cognition in OCD. Each participant underwent the cognitive battery three times in a randomized double-blind, placebo-controlled crossover design. Significant impairments in patients compared with controls were noted on the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) and a measure of sustained attention (rapid visual information processing, RVIP) that persisted across all sessions, with deficient strategy in the CANTAB spatial working memory task in the first session alone. Although the dopamine D2/D3 agonist, pramipexole, led to poorer performance on the PAL and RVIP tasks, no differential effects were noted between the two groups. No significant effects were noted for the D2/D3 antagonist, amisulpride. The results are consistent with a specific associative memory deficit in OCD that remained robust despite possible practice effects and compensatory strategies and point to abnormal medial temporal lobe involvement in OCD in addition to the previously implicated frontostriatal loops, with no clear evidence of D2 receptor mediation.

Dopamine Modulation of the Prefrontal Cortex and Cognitive Function

Abstract: This chapter will review the basic neurobiology of the dopamine (DA) system in the prefrontal cortex (PFC) and its functional role in cognition. It will consider the properties of DA release and of DA receptors in the PFC and how they may contribute to the overall function of the mesocortical DA system. DA release in the PFC occurs in response to a variety of events that can be appetitive or aversive in nature and this release may prepare the PFC networks to deal with environmental or cognitive challenges. The amount of DA released may selectively affect the different subtypes of receptors on PFC neurons, which in turn have different modulatory actions on PFC networks. It has been proposed that the PFC DA system and especially D1 receptors are tuned according to an inverted-U dose–response function such that too much or too little DA or D1 receptor activation is detrimental to cognitive performance. At optimal levels, DA acting via D1 receptors may increase the signal-to-noise ratio to improve the efficiency of active PFC networks, while levels higher or lower levels may reduce the overall signal to noise but allow PFC networks to deal with information in a more flexible manner. The key to understanding the PFC DA system may lie in understanding how a balance is achieved to promote optimal modulation across a variety of situations.

Role of Central Serotonin in Impulsivity and Compulsivity: Comparative Studies in Experimental Animals and Humans

Abstract: The involvement of serotonin in impulsivity (the tendency to respond prematurely) and compulsivity (the tendency to perseverate) is reviewed from the joint perspective of animal and human studies. Evidence is provided to support a role for serotonin in some forms of impulsivity, but not others, and in compulsivity. However, it is difficult to accommodate these roles into a common scheme implicating behavioral inhibition. The implications for neuropsychiatric disorders such as obsessive-compulsive disorder are considered.

Regret and the negative evaluation of decision outcomes in major depression.

Abstract: Disruption of normal emotional experience is central to the phenomenology of depression. Twenty-three depressed outpatients and 23 control subjects performed a computerized decision-making task, during which affective ratings were assessed online to identify various dimensions of emotional experience. We sought to contrast regret (the comparison of the outcomes of selected and nonselected options) with the general negative appraisal of task events. The experience of regret was reduced in depressed patients, an effect that was particularly related to self-reported apathy scores. In an exploratory analysis, we observed that females had a general downward shift in their ratings, as compared with males, but disappointment and regret effects were of similar magnitude. The possible contribution of the orbitofrontal cortex to the phenomenology of regret is discussed. Supplemental materials for this article may be downloaded from http://cabn.psychonomic-journals.org/content/ supplemental.

Impaired performance on the Rapid Visual Information Processing task (RVIP) could be an endophenotype of schizophrenia.

Abstract: The aim of the present study was to investigate whether healthy first-degree relatives of schizophrenia patients show reduced sensitivity performance, higher intra-individual variability (IIV) in reaction time (RT), and a steeper decline in sensitivity over time in a sustained attention task. Healthy first-degree relatives of schizophrenia patients (n=23) and healthy control subjects (n=46) without a family history of schizophrenia performed a demanding version of the Rapid Visual Information Processing task (RVIP). RTs, hits, false alarms, and the sensitivity index A' were assessed. The relatives were significantly less sensitive, tended to have higher IIV in RT, but sustained the impaired level of sensitivity over time. Impaired performance on the RVIP is a possible endophenotype for schizophrenia. Higher IIV in RT, apparently caused by impaired context representations, might result in fluctuations in control and lead to more frequent attentional lapses.

Striatal sensitivity to personal responsibility in a regret-based decision-making task.

Abstract: Regret and relief are complex emotional states associated with the counterfactual processing of nonobtained outcomes in a decision-making situation. In the "actor effect," a sense of agency and personal responsibility is thought to heighten these emotions. Using fMRI, we scanned volunteers (n = 22) as they played a task involving choices between two wheel-of-fortune gambles. We examined how neural responses to counterfactual outcomes were modulated by giving subjects the opportunity to change their minds, as a manipulation of personal responsibility. Satisfaction ratings to the outcomes were highly sensitive to the difference between the obtained and nonobtained outcome, and ratings following losses were lower on trials with the opportunity to change one's mind. Outcome-related activity in the striatum and orbitofrontal cortex was positively related to the satisfaction ratings. The striatal response was modulated by the agency manipulation: Following losses, the striatal signal was significantly lower when the subject had the opportunity to change his/her mind. These results support the involvement of frontostriatal mechanisms in counterfactual thinking and highlight the sensitivity of the striatum to the effects of personal responsibility.

Paradoxical enhancement of choice reaction time performance in patients with major depression.

Abstract: The Cued Reinforcement Reaction Time (CRRT) task is a choice reaction time task in which rewards (points) are available if the subject responds quickly enough and are signalled with a certain probability by stimuli. Reaction times (RTs) are faster following stimuli predicting reward with a high probability than with a low probability. This RT difference is sensitive to manipulations and individual differences in the serotonin (5-HT) system, but the CRRT task performance has not yet been examined in patients with depression. We observed that patients performed better on the task than controls, as evidenced by a greater points score, a greater likelihood of reaching their reinforcement threshold and fewer errors. RT variability was reduced in the patients. No group differences in the effect of the conditioned stimuli on RTs were observed. Accounts of these surprising data are discussed, considering possible effects of antidepressant medication or task-dependent differences in selective attention. Regardless of precise mechanism, the results do indicate that depressed patients are not invariably impaired in motivational paradigms and that their RT performance in certain situations can be superior to that of controls.

The neurobiology of addiction : new vistas

Abstract: Introduction. The neurobiology of drug addiction: new vistas Neurobiological mechanisms for opponent motivational processes in addiction Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction The incentive sensitization theory of addiction: some current issues Psychological and neural mechanisms of relapse Neurobiology of nicotine dependence Cognitive and emotional consequences of binge drinking: role of amygdala and prefrontal cortex The neurobiology of pathological gambling and drug addiction: an overview and new findings Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology Neurogenetic studies of alcohol addiction Genetics of addictions: strategies for addressing heterogeneity and polygenicity of substance use disorders Positron emission tomography imaging studies of dopamine receptors in primate models of addiction Context-induced relapse to drug seeking: a review Transcriptional mechanisms of addiction: role of changes in FosB Parallel studies of cocaine-related neural and cognitive impairment in humans and monkeys Acute effects of cocaine on the neurobiology of cognitive control Evidence-based treatments of addiction

Reply to Harris and Chan: Moral judgment is more than rational deliberation

Abstract: In their letter, Harris and Chan (1) challenge our conclusion that serotonin modulates moral judgment and behavior (2). Unfortunately, their argument is based on a narrow definition of moral judgment, one that is out of touch with empirical research. Harris and Chan (1) seem to subscribe to a rationalist view of moral judgment that defines moral judgment as the exclusive preserve of a conscious, deliberative reasoning process. However, an overwhelming amount of evidence shows that intuitive and emotional processes play significant roles in moral judgment (3). One challenge to the rationalist view is that people often form moral judgments without being able to articulate the reasons … 1To whom correspondence should be addressed. E-mail: mc536{at}cam.ac.uk.