Biomedical subjects

Trevor W Robbins

Publications and source records attributed to Trevor W Robbins.

At least 55 records · Page 3Linked to original sources

PubMed2005

Neural systems of reinforcement for drug addiction: from actions to habits to compulsion.

Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use--when a drug is voluntarily taken because it has reinforcing, often hedonic, effects--through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.

Animals↗

PubMed2005

Cognitive sequelae of intravenous amphetamine self-administration in rats: evidence for selective effects on attentional performance.

Characterizing the nature and severity of cognitive deficits associated with chronic stimulant abuse may provide new insights into the neural substrates of drug addiction because such deficits may contribute to the chronic relapsing nature of compulsive drug use. This investigation examines in rats the long-term cognitive consequences of intravenously self-administered amphetamine, specifically on performance of a 5-choice serial reaction time task (5-CSRTT), which assesses visuo-spatial attention and impulsivity. Rats experienced 5 days of intravenous (i.v.) amphetamine self-administration and were then withdrawn for a period of 9 days, during which time testing on the 5-CSRTT took place. This was repeated on five consecutive occasions for a period of 10 weeks. Controls experienced identical training on the 5-CSRTT but during the self-administration sessions received yoked i.v. infusions of normal saline. The results reveal a selective and reproducible pattern of deficits on the 5-CSRTT following repeated withdrawal from amphetamine self-administration, with deleterious effects on the speed and accuracy of responding as well as increased omission errors. Premature (impulsive) responding, perseveration, and food consumption latencies were not significantly affected. Deficits in attentional performance fully recovered 4-5 days after amphetamine cessation and there was no evidence of any long-term disturbances, even when the attentional load was increased. However, following a 2-month abstinence period, abnormalities in the subsequent effects of acute noncontingent amphetamine were found, with increased omissions, slower response times, and reduced impulsivity. Thus, contingent i.v. amphetamine administration has both short- and long-term consequences, which may be relevant to the complex disturbances that accompany drug addiction.

Amphetamine↗

PubMed2005

Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders.

Forebrain serotonergic lesions attenuate the ability of d-amphetamine to decrease impulsivity in a delay-discounting paradigm, potentially through interactions between the serotonin (5-HT) and dopamine (DA) systems. Nucleus accumbens (NAC) lesions increase impulsivity, but the extent to which accumbal DA is involved in regulating impulsive choice is unknown. In the current study, the effects of intra-accumbal infusions of 6-hydroxydopamine (6-OHDA) on impulsive choice were evaluated, in combination with d-amphetamine and serotonergic drugs, in order to investigate the importance of 5-HT : DA interactions in the control of impulsive behavior. Following training on a delay-discounting task, animals received intra-NAC 6-OHDA or sham surgery. Postoperatively, subjects received systemic injections of d-amphetamine (0, 0.3, 1.0, 1.5 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0, 0.1, 0.3, 1.0 mg/kg). Intra-NAC 6-OHDA, which reduced local DA and NA levels by 70-75%, had no effect on delay-discounting, but transiently potentiated the d-amphetamine-induced decrease in impulsive choice. 8-OH-DPAT (1.0 mg/kg) increased impulsivity in sham-operated controls, an effect which was blocked by the 5-HT(1A) receptor antagonist WAY 100635. However, 8-OH-DPAT had no effect on impulsivity in 6-OHDA NAC lesioned rats. 8-OH-DPAT (0.3 mg/kg), which did not itself alter task performance, blocked the effect of d-amphetamine in sham-operated controls, while WAY 100635 augmented the effect of amphetamine in all subjects. In an additional experiment, intracerebroventricular administration of the selective serotonergic toxin 5,7-dihydroxytryptamine, which decreased forebrain 5-HT levels by 85-90%, did not block 8-OH-DPAT's ability to increase impulsive choice. These data suggest a significant role for 5-HT : DA interactions within the NAC in the control of impulsivity, and in the mechanism by which amphetamine decreases impulsive choice.

5,7-Dihydroxytryptamine↗

PubMed2005

Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning.

This study used functional magnetic resonance imaging to examine the effects of acute tryptophan (TRP) depletion (ATD), a well-recognized method for inducing transient cerebral serotonin depletion, on brain activity during probabilistic reversal learning. Twelve healthy male volunteers received a TRP-depleting drink or a balanced amino-acid drink (placebo) in a double-blind crossover design. At 5 h after drink ingestion, subjects were scanned while performing a probabilistic reversal learning task and while viewing a flashing checkerboard. The probabilistic reversal learning task enabled the separate examination of the effects of ATD on behavioral reversal following negative feedback and negative feedback per se that was not followed by behavioral adaptation. Consistent with previous findings, behavioral reversal was accompanied by significant signal change in the right ventrolateral prefrontal cortex (PFC) and the dorsomedial prefrontal cortex. ATD enhanced reversal-related signal change in the dorsomedial PFC, but did not modulate the ventrolateral PFC response. The ATD-induced signal change in the dorsomedial PFC during behavioral reversal learning extended to trials where subjects received negative feedback but did not change their behavior. These data suggest that ATD affects reversal learning and the processing of aversive signals by modulation of the dorsomedial PFC.

Adolescent↗

PubMed2005

Tryptophan depletion disrupts the motivational guidance of goal-directed behavior as a function of trait impulsivity.

Serotonin (5-HT) is well known to affect the motivational properties of stimuli predictive of rewards as well as the inhibitory control of behavior. Here, central 5-HT depletion was induced by the acute tryptophan (TRP) depletion (ATD) procedure in young healthy volunteers to examine the role of 5-HT in motivated action and prepotent response inhibition. A novel reaction-time task, tailored to individual differences in general cognitive speed, was employed to measure the guidance of behavior by motivationally relevant signals predictive of reinforcement likelihood, while the stop-signal reaction-time task was used to measure response inhibition. Following the TRP-balancing control drink, cues predictive of high-reinforcement certainty induced faster, but less accurate responses compared with cues predictive of lower reinforcement certainty. Depletion of central 5-HT modulated this coupling between motivation and action by slowing responses and increasing accuracy as a function of incentive certainty. These effects of ATD on motivated action correlated highly with individual differences in the personality trait of Nonplanning Impulsiveness (Barratt Impulsivity Scale (BIS-11)), so that strongest effects on motivated action were observed in high-impulsive individuals. By contrast, ATD left unaltered the ability to inhibit prepotent responses. Our findings may have implications for a variety of neuropsychiatric disorders including impulsive aggressive disorders and depression.

Adult↗

PubMed2005

Punishment induces risky decision-making in methadone-maintained opiate users but not in heroin users or healthy volunteers.

Reinforcing properties of psychoactive substances are considered to be critically involved in the development and maintenance of substance dependence. While accumulating evidence suggests that the sensitivity to reinforcement values may generally be altered in chronic substance users, relatively little is known about the influence reinforcing feedback exerts on ongoing decision-making in these individuals. Decision-making was investigated using the Cambridge Risk Task, in which there is a conflict between an unlikely large reward option and a likely small reward option. Responses on a given trial were analyzed with respect to the outcome on the previous trial, providing a measure of the impact of prior feedback in modulating behavior. Five different groups were compared: (i) chronic amphetamine users, (ii) chronic opiate users in methadone maintenance treatment (MMT), (iii) chronic users of illicit heroin, (iv) ex-drug users who had been long-term amphetamine / opiate users but were abstinent from all drugs of abuse for at least 1 year and (v) matched controls without a history of illicit substance use. Contrary to our predictions, choice preference was modified in response to feedback only in opiate users enrolled in MMT. Following a loss, the MMT opiate group chose the likely small reward option significantly less frequently than controls and heroin users. Our results suggest that different opiates are associated with distinctive behavioral responses to feedback. These findings are discussed with respect to the different mechanisms of action of heroin and methadone. Neuropsychopharmacology (2005) 30, 2115-2124. doi:10.1038/sj.npp.1300812; published online 6 July 2005.

Adult↗

PubMed2005

Prolonged neglect following unilateral disruption of a prefrontal cortical-dorsal striatal system.

We investigated the potential function of the system formed by connections between the medial prefrontal cortex and the dorsomedial striatum in aspects of attentional function in the rat. It has been reported previously that disconnection of the same corticostriatal circuit produced marked deficits in performance of a serial, choice reaction-time task while sparing the acquisition of an appetitive Pavlovian approach behaviour in an autoshaping task (Christakou et al., 2001). Here, we hypothesized that unilateral disruption of the same circuit would lead to hemispatial inattention, contrasting with the global attention deficit following complete disconnection of the system. Combined unilateral lesions of the medial prefrontal cortex (mPFC) and the medial caudate-putamen (mCPu) within the same hemisphere produced a severe and long-lasting contralesional neglect syndrome while sparing the acquisition of autoshaping. These results provide further evidence for the involvement of the medial prefrontal-dorsomedial striatal circuit in aspects of attentional function, as well as insight into the nature of neglect deficits following lesions at different levels within corticostriatal circuitry.

Animals↗

PubMed2005

Lesions to the subthalamic nucleus decrease impulsive choice but impair autoshaping in rats: the importance of the basal ganglia in Pavlovian conditioning and impulse control.

Although the subthalamic nucleus (STN) is involved in regulating motor function, and inactivation of this structure relieves the motor symptoms in Parkinsonian patients, recent data indicate that corticosubthalamic connections are involved in both the regulation of attention and the ability to withhold from responding. Considerable evidence suggests that the neural circuitry underlying such behavioural disinhibition or impulsive action can be at least partially dissociated from that implicated in impulsive decision-making and it has been suggested that the tendency to choose impulsively is related to the ability to form and use Pavlovian associations. To explore these hypotheses further, STN-lesioned rats were tested on the delay-discounting model of impulsive choice, where impulsivity is defined as the selection of a small immediate over a larger delayed reward, as well as in a rodent autoshaping paradigm. In contrast to previous reports of increased impulsive action, STN lesions decreased impulsive choice but dramatically impaired the acquisition of the autoshaping response. When the STN was lesioned after the establishment of autoshaping behaviour, lesioned subjects were more sensitive to the omission of reward, indicative of a reduction in the use of Pavlovian associations to control autoshaping performance. These results emphasize the importance of the STN in permitting conditioned stimulus-unconditioned stimulus associations to regulate goal-seeking, a function which may relate to the alterations in impulsive choice observed in the delay-discounting task. These data bear a striking similarity to those observed after lesions of the orbitofrontal cortex and are suggestive of an important role for corticosubthalamic connections in complex cognitive behaviour.

Animals↗

PubMed2004

Dopaminergic basis for deficits in working memory but not attentional set-shifting in Parkinson's disease.

Although Parkinson's disease is a common neurodegenerative disorder characterised by its motoric symptoms, there is an increasing recognition of accompanying impairments in cognition that have a profound impact on the quality of life of these patients. These deficits predominantly affect executive function and impairments of working memory have been frequently reported. However, the underlying neurochemical and pathological basis for these deficits are not well understood. In this study, 20 patients were tested 'on' and 'off' levodopa (L-dopa) medication on a task that allowed different aspects of working memory function such as maintenance, retrieval and manipulation to be tested within the same general paradigm as well as on an unrelated test of attentional set-shifting, which is known to be sensitive to deficits in early Parkinson's disease. Compared to healthy volunteers, PD patients were impaired at manipulation more than maintenance or retrieval of information within working memory. The patients were also impaired at the attentional set-shifting task. However, whereas L-dopa ameliorated the working memory deficit in manipulation (improving both accuracy and cognitive response time), it had no effect on the attentional set-shifting impairment. These results confirm that working memory deficits in PD are both psychologically specific and related to dopamine depletion. It is anticipated that greater understanding of these mechanisms will lead to future therapeutic improvements.

Aged↗

PubMed2004

Chemistry of the adaptive mind.

A failure to adapt to novel or changing environmental demands is a core feature of a wide variety of neuropsychiatric disorders as well as the normal states of stress and fatigue. We review the neurochemistry of cognitive control, which has been associated primarily with the prefrontal cortex. Many drugs affect the functioning of the prefrontal cortex, but the direction and extent of drug effects vary across individuals and tasks. Apparently paradoxical effects are often observed, where the same medication causes both cognitive enhancement as well as cognitive side effects. We review neurobiological research that is beginning to elucidate the nature of these contrasting effects and the factors underlying the large variability across individuals and behaviours. The work has considerable implications for the understanding of and treatment development for abnormalities such as Parkinson's disease, attention deficit hyperactivity disorder and drug addiction.

Adaptation, Physiological↗

PubMed2004

Prediction error during retrospective revaluation of causal associations in humans: fMRI evidence in favor of an associative model of learning.

Associative learning theory assumes that prediction error is a driving force in learning. A competing view, probabilistic contrast (PC) theory, is that learning and prediction error are unrelated. We tested a learning phenomenon that has proved troublesome for associative theory--retrospective revaluation--to evaluate these two models. We previously showed that activation in right lateral prefrontal cortex (PFC) provides a reliable signature for the presence of prediction error. Thus, if the associative view is correct, retrospective revaluation should be accompanied by right lateral PFC activation. PC theory would be supported by the absence of this activation. Right PFC and ventral striatal activation occurred during retrospective revaluation, supporting the associative account. Activations appeared to reflect the degree of revaluation, predicting later brain responses to revalued cues. Our results support a modified associative account of retrospective revaluation and demonstrate the potential of functional neuroimaging as a tool for evaluating competing learning models.

Adult↗

PubMed2004

The relationship between antisaccades, smooth pursuit, and executive dysfunction in first-episode schizophrenia.

BACKGROUND: Both oculomotor and neuropsychologic deficits have been used to support the hypothesis that schizophrenia is associated with prefrontal cortex dysfunction, but studies that have specifically investigated the relationships between these deficits have produced inconsistent findings. METHODS: We measured both smooth pursuit and antisaccade performance in a large group (n = 109) of patients with first-episode schizophrenia and a group of matched control subjects (n = 59) and investigated the relationship between performance on these tasks and performance on a range of executive tasks. We additionally explored the relationship between these variables and measures of psychopathology at presentation and duration of untreated psychosis. RESULTS: Antisaccade errors were significantly correlated with spatial working memory performance. Smooth pursuit gain did not correlate with any neuropsychologic measure. There were no reliable correlations between either oculomotor variables and measures of psychopathology and duration of untreated psychosis. CONCLUSIONS: These findings suggest that in schizophrenia working memory and antisaccade performance reflect the same abnormal prefrontal substrates and that smooth pursuit is mediated by a separate neural abnormality.

Adult↗

PubMed2004

5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion.

RATIONALE: Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT(2A) receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT(2A) and 5-HT(2C) receptors have opposing effects on behaviour, and that the 5-HT(2C) receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion. OBJECTIVES: To assess the effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents. METHODS: The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats. RESULTS. ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls. CONCLUSIONS: These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT(2) receptor family is functionally heterogeneous. Although both 5-HT(2A) and 5-HT(2C) receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.

5,7-Dihydroxytryptamine↗

PubMed2004

Contrasting roles of basolateral amygdala and orbitofrontal cortex in impulsive choice.

The orbitofrontal cortex (OFC) and basolateral nucleus of the amygdala (BLA) share many reciprocal connections, and a functional interaction between these regions is important in controlling goal-directed behavior. However, their relative roles have proved hard to dissociate. Although injury to these brain regions can cause similar effects, it has been suggested that the resulting impairments arise through damage to different, yet converging, cognitive processes. Patients with OFC or amygdala lesions exhibit maladaptive decision making and aberrant social behavior often described as impulsive. Impulsive choice may be measured in both humans and rodents by evaluating intolerance to delay of reinforcement. Rats with excitotoxic lesions of the BLA and OFC were tested on such a delay-discounting procedure. Although lesions of the BLA increased choice of the small immediate reward, indicating greater impulsivity, OFC lesions had the opposite effect, increasing preference for the larger but delayed reward. The fact that the delay did not devalue the large reward to such an extent in OFC-lesioned animals supports the suggestion that the OFC is involved in updating the incentive value of outcomes in response to devaluation. In contrast, the BLA-lesioned animals markedly decreased their preference for the large reward when it was delayed, potentially because of an inability to maintain a representation of the reward in its absence. This is the first time that lesions to these two structures have produced opposite behavioral effects, indicating their distinct contributions to cognition.

Amygdala↗

PubMed2004

Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder.

BACKGROUND: Modafinil, a novel cognitive enhancer, has a clinical profile similar to conventional stimulants such as methylphenidate, despite a seemingly different mechanism of action. Modafinil selectively improves neuropsychological task performance in healthy volunteers, possibly through improved inhibitory control. We examined whether modafinil induced similar improvements in adults with attention-deficit/hyperactivity disorder. METHODS: Twenty patients with a DSM-IV diagnosis of attention-deficit/hyperactivity disorder were entered into a double-blind, randomized, placebo-controlled crossover study using a single 200 mg dose of modafinil. RESULTS: Modafinil produced a similar pattern of cognitive enhancement to that observed in healthy adults, with improvements on tests of short-term memory span, visual memory, spatial planning, and stop-signal motor inhibition. On several measures, increased accuracy was accompanied by slowed response latency. This alteration in the speed-accuracy trade-off may indicate that modafinil increases the ability to "reflect" on problems coupled with decreased impulsive responding. Improvements were also seen in sustained attention, which was unaffected in healthy subjects. CONCLUSIONS: If these benefits are shown to be maintained with chronic administration, modafinil may have potential as an important therapy for attention-deficit/hyperactivity disorder with a similar effect to stimulants such as methylphenidate in improving stop-signal response inhibition but without the side effects commonly experienced with amphetamine-like drugs.

Adult↗

PubMed2004

Pseudo-neglect in Huntington's disease correlates with decreased angular gyrus density.

Visuospatial attentional bias was examined in Huntington's disease (HD) patients with mild disease, asymptomatic gene-positive patients and controls. No group differences were found on the grey scales task (which is a non-motor task of visuospatial attentional bias), although patients' trinucleotide (CAG) repeat length correlated with increasing leftward bias. On the line bisection task, symptomatic patients made significantly larger leftward bisection errors relative to controls, who showed the normal slight degree of leftward error (pseudo-neglect). The asymptomatic group showed a trend for greater leftward error than controls. A subset of participants went on to have structural MRI, which showed a correlation between increased leftward error on the line bisection task and reduced density in the angular gyrus area (BA39) bilaterally. This finding is consistent with recent literature suggesting a critical role for the angular gyrus in the lateralization of visuospatial attention.

Adult↗

PubMed2004

Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers.

RATIONALE: Dopamine (DA) D(2) receptor antagonists have been shown to produce similar impairments to those seen in Parkinson's disease. These include working memory and set-shifting deficits. Theories of DA function have predicted that distraction or impaired switching may be important determinants of such deficits. OBJECTIVES: In order to test these hypotheses, we have followed up our previous findings with more refined tests (1) that allow measurement of spatial working memory (SWM) and distraction, (2) that allow separation of executive and mnemonic components of SWM and (3) that allow isolation of set-shifting from learning deficits. METHODS: Thirty-six young healthy male volunteers were tested on two occasions after oral administration of either 400 mg sulpiride or placebo. All participants performed the delayed response task. Sixteen participants received task-irrelevant distractors during this task, and were also given a self-ordered SWM test. The remaining participants were given delayed response tasks with task-relevant distractors, and tests of attentional and task set-shifting. RESULTS: Sulpiride impaired performance of the delayed-response task both without distraction and with task-relevant distraction. By contrast, the drug protected against deficits from task-irrelevant distraction seen in the placebo group. Task set-switching was also impaired by sulpiride, with participants being slower to respond on switch trials compared with non-switch trials. There was also a trend for attentional set-shifting to be impaired following sulpiride. In contrast, self-ordered SWM performance was enhanced by sulpiride on the second test session only. CONCLUSIONS: These results support models of central DA function that postulate a role in switching behaviour, and in certain aspects of working memory.

Adult↗

PubMed2004

A componential analysis of task-switching deficits associated with lesions of left and right frontal cortex.

Executive functions such as task-set switching are thought to depend on the frontal cortex. However, more precision is required in identifying which components of such high-level processes relate to which, if any, subregions of the brain. In a recent study of 19 patients with focal right frontal (RF) lesions and 17 with left frontal (LF) lesions, we found that response inhibition, as measured by the stop-signal task, was specifically disrupted by damage to the right inferior frontal gyrus (IFG). The present study examined task-switching performance in this same group of patients and in matched controls on the grounds that inhibitory mechanisms may also be required to switch task-set. Both RF and LF patients showed significantly larger switch costs (the difference, in reaction time and errors, between changing tasks and repeating the same task) than controls, but apparently for different reasons. For RF patients, a part of the switch deficit could be accounted for by impaired inhibition of inappropriate responses or task-sets triggered by stimuli, and one measure of the switch cost correlated reliably with damage to the IFG, specifically the pars opercularis (POp). For LF patients, a part of the switch deficit may have arisen from weak top-down control of task-set. The degree of top-down control correlated reliably with the extent of damage to the left middle frontal gyrus (MFG). This study localizes two components of the complex task-switching process (inhibition of task-sets and/or responses and top-down control of task-set) to the right IFG/POp and the left MFG respectively.

Case-Control Studies↗