Showing papers by "Trevor W. Robbins published in 2001"

Enhanced or Impaired Cognitive Function in Parkinson's Disease as a Function of Dopaminergic Medication and Task Demands

Abstract: We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson’s disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex– ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry.

Impulsive choice induced in rats by lesions of the nucleus accumbens core

Abstract: Impulsive choice is exemplified by choosing a small or poor reward that is available immediately, in preference to a larger but delayed reward. Impulsive choice contributes to drug addiction, attention-deficit/hyperactivity disorder, mania, and personality disorders, but its neuroanatomical basis is unclear. Here, we show that selective lesions of the nucleus accumbens core induce persistent impulsive choice in rats. In contrast, damage to two of its afferents, the anterior cingulate cortex and medial prefrontal cortex, had no effect on this capacity. Thus, dysfunction of the nucleus accumbens core may be a key element in the neuropathology of impulsivity.

Impulsive choice induced in rats by lesions of the nucleus accumbens core, but not of anterior cingulate or medial prefrontal cortex

Abstract: Impulsive choice is exemplified by the choice of reward that is small, poor, or ultimately disastrous, but is available immediately, in preference to a larger reward obtainable only after a delay Impulsive choice contributes to neuropsychiatric disorders such as drug addiction as well as attention-deficit/hyperactivity disorder (ADHD), mania, and personality disorders Impulsive choice hypothetically results from dysfunction of limbic corticostriatal circuitry implicated in reinforcement processes, via convergence on the nucleus accumbens In this first study of the neuro- anatomical basis of impulsive choice, we show that lesions of the nucleus accumbens core (AcbC) induce impulsivity by dramatically and persistently impairing rats' ability to choose a delayed reinforcer In contrast, lesions of the ante- rior cingulate cortex (ACC) or medial prefrontal cortex (mPFC) had no effect on this capacity, although mPFC lesions appeared to affect general behavioural timing mechanisms Thus, dysfunction of the AcbC may be a key element in the neuropathology of impulsivity

Mechanisms of cognitive set flexibility in Parkinson's disease.

Abstract: Previous research on cognitive set shifting in patients with Parkinson's disease has often been confounded by concept formation, rule learning, working memory and/or general slowing of cognitive processes. To circumvent this problem, the present study used the task-set switching procedure in which good performance was independent of rule learning, and in which working memory load was reduced by explicitly cueing the task switches. Our results provide strong evidence for a specific cognitive set shifting deficit in patients with mild Parkinson's disease in a non-learning context, which also cannot be explained by general slowing of cognitive processes. Moreover, the deficit was robust in a small sample of patients at the earliest stages of the disease. Finally, the impairment in task-set switching was only apparent when competing information was present, i.e. when the load on selection mechanisms was increased.

Early detection and differential diagnosis of Alzheimer's disease and depression with neuropsychological tasks.

Abstract: The development of novel treatments for Alzheimer’s disease (AD), aimed at ameliorating symptoms and modifying disease processes, increases the need for early diagnosis. Neuropsychological deficits su

Decision-making cognition in mania and depression.

Abstract: Background. Despite markedly different clinical presentations, few studies have reported differences in neuropsychological functioning between mania and depression. Recent work has suggested that differences may emerge on cognitive tasks requiring affective processing, such as decision-making. The present study sought to compare decision-making cognition in mania and depression in order to clarify the current profiles of impairment for these disorders and to contribute to our more general understanding of the relationship between mood and cognition.Methods. Medicated manic patients, depressed patients, and normal healthy controls completed a computerized decision-making task. All subjects were asked to win as many points as possible by choosing outcomes based on variably-weighted probabilities and by placing ‘bets’ on each decision.Results. Both patient groups were impaired on this task, as evidenced by slower deliberation times, a failure to accumulate as many points as controls and suboptimal betting strategies. Manic, but not depressed, patients made suboptimal decisions – an impairment that correlated with the severity of their illness.Conclusions. These findings are consistent with a growing consensus that manic and depressed patients are characterized by significant impairments in cognitive and particularly executive, functioning. Furthermore, the distinct patterns of observed impairment in manic and depressed patients suggests that the nature and extent of cognitive impairment differ between these two groups. Viewed in the context of other recent studies, these findings are consistent with a role for the ventromedial prefrontal cortex in mediating mood–cognition relationships.

Differential Effects of 6-OHDA Lesions of the Frontal Cortex and Caudate Nucleus on the Ability to Acquire an Attentional Set

Abstract: Evidence from both human and animal studies indicates that catecholamine (dopamine and noradrenaline) imbalances in the fronto-striatal circuitry are associated with deficits in higher- order cognitive functions. The present study examined how catecholamines within this circuitry modulate attentional function, specifically the ability to develop, maintain, and shift an attentional set. Catecholamine depletions within the frontal cortex of the common marmoset impaired the ability to acquire an attentional set, and increased susceptibility to distraction from task-irrelevant stimuli. Analysis of set-shifting performance with stimulus dimensions of varying salience suggested that frontal catecholamine depletion selectively disrupts "top-down", but not "bottom-up" attentional processing. In contrast, the ability to acquire and shift an attentional set remained intact following dopaminergic depletion from the caudate nucleus. However, the reduced susceptibility to distraction from task-irrelevant stimuli displayed by monkeys with dopaminergic depletions of the caudate nucleus suggests that responding was under more rigid control by the currently rewarded stimulus. The results demonstrate opposite behavioural effects of 6-hydroxydopamine (6-OHDA) lesions in the frontal cortex and caudate nucleus in tasks requiring selective attention. Frontal catecholamine depletion caused an increase in distractibility while caudate dopamine loss induced greater focusing of responding.

Distinct Changes in Cortical Acetylcholine and Noradrenaline Efflux during Contingent and Noncontingent Performance of a Visual Attentional Task

Abstract: Optimization of cognitive processing may depend on specific and distinct functions of the cortical cholinergic and noradrenergic systems. This investigation dissociates functions of cortical acetylcholine (ACh) and noradrenaline (NA) in arousal and visual attention by simultaneously measuring ACh and NA efflux in the rat prefrontal cortex during sustained attentional performance. The five-choice serial reaction time task was used to provide a continuous assessment of visuospatial attention. Previous studies using this task have established a critical role for the cortical cholinergic system in the detection of visual targets. However, selective lesions of the locus coeruleus noradrenergic system impair performance only when additional attentional demands are placed on the subject by distractors or temporally unpredictable targets. To test the hypothesis that the cortical noradrenergic system is particularly sensitive to novel task contingencies, we also assessed NA and ACh efflux in rats that been trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished. Cortical ACh efflux showed a robust and task-related increase during established contingent performance. This response was significantly attenuated in noncontingent subjects, although it still exceeded pretask values. In contrast, NA efflux only increased transiently in contingent subjects after task onset but showed sustained elevations in noncontingent subjects on the first day when contingencies were changed. These data also implicate cortical ACh in aspects of attentional functioning but highlight a specific involvement of the cortical noradrenergic system in detecting shifts in the predictive relationship between instrumental action and reinforcement.

Improved short-term spatial memory but impaired reversal learning following the dopamine D(2) agonist bromocriptine in human volunteers.

Abstract: Rationale: Studies in humans of cognitive effects of dopaminergic drugs have largely focused on tasks of working memory, with a few studies also examining executive function. Objectives: This study was designed to investigate the effects of 1.25 mg of the dopamine D2 agonist bromocriptine on spatial working memory, planning and discrimination reversal learning in young healthy volunteers. Methods: Twenty volunteers were tested in a double-blind, placebo-controlled, cross-over design. The cognitive assessment included tests taken from the Cambridge Neuropsychological Test Automated Battery (CANTAB) designed to test visuo-spatial recognition memory and spatial working memory. In addition, tests of spatial planning and discrimination reversal learning were used to assess the more general effects of bromocriptine. Tests of subjective feelings and motivation were also incorporated into the battery. Results: Bromocriptine enhanced the spatial memory span of subjects, whilst impairing their ability to reverse a learned probabilistic discrimination. Tests of recognition memory and planning were unaffected by the drug. The findings were not explained by changes in subjective mood or motivational measures. Conclusions: The pattern of findings observed here mirror medication-dependent observations seen in Parkinson's disease. The results are discussed with reference to the different anatomical networks known to subserve performance of the differentially affected tasks.

Decision-making in mania: a PET study.

Abstract: Poor decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania.

Periodic maternal separation of neonatal rats produces region- and gender-specific effects on biogenic amine content in postmortem adult brain.

Abstract: Early environment exerts profound effects on mammalian behavioral and neural development. The aim of this study was to describe changes in adult neurochemistry in the rat following repeated neonatal maternal separation (RMS) during the preweaning period, a procedure known to induce enduring behavioral effects. Following RMS, rats show an attenuated locomotor response to novelty, to D-amphetamine, and attenuated behavioral responses for conditioned incentives as adults. These behavioral effects are broadly opposite in direction to those found following postweaning isolation rearing. Isolation rearing-induced behavioral changes are associated with profound changes in central monoamine function. Following RMS, adult rats had increased tissue levels of dopamine in both dorsal and ventral striatum. The turnover of dopamine, as determined by the ratio of DOPAC to dopamine, was decreased in the mPFC of RMS subjects. Serotonin levels were reduced in dorsal hippocampus of RMS rats of both sexes and in the mPFC of male RMS rats. Noradrenaline levels were increased in the dorsal hippocampus in female, but not in male, RMS rats. These data provide evidence that, in addition to the adult behavioral consequences, RMS leads to profound, region-, and gender-specific changes in brain monoamine content. The developmental specificity of these results is discussed with respect to their possible role in altered behavioral development and psychopathology.

The role of withdrawal in heroin addiction: enhances reward or promotes avoidance?

Abstract: The compulsive nature of heroin abuse has been attributed to the fact that drug self-administration enables an addict to escape from and avoid the severe withdrawal symptoms resulting from opiate dependence. However, studies of incentive learning under natural motivational states suggest an alternative hypothesis, that withdrawal from heroin functions as a motivational state that enhances the incentive value of the drug, thereby enabling it to function as a much more effective reward for self-administration. In support of this hypothesis, we show here that previous experience with heroin in withdrawal is necessary for subsequent heroin-seeking behavior to be enhanced when dependent rats once again experience withdrawal.

Lesions of the medial and lateral striatum in the rat produce differential deficits in attentional performance.

Abstract: Excitotoxic lesions of the medial frontal cortex and anterior cingulate cortex in rats have been shown to produce dissociable impairments on a reaction time visual attention (5-choice) task. Because these cortical areas project to the medial striatal region, the authors predicted similar deficits after lesions of this striatal area compared with the lateral area. Compared with sham-operated controls, rats with quinolinic acid-induced medial striatal lesions showed all the behavioral changes associated with medial frontal cortex and anterior cingulate cortex lesions. In contrast, lateral striatal lesions produced profound disturbances in the performance of the task. Control tests showed little evidence of gross deficits in either group of rats in terms of motivation, locomotor function, or Pavlovian appetitive conditioning. These data suggest that the medial and lateral striatum have contrasting roles in the control of instrumental responding related to the primary sources of their cortical innervation.

Effects of STN lesions on simple vs choice reaction time tasks in the rat: preserved motor readiness, but impaired response selection

Abstract: The subthalamic nucleus (STN) is a key structure within the basal ganglia, inactivation of which is a current strategy for treating parkinsonism. We have previously shown that bilateral lesions of the STN or pharmacological inactivation of this structure in the rat induce multiple deficits in serial reaction time tasks. The aim of the present study was to investigate further a possible role for the STN in response preparatory processes by using simple (SRT) and choice (CRT) reaction time tasks. In contrast to the CRT procedure, the information related to the location of where the response had to be made was given in advance in the SRT procedure. Accurate performance on these tasks requires not only the selection of the correct response (i.e. which response), but also preparation in order to perform when required. A comparison between the two tasks allows assessment of whether STN lesions affect which response ("which") or when to perform it ("when"). As previously observed in these procedures, the responses were faster as a function of the variable foreperiod preceding the trigger stimulus. This well-known effect, termed "motor readiness, was maintained after STN lesions, suggesting that STN lesions did not affect the "when" phase of action preparation. However, while performance on the SRT was faster than on the CRT task preoperatively, STN lesions slowed RTs and abolished the beneficial effect of advance information, suggesting a deficit in the selection ("which") phase of response preparation. This deficit in the selection phase was further supported by deficits in accuracy of responding after STN lesions, as well as increases in mislocated premature responding in the SRT condition. Together, these results suggest that the STN plays an important role in response preparatory processes, including response selection and inhibitory control processes.

Dissociable contributions of the orbitofrontal and lateral prefrontal cortex of the marmoset to performance on a detour reaching task.

Abstract: To gain insight into the nature and neural specificity of the relationship between simple problem solving, inhibitory control and prefrontal cortex, comparison of the effects of excitotoxic lesions of the orbitofrontal and lateral prefrontal cortex were examined on the performance of common marmosets on a detour reaching task. Monkeys were required to inhibit reaching directly for food reward in a transparent box and instead make a detour reach around to the side of the box either having had (i) no prior experience on the task (experiment 1) or (ii) previous experience in reaching around the sides of an opaque box (experiment 2). Whilst monkeys with orbitofrontal lesions had difficulty in inhibiting direct reaches to visible food reward (experiment 1), they could resist this prepotent response tendency following extensive prior experience of detour reaching with an opaque box (experiment 2). In marked contrast, monkeys with lateral prefrontal lesions exhibited no difficulty in inhibiting reaching to visible food reward or acquiring detour reaching per se (experiment 1). However, having been given the opportunity to acquire an efficient detour reaching strategy to hidden food reward these lateral prefrontal lesioned monkeys were impaired at transferring this strategy to the new context in which the food reward was made visible (experiment 2). This double dissociation between the effects of orbitofrontal and lateral prefrontal lesions on detour reaching provides evidence for a clear distinction in the level of control over responding exerted by the orbitofrontal and lateral prefrontal cortex, consistent with hierarchical ordering of response control processes within prefrontal cortex.

Functional disconnection of a prefrontal cortical-dorsal striatal system disrupts choice reaction time performance: implications for attentional function.

Abstract: This series of experiments investigated the role of a prefrontal cortical-dorsal striatal circuit in attention, using a continuous performance task of sustained and spatially divided visual attention. A unilateral excitotoxic lesion of the medial prefrontal cortex and a contralateral lesion of the medial caudate-putamen were used to "disconnect" the circuit. Control groups of rats with unilateral lesions of either structure were tested in the same task. Behavioral controls included testing the effects of the disconnection lesion on Pavlovian discriminated approach behavior. The disconnection lesion produced a significant reduction in the accuracy of performance in the attentional task but did not impair Pavlovian approach behavior or affect locomotor or motivational variables, providing evidence for the involvement of this medial prefrontal corticostriatal system in aspects of visual attentional function.

Spatial Working Memory Deficits in Schizophrenia: Relationship With Tardive Dyskinesia and Negative Symptoms

Abstract: OBJECTIVE: This study examined the interrelationship between negative symptoms, orofacial tardive dyskinesia, and specific neurocognitive processes, particularly those involved in memory and executive function, in patients with schizophrenia. METHOD: A set of computerized neurocognitive tasks, the Cambridge Neuropsychological Test Automated Battery, was used to assess executive and memory function in 54 hospitalized patients with chronic schizophrenia. Analysis of covariance was used to examine differences between groups with or without the topographical syndromes of orofacial tardive dyskinesia and between groups with high or low negative symptom scores. Principal-components and path analyses were used to examine further the influence of negative symptoms and orofacial tardive dyskinesia on performance on tests of memory and executive function. RESULTS: Both orofacial tardive dyskinesia and negative symptoms were significantly and independently associated with deficits on measures of spatial working memo...

Acute dietary tryptophan depletion impairs maintenance of "affective set" and delayed visual recognition in healthy volunteers.

Abstract: Rationale: Altered serotonergic transmission in affective disorders and Alzheimer's disease has prompted research aimed at defining the precise cognitive effects of depleting central serotonin in humans, using acute dietary tryptophan depletion. Objective: We examined the effects of tryptophan depletion on mood and cognition in healthy volunteers. Cognitive tests of memory and attentional processing were employed to test hypotheses of central 5-hydroxytryptamine (5-HT) function related to cortical processing. Methods: A double-blind, parallel design, placebo control study was employed with 15 subjects in each group. Mood rating scales were performed at the start and 5 h after ingestion of the drink. Cognitive tests were also performed at 5 h, after completion of the subjective rating scales. Results: A robust reduction in total tryptophan was achieved in the test group. Subjects receiving the placebo drink showed the expected effect of shift on the affective shifting task, that is, more errors in the more difficult shift versus the non-shift condition. The tryptophan-depleted group made a similar number of errors in the shift trials but failed to reduce the number of errors in the non-shift trials. The tryptophan-depleted group showed a significant impairment on the delayed pattern recognition task. No significant effects on the subjective mood measures were found. Conclusions: Tryptophan depletion abolished the normal tendency to improve error scores on non-shift trials in response to affective cues on a go/no-go task. We suggest that this inability to "maintain set" in the non-shift condition may be due to a disruption of semantic retrieval processes concerned with affect. The novel finding of impairment on a delayed visual pattern recognition task confirms and extends previous studies where selective effects on memory and learning have been found following acute tryptophan depletion.

Behavioral effects of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: locomotion, cocaine self-administration, and prepulse inhibition of startle.

Abstract: Compelling evidence suggests a primary role for the mesoaccumbens dopaminergic pathway in the behavioral effects of amphetamine and cocaine, but the roles of other projections to the accumbens, including those arising in the hippocampal formation, are less clear. The authors evaluated the effects of discrete excitotoxic lesions of either the dorsal or ventral subiculum on the locomotor activating, reinforcing, and sensorimotor gating-disruptive effects of psychomotor stimulant drugs. Whereas dorsal subiculum-lesioned rats were hyperactive in tests of exploratory locomotion and startle reactivity, ventral subiculum-lesioned rats exhibited an attenuated locomotor response to amphetamine, moderately impaired acquisition of cocaine self-administration, and reduced levels of prepulse inhibition of startle. These 2 behavioral profiles overlap considerably with those previously observed in rats with lesions of the rostrodorsal and caudomedial accumbens, respectively, and suggest that projections from dorsal subiculum to accumbens core and ventral subiculum to accumbens shell exert distinct influences on behavioral responses that are amplified by psychomotor stimulant drugs.

The effects of nucleus accumbens core and shell lesions on intravenous heroin self-administration and the acquisition of drug-seeking behaviour under a second-order schedule of heroin reinforcement

Abstract: Rationale: Evidence has implicated the nucleus accumbens (NAcc) in drug-seeking and -taking behaviour. However, the importance of the "core" and "shell" subdivisions of the NAcc in heroin-seeking and -taking behaviour remains unclear. Objectives: To investigate the function of the NAcc core and shell in heroin self-administration and heroin-seeking behaviour. Methods: Male rats were trained to self-administer heroin (0.12 mg/kg per infusion) under a continuous reinforcement (CRF) schedule. After responding stabilised, rats were given excitotoxic (or sham) lesions of either the NAcc core or shell and after recovery were assessed for their retention of heroin self-administration under CRF. At this point a second-order schedule of reinforcement was introduced, commencing at FR10 (FR1:S) and terminating at FR10 (FR10:S), in which ten lever presses resulted in presentation of the heroin-associated CS+, and completion of ten such units resulted in drug infusion. Results: Within 7 days, all groups re-acquired responding for heroin under CRF at rates similar to their pre-lesion performance. However, rats with lesions of the NAcc core, but not shell, were severely impaired in the acquisition of heroin-seeking behaviour. Conclusions: These results indicate an important role for the core of the NAcc in the acquisition of heroin-seeking behaviour under the control of drug-associated stimuli.

The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats

Abstract: Rationale: It has been suggested that the nucleus accumbens (NAcc) may be involved in heroin reward, and the core and shell regions respond differently following administration of a number of drugs of abuse. Objective: The possible role of the NAcc core and shell subregions in the acquisition of heroin self-administration behaviour was investigated. Methods: Rats were given selective excitotoxic lesions of either the nucleus accumbens core or shell before the acquisition of responding for IV heroin (0.04 mg/infusion) under a continuous reinforcement schedule in daily 3 h sessions. After sham-lesioned rats reached a stable baseline, a between-sessions heroin dose-response function was established. Results: Rats with lesions of the NAcc shell did not differ significantly from sham controls in either the acquisition of heroin self-administration or in their heroin dose-response function. The NAcc core lesion group showed reduced levels of responding during the acquisition of heroin self-administration and a reduction in responding during the heroin dose-response function, although this behaviour was sensitive to changes in the dose of heroin. Conclusions: The NAcc shell does not appear to be critical for heroin self-administration, whereas the NAcc core, although apparently not essential in mediating the rewarding effect of IV heroin, may mediate processes that are of special importance during the acquisition of instrumental behaviour.

Rule-abstraction deficits following a basal ganglia lesion.

Abstract: The cognitive profile of a patient, PM, who had damage to the right basal ganglia as the result of a stroke was investigated. Whilst most cognitive functions were intact, she showed specific neuropsychological deficits, most notably a difficulty in developing, through ion of the relevant information, a higher-level rule by which to guide behaviour. The types of rule affected were those based upon an attentional set (attending to a particular dimension of stimulus features, such as ‘shape’) or a response strategy (continuing to apply a previously successful pattern of responses). The learning of lower-level rules based on stimulus-reward values was spared, as was the ability to apply an instructed rule and to discontinue use of rules which were no longer appropriate. These data provide evidence for the dissociability of cognitive functions within the basal ganglia.