Showing papers by "Trevor W. Robbins published in 2004"

The cognitive ability of an incident cohort of Parkinson's patients in the UK. The CamPaIGN study

Abstract: We have used multiple sources to identify a population-representative cohort of newly diagnosed patients with parkinsonism and Parkinson's disease in the UK over a 2-year period. All patients have been invited to participate in a detailed clinical assessment either at home or in an outpatient clinic. These assessments have been used to refine clinical diagnoses of parkinsonism using established criteria, and describe some of the phenotypic variability of Parkinson's disease at the time of diagnosis. The crude incidence of Parkinson's disease was 13.6/10(5yr-1) [confidence interval (CI) 11.8-15.6 and of parkinsonism was 20.9/10(5yr-1) (CI 18.7-23.3). Age-standardized to the 1991 European population, the incidence figures become 10.8/10(5yr-1) (CI 9.4-12.4) for Parkinson's disease and 16.6/10(5yr-1) (CI 14.8-18.6) for parkinsonism. Thirty-six per cent of the Parkinson's disease patients had evidence of cognitive impairment based on their performance in the Mini-Mental State Examination, a pattern recognition task, and the Tower of London task. The pattern of cognitive deficits seen among these patients using these and further cognitive tasks suggests that sub-groups of patients based on cognitive ability might be identifiable even in the early stages of disease, which may reflect regional differences in the underlying neuropathological processes.

Cognitive inflexibility after prefrontal serotonin depletion.

Abstract: Serotonergic dysregulation within the prefrontal cortex (PFC) is implicated in many neuropsychiatric disorders, but the precise role of serotonin within the PFC is poorly understood. Using a serial discrimination reversal paradigm, we showed that upon reversal, selective serotonin depletion of the marmoset PFC produced perseverative responding to the previously rewarded stimulus without any significant effects on either retention of a discrimination learned preoperatively or acquisition of a novel discrimination postoperatively. These results highlight the importance of prefrontal serotonin in behavioral flexibility and are highly relevant to obsessive-compulsive disorder, schizophrenia, and the cognitive sequelae of drug abuse in which perseveration is prominent.

Contrasting Roles of Basolateral Amygdala and Orbitofrontal Cortex in Impulsive Choice

Abstract: 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.

Differential control over cocaine-seeking behavior by nucleus accumbens core and shell.

Abstract: Nucleus accumbens (NAc) dopamine is widely implicated in mediating the reinforcing effects of drugs of abuse. However, the precise function of the NAc itself in drug self-administration has been difficult to establish. Here we show a neural double-dissociation of the behavioral processes that underlie cocaine self-administration in rats. Whereas selective excitotoxic lesions of the NAc core had only a minor effect on the acquisition of responding for cocaine under a standard schedule of continuous reinforcement, these lesions profoundly impaired the acquisition of drug-seeking behavior that was maintained by drug-associated conditioned reinforcers and assessed using a second-order schedule of cocaine reinforcement. In contrast, selective excitotoxic lesions of the NAc shell did not impair drug self-administration or the acquisition of cocaine-seeking, but they did attenuate the psychostimulant effects of cocaine. These results further our understanding of how the NAc controls drug-seeking and drug-taking behavior.

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

Abstract: 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

Detecting dementia: novel neuropsychological markers of preclinical Alzheimer's disease.

Abstract: The results of a previous study have suggested that impaired performance on one neuropsychological test, CANTAB Paired Associates Learning (PAL), may serve as a marker for preclinical Alzheimer’s dise

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

Abstract: 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-HT2A receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT2A and 5-HT2C receptors have opposing effects on behaviour, and that the 5-HT2C receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion. To assess the effects of 5-HT2A and 5-HT2C 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. 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. 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. These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT2 receptor family is functionally heterogeneous. Although both 5-HT2A and 5-HT2C receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.

Risk taking during decision-making in normal volunteers changes with age.

Abstract: Risk taking in a large cohort of adults (N = 177; ages 17-73) decreased with age, demonstrated by performance on a computer based gambling task, which has previously been shown to be sensitive to certain pharmacological manipulations including tryptophan depletion, lesions of the orbitofrontal cortex and neuropsychiatric disorders such as mania. Aging was also associated with longer deliberation times, poorer decision making, reduced risk taking, but no significant change in delay aversion. Subjects with a higher (NART-estimated) IQ were faster to make decisions and showed a greater modulation of risk-taking. Both sexes showed similar patterns of decision making, although male participants exhibited a greater modulation of risk-taking in response to the probability of winning. The Decision-Gamble task provides a variety of behavioral measures, corresponding to different aspects of impulsivity. Factor analysis of these measures suggested that two independent traits underlies performance on the task in normal individuals: one associated with risk tolerance, and a second associated with delay aversion. Age was related to decreases in the risk tolerance factor, but unrelated to the delay aversion; neither factor was significantly related to verbal IQ. This study thus provides support for the concept that impulsivity can be fractionated into 2 or more components.

Striatal contributions to working memory: a functional magnetic resonance imaging study in humans.

Abstract: Although the role of the frontal cortex in executive performance has been widely accepted, issues regarding the contribution of subcortical structures to these functions remain unresolved. In this study, the neural circuitry underlying selective subcomponents of working memory was investigated using event-related functional magnetic resonance imaging (fMRI). Ten healthy volunteers performed a verbal memory task, which allowed different aspects of working memory function such as maintenance, retrieval and manipulation to be tested within the same general paradigm. During performance of this task as a whole, fMRI revealed increases in signal intensity throughout the frontostriatal network. However, when signal intensity during the manipulation of information within working memory was compared to that during periods requiring only simple maintenance and retrieval, significant changes were observed only in the caudate nuclei, bilaterally. These results suggest an essential and specific role for the caudate nucleus in executive function, which may underlie the cognitive disturbances observed in frontostriatal neurodegenerative disorders such as Parkinson's disease.

Limbic corticostriatal systems and delayed reinforcement.

Abstract: Impulsive choice, one aspect of impulsivity, is characterized by an abnormally high preference for small, immediate rewards over larger delayed rewards, and can be a feature of adolescence, but also attention-deficit/hyperactivity disorder (ADHD), addiction, and other neuropsychiatric disorders. Both the serotonin and dopamine neuromodulator systems are implicated in impulsivity; manipulations of these systems affect animal models of impulsive choice, though these effects may depend on the receptor subtype and whether or not the reward is signaled. These systems project to limbic cortical and striatal structures shown to be abnormal in animal models of ADHD. Damage to the nucleus accumbens core (AcbC) causes rats to exhibit impulsive choice. These rats are also hyperactive, but are unimpaired in tests of visuospatial attention; they may therefore represent an animal model of the hyperactive-impulsive subtype of ADHD. Lesions to the anterior cingulate or medial prefrontal cortex, two afferents to the AcbC, do not induce impulsive choice, but lesions of the basolateral amygdala do, while lesions to the orbitofrontal cortex have had opposite effects in different tasks measuring impulsive choice. In theory, impulsive choice may emerge as a result of abnormal processing of the magnitude of rewards, or as a result of a deficit in the effects of delayed reinforcement. Recent evidence suggests that AcbC-lesioned rats perceive reward magnitude normally, but exhibit a selective deficit in learning instrumental responses using delayed reinforcement, suggesting that the AcbC is a reinforcement learning system that mediates the effects of delayed rewards.

Prefrontal Cortical–Ventral Striatal Interactions Involved in Affective Modulation of Attentional Performance: Implications for Corticostriatal Circuit Function

Abstract: Anatomically segregated systems linking the frontal cortex and the striatum are involved in various aspects of cognitive, affective, and motor processing. In this study, we examined the effects of combined unilateral lesions of the medial prefrontal cortex (mPFC) and the core subregion of the nucleus accumbens (AcbC) in opposite hemispheres (disconnection) on a continuous performance, visual attention test [five-choice serial reaction-time task (5CSRTT)]. The disconnection lesion produced a set of specific changes in performance of the 5CSRTT, resembling changes that followed bilateral AcbC lesions while, in addition, comprising a subset of the behavioral changes after bilateral mPFC lesions previously reported using the same task. Specifically, both mPFC/AcbC disconnection and bilateral AcbC lesions markedly affected aspects of response control related to affective feedback, as indexed by perseverative responding in the 5CSRTT. These effects were comparable, although not identical, to those in animals with either bilateral AcbC or mPFC/AcbC disconnection lesions. The mPFC/AcbC disconnection resulted in a behavioral profile largely distinct from that produced by disconnection of a similar circuit described previously, between the mPFC and the dorsomedial striatum, which were shown to form a functional network underlying aspects of visual attention and attention to action. This distinction provides an insight into the functional specialization of corticostriatal circuits in similar behavioral contexts.

Differential Responses in Human Striatum and Prefrontal Cortex to Changes in Object and Rule Relevance

Abstract: Event-related functional magnetic resonance imaging was used to measure blood oxygenation level-dependent responses in 16 young healthy human volunteers during performance of an attentional switching task. The task allowed the separate investigation of lower-order switching between concrete objects and higher-order switching between abstract task rules. Significant signal change in the ventral striatum was demonstrated on trials when subjects switched between objects but not when subjects switched between abstract task rules. In contrast, signal change in the lateral prefrontal cortex (PFC) was observed during all switch trials. The switch-related responses were not contaminated by task difficulty, because the greatest signal change was observed during the relatively easy switch trials, which required both lower-order and higher-order switching at the same time. The present data suggest that mechanisms of inhibitory response control in frontostriatal systems are organized according to distinct levels of abstraction. Specifically, the response selection computation carried by the ventral striatum, which projects to the orbitofrontal cortex and the medial PFC, is restricted to the transformation of concrete stimulus exemplar information into motor responses, whereas the adaptive function of the lateral PFC extends to the transformation of abstract task-rule representations into action.

Chemistry of the adaptive mind

Abstract: 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.

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

Abstract: Rationale Dopamine (DA) D2 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.

Cortical Cholinergic Function and Deficits in Visual Attentional Performance in Rats Following 192 IgG–Saporin-induced Lesions of the Medial Prefrontal Cortex

Abstract: Lesions of the basal forebrain (BF) cortical cholinergic system impair performance on a rodent five-choice visual attentional task. This study examines the effects on the same task of selective depletion of acetylcholine from the prefrontal cortex (PFC) using 192 IgG–saporin, the cholinergic immunotoxin. Rats were trained to detect brief visual stimuli, either presented unpredictably both temporally and spatially to increase attentional load, or under less demanding conditions where stimuli were temporally and spatially predictable. Following training, 192 IgG–saporin (50 ng or 100 ng/ infusion) or its vehicle was infused bilaterally into the ventromedial PFC. The 100 ng lesion group exhibited post-operatively a transient increase in perseveration, specifically when the visual stimuli were temporally unpredictable. A vigilance decrement, as well as a reinstatement of perseverative responding occurred in both lesion groups under conditions of enhanced attentional load, specifically with high target frequency sustained over many trials. Lesioned subjects were also more impulsive with increased anticipatory errors. Systemic administration of the muscarinic receptor antagonist scopolamine further dissociated the groups with attentional accuracy in the 100 ng group decreasing relative to shams. These findings are consistent with an important modulatory influence of PFC function by BF cholinergic neurons, particularly during increased attentional demand.

Characteristic neurocognitive profile associated with adult attention-deficit/hyperactivity disorder.

Abstract: Background. It is now accepted that attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood. However, relative to the considerable literature concerning the profile of neurocognitive deficits associated with this disorder in childhood, equivalent investigations in adult populations have been less common. The current study examined cognitive function in adults diagnosed with ADHD employing well-validated neuropsychological tasks.Method. Nineteen adult patients who satisfied DSM-IV criteria for ADHD and 19 matched (gender, age and verbal IQ), non-clinical control subjects were recruited. Patients were either unmedicated or had abstained from a psychostimulant medication regime for at least 24 h prior to neurocognitive assessment. A functionally wide-ranging test battery was administered.Results. Relative to controls, ADHD adults performed significantly worse on spatial working memory, planning, and attentional-set shifting tests and were significantly slower to respond to target stimuli on the go/no-go task. In contrast, the two subject groups performed equivalently on decision-making and pattern/spatial recognition memory assessments.Conclusions. The demonstration of neuropsychological dysfunction in the adult ADHD cohort provides some support for the validity of this diagnosis in adulthood. In particular, there is broad consistency between the cognitive profile revealed in the current investigation and that previously demonstrated in a study of medication-naive ADHD children. There is evidence that frontostriatal function is especially disrupted.

Cholinergic modulation of visual attention and working memory: dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine.

Abstract: Two experiments examined the effects of reductions in cortical cholinergic function on performance of a novel task that allowed for the simultaneous assessment of attention to a visual stimulus and memory for that stimulus over a variable delay within the same test session. In the first experiment, infusions of the muscarinic receptor antagonist scopolamine into the medial prefrontal cortex (mPFC) produced many omissions but did not impair rats' ability to correctly detect a brief visual stimulus. However, these animals were highly impaired in remembering the location of that stimulus following a delay period, although in a delay-independent manner. In the second experiment, another group of animals with selective 192 IgG-saporin lesions of the nucleus basalis magnocellularis (nBM) were not impaired under conditions of low-attentional demand. However, when the stimulus duration was reduced, a significant memory impairment was observed, but similar to the results of the first experiment, the nBM-lesioned animals were not impaired in attentional accuracy, although aspects of attention were compromised (e.g., omissions). These findings demonstrate that (1) cortical cholinergic depletion produces dissociable deficits in attention and memory, depending on the task demands, (2) delay-independent mnemonic deficits produced by scopolamine are probably due to impairments other than simple inattention, and (3) working memory deficits are not simply dependent on attentional difficulties per se. Together, these findings implicate the nBM cortical cholinergic system in both attentional and mnemonic processing.

Psychopharmacological approaches to modulating attention in the five-choice serial reaction time task: implications for schizophrenia

Abstract: In schizophrenia, attentional disturbance is a core feature which may not only accompany the disorder, but may precede the onset of psychiatric symptoms. The five-choice serial reaction time task (5CSRTT) is a test of visuo-spatial attention that has been used extensively in rats for measuring the effects of systemic and central neurochemical manipulations on various aspects of attentional performance, including selective attention, vigilance and executive control. These findings are relevant to our understanding of the neural systems that may be compromised in patients with schizophrenia. The 5CSRTT is conducted in an operant chamber that has multiple response locations, in which brief visual stimuli can be presented randomly. Performance is maintained using food reinforcers to criterion levels of accuracy. Various aspects of performance are measured, including attentional accuracy and premature responding, especially under different attentional challenges. The effects of systemic and intra-cerebral infusions of selective dopamine, serotonin and cholinergic receptor agents on the 5CSRTT are reviewed with a view to identifying attention-enhancing effects that may be relevant to the treatment of cognitive deficits in schizophrenia. In addition, some novel agents such as modafinil and histamine receptor agents are also considered. Examining the effects of selective neurochemical lesions helped define the neural locus of attentional effects. Similarly, findings from microdialysis studies helped identify the extracellular changes in neurotransmitters and their metabolites in freely moving rats during performance of the 5CSRTT. The monoaminergic and cholinergic systems have independent but complementary roles in attentional function, as measured by the 5CSRTT. These functions are predominantly under the control of the prefrontal cortex and striatum. These conclusions are considered in the context of their application towards therapeutic approaches for attentional disturbances that are typically observed in schizophrenic patients.

Planning ability in Parkinson's disease is influenced by the COMT val158met polymorphism.

Abstract: Parkinson's disease (PD) patients show a range of executive deficits involving dopaminergic transmission in the prefrontal cortex. In this study, we have investigated the impact of catechol-O-methyl-transferase (COMT) val158met polymorphisms on performance of the Tower of London (TOL) test of planning by PD patients. Motor and cognitive assessments were performed on 288 patients as part of a population-based study of PD. These patients were subsequently genotyped for the COMT val158met polymorphism. Patients with high activity COMT genotypes performed significantly better at the TOL task than those with low activity genotypes. Subgroup analyses suggest that this effect is greatest in patients exposed to dopaminergic agents. We hypothesise that the inferior performance in patients with the low activity COMT genotype is attributable to a state of relative hyperdopaminergic activity in the dorsolateral prefrontal cortex compared with that in the striatum. We suggest that polymorphisms of common genes, which regulate central nervous system dopaminergic transmission, can influence some of the phenotypic manifestations of PD. © 2004 Movement Disorder Society

The effects of tyrosine depletion in normal healthy volunteers: implications for unipolar depression

Abstract: In recent years, there has been a growing interest in the role of dopamine (DA) both in the pathogenesis of unipolar depression and in motivated behaviour. The innovative technique of acute tyrosine depletion presents an opportunity to characterise further its function in these domains. The present study examined the physiological, subjective and cognitive effects of acute tyrosine depletion in healthy volunteers. A double-blind, placebo-controlled, parallel group design was employed. Half of the participants ingested a balanced amino-acid mixture (BAL) and the other half received an identical mixture except that tyrosine and phenylalanine were absent (TYR-free). Plasma amino acid concentrations and subjective ratings were monitored at both baseline (T0) and 5 h following consumption (T5) of the mixtures. A comprehensive neuropsychological test battery was also administered at T5. Relative to the BAL group, the reduction in TYR availability to the brain was more marked in the TYR-free group. Employment of psychological rating scales revealed that, compared with the BAL group, the TYR-free group became less content and more apathetic. For the affective go/no-go task, whilst the BAL group exhibited a happy latency bias, the TYR-free group demonstrated a sad latency bias. Furthermore, in the decision-making task, the rate at which the TYR-free group increased their bets in response to more likely outcomes was lower than that of the BAL group. Taken together, these neuropsychological findings strikingly paralleled those reported in previous investigations of unipolar depression. The experimental groups could not be differentiated on any of the other neuropsychological measures, including more classical assessments of fronto-executive function. These findings are consistent with the hypothesis that dopaminergic factors are particularly involved in disrupted affect/reward-based processing characteristic of clinical depression.