Biomedical subjects

Trevor W Robbins

Publications and source records attributed to Trevor W Robbins.

At least 73 records · Page 4Linked to original sources

PubMed2004

Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-saporin-induced lesions of the medial prefrontal cortex.

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.

Acetylcholine↗

PubMed2004

The role of the lateral frontal cortex in causal associative learning: exploring preventative and super-learning.

Prediction error--a mismatch between expected and actual outcome--is critical to associative accounts of inferential learning. However, it has proven difficult to explore the effects of prediction error using functional magnetic resonance imaging (fMRI) while excluding the confounding effects of stimulus novelty and incorrect responses. In this event-related fMRI study we used a three-stage experiment generating preventative- and super-learning conditions. In both cases, it was possible to generate prediction error within a causal associative learning experiment while subtracting the effects of novelty and error. We show that right lateral prefrontal cortex (PFC) activation is sensitive to the magnitude of prediction error. Furthermore, super-learning activation in this region of PFC correlates, across subjects, with the amount learned. We thus provide direct evidence for a brain correlate of the surprise-dependent mechanisms proposed by associative accounts of causal learning. We show that activity in right lateral PFC is sensitive to the magnitude, though not the direction, of the prediction error. Furthermore, its activity is not directly explicable in terms of novelty or response errors and appears directly related to the learning that arises out of prediction error.

Adult↗

PubMed2004

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

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.

Animals↗

PubMed2004

Differential responses in human striatum and prefrontal cortex to changes in object and rule relevance.

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.

Adolescent↗

PubMed2004

Prefrontal cortical-ventral striatal interactions involved in affective modulation of attentional performance: implications for corticostriatal circuit function.

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.

Affect↗

PubMed2004

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

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) val(158)met 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 val(158)met 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.

Adult↗

PubMed2004

Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates.

The prefrontal cortex has been implicated in a variety of cognitive and executive processes, including working memory, decision-making, inhibitory response control, attentional set-shifting and the temporal integration of voluntary behaviour. This article reviews current progress in our understanding of the rodent prefrontal cortex, especially evidence for functional divergence of the anatomically distinct sub-regions of the rat prefrontal cortex. Recent findings suggest clear distinctions between the dorsal (precentral and anterior cingulate) and ventral (prelimbic, infralimbic and medial orbital) sub-divisions of the medial prefrontal cortex, and between the orbitofrontal cortex (ventral orbital, ventrolateral orbital, dorsal and ventral agranular cortices) and the adjacent medial wall of the prefrontal cortex. The dorso-medial prefrontal cortex is implicated in memory for motor responses, including response selection, and the temporal processing of information. Ventral regions of the medial prefrontal cortex are implicated in interrelated 'supervisory' attentional functions, including attention to stimulus features and task contingencies (or action-outcome rules), attentional set-shifting, and behavioural flexibility. The orbitofrontal cortex is implicated in lower-order discriminations, including reversal of stimulus-reward associations (reversal learning), and choice involving delayed reinforcement. It is anticipated that a greater understanding of the prefrontal cortex will come from using tasks that load specific cognitive and executive processes, in parallel with discovering new ways of manipulating the different sub-regions and neuromodulatory systems of the prefrontal cortex.

Acetylcholine↗

PubMed2004

Inhibition and the right inferior frontal cortex.

It is controversial whether different cognitive functions can be mapped to discrete regions of the prefrontal cortex (PFC). The localisationist tradition has associated one cognitive function - inhibition - by turns with dorsolateral prefrontal cortex (DLPFC), inferior frontal cortex (IFC), or orbital frontal cortex (OFC). Inhibition is postulated to be a mechanism by which PFC exerts its effects on subcortical and posterior-cortical regions to implement executive control. We review evidence concerning inhibition of responses and task-sets. Whereas neuroimaging implicates diverse PFC foci, advances in human lesion-mapping support the functional localization of such inhibition to right IFC alone. Future research should investigate the generality of this proposed inhibitory function to other task domains, and its interaction within a wider network.

Animals↗

PubMed2004

Putting a spin on the dorsal-ventral divide of the striatum.

Since its conception three decades ago, the idea that the striatum consists of a dorsal sensorimotor part and a ventral portion processing limbic information has sparked a quest for functional correlates and anatomical characteristics of the striatal divisions. But this classic dorsal-ventral distinction might not offer the best view of striatal function. Anatomy and neurophysiology show that the two striatal areas have the same basic structure and that sharp boundaries are absent. Behaviorally, a distinction between dorsolateral and ventromedial seems most valid, in accordance with a mediolateral functional zonation imposed on the striatum by its excitatory cortical, thalamic and amygdaloid inputs. Therefore, this review presents a synthesis between the dorsal-ventral distinction and the more mediolateral-oriented functional striatal gradient.

Animals↗

PubMed2004

Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior.

Reducing levels of 5-HT in the central nervous system has been associated with increases in impulsive behavior. However, the impulsivity construct describes a wide range of behaviors, including the inability to withhold a response, intolerance to delay of reward and perseveration of a nonrewarded response. Although these behaviors are generally studied using instrumental paradigms, impulsivity may also be reflected in simple Pavlovian tasks such as autoshaping and conditioned activity. This experiment aimed to characterize further the effects of central 5-HT depletion and to investigate whether different behavioral measures of impulsivity are inter-related, thus validating the construct. Rats received intracerebroventricular (ICV) infusions of vehicle (n=10) or the serotonergic neurotoxin 5,7-dihydroxytryptamine (n=12) which depleted forebrain 5-HT levels by about 90%. Lesioned animals showed significant increases in the speed and number of responses made in autoshaping, increased premature responding on a simple visual attentional task, enhanced expression of locomotor activity conditioned to food presentation, yet no change in impulsive choice was observed, as measured by a delay-discounting paradigm. Significant positive correlations were found between responses made in autoshaping and the level of conditioned activity, indicating a possible common basis for these behaviors, yet no correlations were found between other behavioral measures. These data strengthen and extend the hypothesis that 5-HT depletion increases certain types of impulsive responding. However, not all measures of impulsivity appear to be uniformly affected by 5-HT depletion, or correlate with each other, supporting the suggestion that impulsivity is not a unitary construct.

5,7-Dihydroxytryptamine↗

PubMed2004

Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia.

Modafinil, a novel cognitive enhancer, selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder (ADHD). It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission. The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia. Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind, randomized, placebo-controlled crossover study using a 200 mg dose of modafinil. Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD. Improvement was seen on short-term verbal memory span, with trends towards improved visual memory and spatial planning. This was accompanied by slowed response latency on the spatial planning task. No effect on stop-signal performance was seen. Importantly, significant improvement in attentional set shifting was seen, despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.

Adult↗

PubMed2004

Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex.

Converging evidence suggests that dopaminergic projections to the prefrontal cortex (PFC) modulate both attention and working memory processes that may be related to either insufficient or excessive dopamine activity specific to a D1 receptor mechanism. We examined the effects of bilateral intraprefrontal cortical infusions of the D1 agonist (SKF 81297) on a novel task specifically designed to assess the animals' ability to attend to a visual target (0.7 or 0.5 s) and then remember the location of that target over a variable delay (0-16 s) within the same test session. Bilateral prefrontal infusions of the low dose of SKF 81297 (0.01 microg) had no effect on visual attention or memory throughout the entire testing schedule. The medium (0.06 microg) dose preferentially increased attention to the stimulus target but only improved memory for that stimulus at a duration of 0.7 s, although in a delay-independent manner. The high dose (0.3 microg) of the D1 agonist also increased attentional accuracy. However, it was only under the more attention challenging condition (0.5 s) that this high dose also produced a baseline delay-dependent modulation of memory for the stimulus target. Specifically, good memory at the short delay was impaired and poor memory at the long delay was improved. These data provide the first demonstration that dopamine D1 receptor stimulation sufficient to improve attentional accuracy, can also disrupt, and facilitate short-term working memory performance in a delay-dependent manner.

Animals↗

PubMed2004

Selective cholinergic denervation of the cingulate cortex impairs the acquisition and performance of a conditional visual discrimination in rats.

Results from excitotoxic lesion studies have implicated the cingulate cortex and its basal forebrain afferents in the acquisition and performance of conditional discrimination tasks. In the present work, we sought to clarify the role of specifically cholinergic projections from the vertical limb nucleus of the diagonal band (VDB) to the cingulate cortex in conditional visual discrimination (CVD) learning and performance in rats. We injected the cholinergic immunotoxin 192 IgG-saporin into the cingulate cortex to produce selective retrograde lesions of the cholinergic neurons projecting from the VDB to the cingulate cortex with the aim of sparing afferents of non-cingulate regions that can be disrupted by excitotoxic or immunotoxic VDB injections and non-cholinergic VDB projections that can also be damaged by excitotoxic lesions. Rats sustaining selective cholinergic denervation in this manner were significantly impaired relative to sham-operated animals in the acquisition and performance of a CVD rule of the type 'If lights are flashing FAST, press the left lever; if SLOW, press right'. Asymptotic performance of the lesion group was substantially lower than for control rats, indicating an enduring performance deficit. This impairment was associated with a selective disruption on trials with the FAST flashing stimulus. The results confirm the involvement of cholinergic innervation of the cingulate cortex in CVD performance; however, the nature of the deficit suggests a role for cholinergic modulation in task-relevant stimulus processing rather than stimulus-response learning per se.

Animals↗

PubMed2004

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

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.

Aged↗

PubMed2004

Limbic corticostriatal systems and delayed reinforcement.

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.

Adolescent↗

PubMed2004

Random number generation in patients with symptomatic and presymptomatic Huntington's disease.

Random number generation (RNG), which involves producing lists of numbers at random, requires response selection and inhibition, which are aspects of executive function mediated by the frontal lobe. This study examined RNG performance in a group of mild to moderate Huntington's disease (HD) patients, asymptomatic gene-positive HD patients, and controls. The HD symptomatic group was significantly less random in their choices than controls. The gene-positive asymptomatic HD patients also showed a tendency toward abnormal RNG measures compared with controls, although this did not reach statistical significance after correction for multiple comparisons. However, analyzing the HD group as a whole showed that the frequency of errors, preferential selection of favorite numbers, and counting in 1's correlated significantly with the degree of symptom severity. Furthermore, counting in 1's correlated with degree of vulnerability to symptoms. A subset of patients and controls were retested 6 months later, and all RNG measures showed high correlations over time, highlighting the robust reliability of this test. The data therefore suggest that RNG is a useful, brief and reliable test of executive function and may be of value in studies investigating the longitudinal effects of disease-modifying treatment in HD.

Adult↗

PubMed2003

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

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.

Adult↗

PubMed2003

Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Response inhibition is an executive function that requires voluntary control over responses when there is a change of context. The right inferior frontal cortex is necessary for response inhibition, and a deficit in right frontostriatal circuitry might underlie attention-deficit/hyperactivity disorder (ADHD). Many studies of childhood ADHD have demonstrated impaired response inhibition and its amelioration by methylphenidate (MPH). The current study tested response inhibition and the effect of MPH in adult ADHD. METHODS: Response inhibition was assessed with the "tracking" stop-signal test in 13 adults with a diagnosis of ADHD, both while taking and while not taking medication, and 13 healthy, unmedicated, age- and intelligence quotient-matched control subjects. RESULTS: Stop-signal reaction time was significantly slower in unmedicated adults with ADHD relative to healthy control subjects, and this deficit was significantly ameliorated by medication. CONCLUSIONS: Adult ADHD patients had a response inhibition profile similar to that produced by lesions to the right inferior frontal cortex, which was remedied by stimulant medication.

Adolescent↗