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Trevor W Robbins

Publications and source records attributed to Trevor W Robbins.

At least 19 recordsLinked to original sources
PubMed2003

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

RATIONALE: 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. OBJECTIVE: The present study examined the physiological, subjective and cognitive effects of acute tyrosine depletion in healthy volunteers. METHODS: 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 (T(0)) and 5 h following consumption (T(5)) of the mixtures. A comprehensive neuropsychological test battery was also administered at T(5). RESULTS: 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. CONCLUSION: These findings are consistent with the hypothesis that dopaminergic factors are particularly involved in disrupted affect/reward-based processing characteristic of clinical depression.

Adult↗
PubMed2003

Global 5-HT depletion attenuates the ability of amphetamine to decrease impulsive choice on a delay-discounting task in rats.

RATIONALE: Psychomotor stimulant drugs such as methylphenidate and amphetamine decrease impulsive behaviour in attention deficit hyperactivity disorder patients by unknown mechanisms. Although most behavioural effects of amphetamine are attributed to the dopaminergic system, some recent evidence suggests a role for serotonin in this paradoxical "calming" effect. OBJECTIVES: To investigate whether forebrain serotonin depletion affects the action of amphetamine in the rat on a delayed reward task where impulsive choice is measured as the selection of a smaller immediate over a larger delayed reward. METHODS: . Following behavioural training, rats received i.c.v. infusions of either vehicle (n=10) or the serotonergic neurotoxin 5,7-DHT (n=10). Post-operatively, animals received i.p. d-amphetamine (0.3,1.0,1.5, and 2.3 mg/kg/ml), and d-amphetamine co-administered with the dopamine antagonist cis-z-flupenthixol. RESULTS: 5,7-DHT (i.c.v.) itself did not affect choice behaviour, despite depleting forebrain serotonin levels by over 85%. Amphetamine increased choice for the large reward, i.e. decreased impulsivity. This effect was attenuated by 5-HT depletion, particularly in animals showing a high level of impulsive choice. Co-administration of cis-z-flupenthixol (0.125 mg/kg) with d-amphetamine abolished the effect of amphetamine in the lesioned group, whereas this was only partially attenuated in the vehicle control group. CONCLUSIONS: These data suggest that the ability of amphetamine to decrease impulsivity is not solely due to its effects on dopaminergic systems, but may also depend on serotonergic neurotransmission.

5,6-Dihydroxytryptamine↗
PubMed2003

Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry.

Studies in patients with Parkinson's disease (PD) suggest that the characteristic motor symptoms of the disorder are frequently accompanied by impairments in cognition that are most profound in tasks of executive function. Neuropsychological deficits are not an inevitable consequence of the disease, yet the reasons underlying cognitive heterogeneity in PD are not well understood. To determine the underlying neural correlate of these cognitive deficits, we used event-related functional magnetic resonance imaging (fMRI) to compare groups of cognitively impaired and unimpaired patients, matched on all other clinical measures. fMRI revealed significant signal intensity reductions during a working-memory paradigm in specific striatal and frontal lobe sites in patients with cognitive impairment compared with those patients who were not cognitively unimpaired. These results demonstrate that cognitive deficits in PD are accompanied by neural changes that are related to, but distinct from, those changes that underlie motoric deficits in these patients. Furthermore, they suggest that fMRI may provide a valuable tool for identifying patients who may benefit from targeted therapeutic strategies.

Adult↗
PubMed2003

Functional disconnection of the medial prefrontal cortex and subthalamic nucleus in attentional performance: evidence for corticosubthalamic interaction.

The present study used a disconnection procedure to test whether the medial prefrontal cortex (mPFC) and the subthalamic nucleus (STN) were functional components in a common neural system that controlled continuous performance in a test of sustained and divided visual attention. Animals with disconnected lesions of the mPFC and STN in contralateral hemispheres were severely impaired in several aspects of performance, including discriminative accuracy, increased perseveration, and slowed response latencies during postoperative testing. These deficits persisted throughout the entire experimental test period. Increasing the stimulus duration alleviated the accuracy deficit but failed to improve speed of responding or reduce perseverative responses. These deficits were in marked contrast to animals with combined mPFC and STN lesions made on the ipsilateral side, which produced behavior not different from that of sham controls. Rats with unilateral lesions of either structure alone were also impaired in terms of accuracy and perseveration. These data suggest that some of the deficits observed after bilateral STN lesions (attention and perseveration) may be attributable to a disrupted corticosubthalamic projection. This study provides direct evidence that performance in tasks that require optimal attentional and executive control relies on a corticosubthalamic interaction within the neural circuitry of the basal ganglia.

Animals↗
PubMed2003

Task-set switching deficits in early-stage Huntington's disease: implications for basal ganglia function.

Executive functions are likely mediated by interconnected circuits including frontal lobe and basal ganglia structures. We assessed the executive function of task switching in patients with early-stage Huntington's disease (HD), a neurodegenerative disease affecting the basal ganglia. In two experiments, the HD patients had greater difficulty when switching than when repeating a task than matched controls, and this was true even when scaling for the overall slowing of the patients. In the first experiment, HD patients had a switching deficit even in a "pure" condition where they had to switch, predictably, and with substantial preparation time, between stimuli having only one possible response, indicating a switching deficit different from that for patients with Parkinson's disease or frontal lobe trauma, and possibly relating to inadequate activation of stimulus-response links or "response set." In the more elaborate second experiment, we could not account for the switching deficit of the patients in terms of inadequate preparation in advance of a switch, deficient suppression of task-set processing from the preswitch trial, or impaired suppression of interference due to the presence of a competing task set. Instead, we found that part of the switching deficit was due to elevated reaction time and errors on switch trials for a repeated response (same button press as on preswitch trial) relative to an alternated response (different button press from preswitch trial). We argue that this elevated "repetition effect" for the HD patients is due to excessive inhibition of the just-performed response in advance of a switch. Alterations in the "response-setting" process alone (Experiment 1) and both the response-setting and "response inhibition" process (Experiment 2) probably arise from striatal pathology in HD, thus accounting for the task-switching deficits and showing how basal ganglia implemented response processes may underpin executive function.

Adult↗
PubMed2003

Relative lack of cognitive effects of methylphenidate in elderly male volunteers.

RATIONALE: Methylphenidate, a dopaminergic and noradrenergic reuptake inhibitor, has been shown in young, healthy adult volunteers to produce pronounced effects on working memory and sustained attention. We were interested in assessing whether similar improvements could be conferred upon elderly volunteers in order to gain a more complete understanding of the effects of age on monoaminergic manipulations of working memory and attention, as well as to explore the potential for pharmacological intervention in attention and executive dysfunction disorders in this age group. OBJECTIVES: The main aim of the study was to characterise the dose-related effects of methylphenidate on a range of neuropsychological functions in elderly healthy volunteers. METHODS: Sixty healthy elderly adult male volunteers received either a single oral dose of placebo, 20 mg or 40 mg methylphenidate prior to performing a variety of tasks designed to assess memory, attention and executive function. A randomised double-blind, between-subjects design was used. RESULTS: Methylphenidate had significant cardiovascular and subjective effects. However, unlike in younger volunteers, no significant effects of drug on working memory (spatial span and spatial working memory), response inhibition (stop-signal) or sustained attention (rapid visual information processing) were seen. Subtle effects on latency similar to those in younger volunteers were identified: both doses of methylphenidate resulted in a slowing in response time during set-shifting and decision-making. CONCLUSIONS: The results of this study demonstrate that, in elderly subjects, the cognitive effects of methylphenidate are grossly attenuated and distinct from the profile previously described in younger volunteers. It is suggested that methylphenidate may not be appropriate as a pharmacological intervention in elderly patient groups, such as those reporting age-related cognitive decline.

Administration, Oral↗
PubMed2003

Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats.

RATIONALE: The central serotonergic systems are a major target for drugs used to treat neuropsychiatric disorders such as depression and schizophrenia in which disruption of frontal cortex function has been implicated. However, it is not known precisely how serotonin (5-HT) modulates the medial prefrontal cortex (mPFC) to affect cognitive function and behaviour. OBJECTIVE: To investigate the roles of 5-HT(1A) and 5-HT(2A) receptors in mPFC on performance of the five-choice serial reaction time task (5CSRT), which assesses visuospatial attention, impulsivity and motivational processes. METHODS: Following training on the 5CSRT, rats were implanted with bilateral guide cannulae aimed at the mPFC. Rats received intra-mPFC infusions of either 8-OH-DPAT (10, 30 and 100 ng) or M100907 (30, 100 and 300 ng) according to a Latin square design. RESULTS: Both 8-OH-DPAT and M100907 selectively enhanced accuracy of target detection. When the stimulus duration was shortened, infusions of 8-OH-DPAT continued to improve accuracy, whereas M100907 decreased premature responding and omissions, thus partly dissociating the effects of these two compounds. Similar effects were obtained following systemic administration of M100907 and 8-OH-DPAT. The effects of 8-OH-DPAT were blocked by the 5-HT(1A) antagonist WAY 100635, at a dose that itself had no significant effects on behaviour. CONCLUSIONS: These results indicate that modulation of 5-HT function within the mPFC via distinct receptors can enhance performance on the 5CSRT. These findings suggest a mechanism by which serotonergic agents improve cognitive function, which may be relevant to their therapeutic benefit in the treatment of neuropsychiatric disorders.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2003

Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions.

Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a number of rodent tests of attention. Although this evidence clearly suggests a role for the rat mPFC in attentional functions, it is unclear whether subcortical changes associated with mPFC lesions might also be relevant to the neuropsychological deficits observed. Given the ample evidence suggesting increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we investigated the effects of dopamine receptor agonists and antagonists on the attentional deficits associated with mPFC lesions. Rats trained on a five-choice reaction time task received either complete mPFC lesions or lesions restricted to its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared with sham-operated rats, animals in both the lesioned groups were impaired at responding correctly to the visual targets, although this deficit was more marked in mPFC-lesioned rats. In addition, both lesions were associated with increased perseverative responding. The accuracy deficits of rats with mPFC lesions were alleviated by systemic administration of the dopamine D2 receptor antagonist sulpiride. In contrast, rats with PRL-IL damage were not affected and control rats were impaired by sulpiride. Administration of either the dopamine D1 receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had similar, albeit non-significant effects. Higher doses of any of these drugs non-specifically impaired performance. These results extend previous findings of attentional impairments in rats with mPFC lesions and are compatible with recent hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis of schizophrenia.

Animals↗
PubMed2003

Using executive heterogeneity to explore the nature of working memory deficits in Parkinson's disease.

Idiopathic Parkinson's disease (IPD) is characterised by a triad of motor symptoms, namely bradykinesia, rigidity and resting tremor, although cognitive impairment is a common feature of the disease and has been accepted as one of the strong predictors of quality of life in such patients. Neuropsychological testing in Parkinson's disease often reveals a pattern of cognitive impairment similar to that observed in patients with frontal lobe lesions, although clear differences between the two groups have also often been reported. This apparent inconsistency in the literature may reflect heterogeneity among different groups of patients with Parkinson's disease, although to date this possibility has not been formally addressed. In this study, two groups of patients with Parkinson's disease were assessed on a novel 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. The two groups were selected according to either good or bad performance on a 'standard', visuospatial test of executive function (The Tower of London Task), but were well matched on all other demographic and cognitive measures tested. The sub-group of Parkinson's disease patients with Tower of London defined executive deficit were specifically impaired at manipulating information within verbal working memory, both compared to controls and to the group of patients with no predefined executive impairments. In contrast, the three groups did not differ in their ability to maintain or retrieve information within verbal working memory. Given the known preferential role of the dorsolateral frontal cortex in higher executive functions, (including both planning and the manipulation of information within working memory), these results suggest that, in a subset of Parkinson's disease patients, it is the frontostriatal circuitry involving this region which is primarily affected, while other components of this circuitry may be relatively spared. The results also suggest that performance on the Tower of London task may prove to be a useful discriminant variable in defining the nature of cognitive heterogeneity in Parkinson's disease.

Aged↗
PubMed2003

Distractibility during selection-for-action: differential deficits in Huntington's disease and following frontal lobe damage.

Selective attention can be measured through analysis of errors and reaction time (RT) for trials in which targets are presented alone compared with trials in which targets and distractors are presented. This study investigated selective attention using a reaching task, in which subjects made rapid reaches to targets. Thirty-seven patients with lesions of the prefrontal cortex (PFC) were compared with 19 healthy age- and IQ-matched volunteers and 18 patients with early-stage Huntington's disease (HD), a neurodegenerative disease primarily affecting the basal ganglia. It was hypothesised that, if fronto-striatal circuits as a whole support selection-for-action, then the pattern of behavioural performance of both patient groups would be similar. Alternatively, if the functional roles of PFC and basal ganglia in selection-for-action are dissociable, then two different patterns would emerge. It was found that that both HD and frontal groups were significantly more distractible than controls for RT, but they had a different pattern of errors. Frontal patients made significantly more touches of the distractor location itself than did controls, while this was not the case for HD. It is argued that a reactive-inhibition mechanism, required in the circumstance of strong distractor activation, is affected by frontal damage, while a lateral-inhibition mechanism, invoked during the recruitment of selective attention, is affected in HD. Additionally, there were significant correlations between the degree of distractibility for RT and the extent of lateral PFC damage, and between cue-generated preparation and lateral PFC damage, thus highlighting the critical importance of lateral, rather than orbital or medial, PFC for attention to action.

Attention↗
PubMed2003

The contributions of lesion laterality and lesion volume to decision-making impairment following frontal lobe damage.

Lesions to prefrontal cortex (PFC) in humans can severely disrupt everyday decision-making, with concomitant effects on social and occupational functioning. Forty-six patients with unilateral lesions to prefrontal cortex and 21 healthy control subjects were administered three neuropsychological measures of decision-making: the Iowa Gambling Task, the Cambridge Gamble Task, and the Risk Task. Magnetic resonance imaging (MRI) scans were acquired from 40 patients, with region of interest (ROI) mapping of prefrontal subregions. The frontal patients showed only limited damage in medial and orbital prefrontal cortex, but greater damage in lateral prefrontal regions of interest. Patients with right frontal lesions preferred the risky decks on the Iowa Gambling Task, and differed significantly from left frontal and control subjects. Within the right frontal group, the preference for the risky decks was correlated with the total lesion volume and the volume of damage outside of the ventromedial prefrontal region. Right and left frontal groups did not differ significantly on the Cambridge Gamble Task or the Risk Task, and performance was not associated with lesion volume. The results indicate a laterality effect on the Iowa Gambling Task, and the contribution of prefrontal regions outside the ventromedial region to task performance. The Cambridge Gamble Task and Risk Task were less sensitive to the effects of unilateral frontal lobe lesions, and may be more selectively associated with ventral prefrontal damage.

Adult↗
PubMed2003

L-Dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson's disease.

In the current study we investigated the role of dopamine in attentional and socio-emotional functioning by examining effects of withdrawing dopaminergic medication in patients with Parkinson's disease (PD). Patients "on" medication exhibited abnormal betting strategies on a task of decision-making, reflecting impulsive behaviour and/or delay aversion, whilst the same patients "off" medication exhibited abnormally increased switch costs when switching between two tasks, reflecting attentional inflexibility. Hence, these data replicate and extend previous findings that dopaminergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of dopamine function in underlying cortico-striatal circuitry.

Aged↗
PubMed2003

Impaired visual discrimination learning in anorexia nervosa.

The primate dopamine system is involved in appetitively motivated behaviours, including certain forms of learning, for example, visual discrimination learning. Furthermore, food restriction in animals and anorexia in humans is associated with impaired dopamine signaling. Based on this, we hypothesized that patients with anorexia nervosa (AN) would show a deficit in visual discrimination learning. In a dynamic categorization task involving the learning of a series of two-alternative forced-choice visual discriminations, conceptually identical to one shown to activate dopamine neurons in primates, and sensitive to dopaminergic manipulations in humans, patients with AN showed a deficit in learning that was most pronounced in the early stages of acquisition. In contrast, AN showed spared performance on a pattern recognition memory test sensitive to medial temporal lobe lesions, but insensitive to dopaminergic manipulations. We conclude that impaired appetitive function in patients with AN extends to include deficits in visual discrimination learning, and that this deficit represents indirect evidence for altered dopaminergic neurotransmission in AN.

Adult↗
PubMed2003

Role of the anterior cingulate cortex in the control over behavior by Pavlovian conditioned stimuli in rats.

To investigate the contribution of the anterior cingulate cortex (ACC) to stimulus-reward learning, rats with lesions of peri- and postgenual ACC were tested on a variety of Pavlovian conditioning tasks. Lesioned rats learned to approach a food alcove during a stimulus predicting food, and responded normally for conditioned reinforcement. They also exhibited normal conditioned freezing and Pavlovian-instrumental transfer, yet were impaired at autoshaping. To resolve this apparent discrepancy, a further task was developed in which approach to the food alcove was under the control of 2 stimuli, only 1 of which was followed by reward. Lesioned rats were impaired, approaching during both stimuli. It is suggested that the ACC is not critical for stimulus-reward learning per se, but is required to discriminate multiple stimuli on the basis of their association with reward.

Amphetamine↗
PubMed2003

A case of unilateral neglect in Huntington's disease.

Unilateral neglect, an attentional deficit in detecting and acting on information coming from one side of space, is a relatively common consequence of right hemisphere stroke. Although neglect has been observed following damage to a variety of brain structures, to date no reports exist of neglect phenomena arising from Huntington's Disease (HD). However, reports in the animal and human literature suggest that neglect is possible following damage to a primary site for Huntington's pathology, the basal ganglia. Here we present a patient (BG) with genetically proven HD who, in the context of the mild intellectual, executive and attentional impairments associated with the disorder, showed a remarkably severe and stable neglect for left space. MRI and electrophysiological results make it unlikely that the spatial bias could be accounted for by basic sensory loss. In addition, behavioural investigation indicated that, although BG's neglect operated in a very striking manner along body-centred co-ordinates (missing almost all information presented to her left), more general limitations in visual attention were apparent to the left-side of information presented entirely to the right of the body midline. Further evidence is presented showing that the neglect was manifest on tactile and auditory tasks as well as those presented in the visual domain. The presence of neglect in HD in this case is novel and somewhat puzzling, particularly as flourodeoyglucose positron emission tomography revealed bilateral caudate hypoperfusion. Reducing the statistical threshold on this analysis revealed a potential frontal hypometabolism that was more marked in the right than left hemisphere. However, as this was only apparent at a threshold below that normally considered acceptable (due to the resulting number of false positives), this possible account of the neglect must be viewed very cautiously.

Attention↗
PubMed2003

Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study.

We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.

Adult↗