Showing papers by "Trevor W. Robbins published in 1998"

A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: Implications for theories of executive functioning and cognitive aging

Abstract: Several tests from the CANTAB neuropsychological test battery previously shown to be sensitive to frontal lobe dysfunction were administered to a large group of normal volunteers (N = 341) ranging in age from 21 to 79 years The main tests included a computerized form of the Tower of London test of planning, a self-ordered spatial working memory task, and a test of attentional set formation and shifting A computerized form of the Corsi spatial span task was also given Age-related graded declines in performance were seen, sometimes in a discontinuous manner, especially for the attentional set shifting task (at the extradimensional shift stage) Patterns of deficits reminiscent of frontal lobe or basal ganglia damage were observed in the oldest age group (74–79) However, overall the data were only partially consistent with the hypothesis that frontal lobe functions are the most sensitive to effects of aging Factor analyses showed that performance in the executive tests was not simply related to a measure of fluid intelligence, and their performance had a factor loading structure distinct from that for the CANTAB tests of visual memory and learning previously administered to the same sample Finally, only limited support was found for the hypothesis that cognitive aging depends on slowed information processing (JINS, 1998, 4, 474–490)

The prefrontal cortex: Executive and cognitive functions.

Abstract: Roberts, theories and models of executive function based on neuropsychological studies in humans - introduction Baddeley and Della Sala, working memory and executive control Shallice and Burgess, the domain of supervisory processes and temporal organization of behaviour Damasio, neurobiological and neuropsychological approaches to the study of cognitive and executive function - the somatic marker hypothesis and the possible functions of the prefrontal cortex Pandya and Yeterian, comparison of prefrontal architecture and connections Rolls, the orbitofrontal cortex Goldman-Rakic, the prefrontal landscape - implications of functional architecture for understanding human mentation and the central executive Petrides, specialized systems for the processing of mnemonic information within the primate frontal cortex Robbins, dissociating executive functions of the prefrontal cortex Passingham, attention to action Diamond, evidence of the importance of dopamine for prefrontal cortex functions early in life Weinberger and Berman, prefrontal function in schizophrenia - confounds and controversies Frith, the role of the prefrontal cortex in self-consciousness - the case of auditory hallucinations Cohen, Braver, O'Reilly, a computational approach to prefrontal cortex, cognitive control and schizophrenia - recent developments and current challenges.

Evidence for specific cognitive deficits in preclinical Huntington's disease.

Abstract: The performance of 54 subjects genetically at risk for Huntington's disease was examined in double-blind fashion on a series of computerized tests from the Cambridge Neuropsychological Test Automated Battery. None of the subjects exhibited clinical movement disorder characteristic of Huntington's disease. Of the 54 subjects, 22 were Huntington's disease mutation carriers and 32 were non-carriers. On a comprehensive battery of neuropsychological tests previously shown to be sensitive to the early stages of clinical Huntington's disease, Huntington's disease mutation carriers exhibited highly specific cognitive deficits. In particular, Huntington's disease mutation carriers performed significantly less well than non-carriers, matched for age and IQ, on tests of attentional set shifting and semantic verbal fluency. Furthermore, performance on these two tests was significantly correlated, even after partialling out the effects of age and IQ. It is suggested that these cognitive impairments relate to a common deficit in inhibitory control mechanisms, under the control of striatofrontal mechanisms, and that such a deficit is present in Huntington's disease mutation carriers prior to the onset of definite motor symptomatology. The implications for the nature of the cognitive decline seen in Huntington's disease, and possible future treatment strategies, are discussed.

Dissociating executive mechanisms of task control following frontal lobe damage and Parkinson's disease

Abstract: Twelve patients with focal damage of the frontal cortex and 12 patients with mild, medicated, early stage Parkinson's disease switched between letter- and digit=naming tasks on every second trial of a task-switching paradigm. Compared with age- and IQ-matched control performance, patients with left-sided, but not right-sided, frontal damage exhibited markedly increased time costs associated with these predictable switches only when there was a general incidence of interference or 'crosstalk' between the tasks, and particularly so when the available task cues were relatively weak and arbitrary. The same patients also showed evidence of an increased sensitivity to the facilitatory and inhibitory effects of previous processing, when required to switch between tasks. Both groups of patients (with left- or right-sided frontal damage) exhibited slow, disorganized performance early in practice. In contrast to these frontal effects, the Parkinson's disease patients showed little indication of larger time costs of task switches but they did show progressive increases in the error costs, while age- and IQ-matched control subjects showed reductions. We propose that while both left and right frontal cortical areas are involved in the organization of cognitive and motor processes in situations involving novel task demands, only the left frontal cortex is involved in the dynamic reconfiguring between already-established task-sets, and specifically, that it is the site of an executive mechanism responsible for the modulation of exogenous task-set activity. Finally, dopaminergic transmission, along the nigrostriatal pathway, may be implicated in sustaining various cognitive and motor processes over prolonged periods, including the operation of those executive control mechanisms that accomplish reconfiguring between task-sets.

Executive function in first-episode schizophrenia

Abstract: Background. We tested the hypothesis that schizophrenia is primarily a frontostriatal disorder by examining executive function in first-episode patients. Previous studies have shown either equal decrements in many cognitive domains or specific deficits in memory. Such studies have grouped test results or have used few executive measures, thus, possibly losing information. We, therefore, measured a range of executive ability with tests known to be sensitive to frontal lobe function. Methods. Thirty first-episode schizophrenic patients and 30 normal volunteers, matched for age and NART IQ, were tested on computerized test of planning, spatial working memory and attentional set shifting from the Cambridge Automated Neuropsychological Test Battery. Computerized and traditional tests of memory were also administered for comparison. Results. Patients were worse on all tests but the profile was non-uniform. A componential analysis indicated that the patients were characterized by a poor ability to think ahead and organize responses but an intact ability to switch attention and inhibit prepotent responses. Patients also demonstrated poor memory, especially for free recall of a story and associate learning of unrelated word pairs. Conclusions. In contradistinction to previous studies, schizophrenic patients do have profound executive impairments at the beginning of the illness. However, these concern planning and strategy use rather than attentional set shifting, which is generally unimpaired. Previous findings in more chronic patients, of severe attentional set shifting impairment, suggest that executive cognitive deficits are progressive during the course of schizophrenia. The finding of severe mnemonic impairment at first episode suggests that cognitive deficits are not restricted to one cognitive domain.

Isolation rearing in rats: Pre- and postsynaptic changes in striatal dopaminergic systems

Abstract: Isolationrearing of rats produces a behavioral syndrome indicative of altered dopamine (DA) function in the nucleus accumbens (NAC). The present experiments extend these findings by investigating: (a) interactions between isolationrearing and repeated handling/testing on presynaptic DA function in the NAC using in vivo microdialysis; (b) the dose–response curve for the effects of d-amphetamine, and the responses elicited by high potassium, using in vivo microdialysis; and (c) postsynaptic function in isolates as indexed by DA receptor-linked cAMP production. Experiment 1 showed that both isolationrearing and repeated handling/testing had effects on monoamine function in the NAC. However, while both manipulations enhanced DA release evoked by d-amphetamine, only isolated rats had elevated basal DA levels. Opposite neurochemical changes were observed with respect to the serotonin metabolite 5-HIAA, isolates having lower, and repeatedly handled/tested animals having higher, extracellular levels. Experiment 2 provided evidence for enhanced d-amphetamine–evoked DA release in isolated animals, while potassium-evoked DA release was reduced. Experiment 3 provided evidence that the isolationrearing induced changes in presynaptic DA function were accompanied by postsynapticchanges. Specifically, the inhibitory influence of the D2 receptor on D1 receptor-stimulated cAMP production was attenuated in ventral striatal slices taken from isolates, suggesting a functional downregulation of D2 receptors.

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine.

Abstract: Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals’ responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.

Perseveration and Strategy in a Novel Spatial Self-Ordered Sequencing Task for Nonhuman Primates: Effects of Excitotoxic Lesions and Dopamine Depletions of the Prefrontal Cortex

Abstract: Damage to the prefrontal cortex disrupts the performance of self-ordered sequencing tasks, although the precise mechanisms by which this effect occurs is unclear. Active working memory, inhibitory control, and the ability to generate and perform a sequence of responses are all putative cognitive abilities that may be responsible for the impaired performance that results from disruption of prefrontal processing. In addition, the neurochemical substrates underlying prefrontal cognitive function are not well understood, although active working memory appears to depend upon an intact mesocortical dopamine system. The present experiments were therefore designed to evaluate explicitly the contribution of each of these abilities to successful performance of a novel spatial self-ordered sequencing task and to examine the contribution of the prefrontal cortex and its dopamine innervation to each ability in turn. Excitotoxic lesions of the prefrontal cortex of the common marmoset profoundly impaired the performance of the self-ordered sequencing task and induced robust perseverative responding. Task manipulations that precluded perseveration ameliorated the effect of this lesion and revealed that the ability to generate and perform sequences of responses was unaffected by excitotoxic damage to prefrontal cortex. In contrast, large dopamine and noradrenaline depletions within the same areas of prefrontal cortex had no effect on any aspect of the self-ordered task but did impair the acquisition of an active working memory task, spatial delayed response, to the same degree as the excitotoxic lesion. These results demonstrate that a lesion of the ascending monoamine projections to the prefrontal cortex is not always synonymous with a lesion of the prefrontal cortex itself and thereby challenge existing concepts concerning the neuromodulation of prefrontal cognitive function.

The relationship between striatal dopamine receptor binding and cognitive performance in Huntington's disease

Abstract: Seventeen individuals at risk for Huntington's disease and five symptomatic patients, who had previously undergone [11C]SCH23390 and [11C]raclopride PET to assess in vivo levels of striatal dopamine D1 and D2 receptor binding, had neuropsychological assessment on a series of tests known to be sensitive to symptomatic Huntington's disease, including tests of verbal fluency, memory, attention and planning. Compared with age- and IQ-matched healthy volunteers, clinically symptomatic carriers of the Huntington's disease mutation were found to be impaired on tests of verbal fluency, spatial span, planning and sequence generation, as were clinically asymptomatic Huntington's disease mutation carriers. In asymptomatic individuals, both striatal dopamine receptor levels and cognitive performance were lower in subjects approaching their estimated age of onset. In addition, performance on these tasks was found to correlate with PET measures of striatal D1 and D2 receptor binding levels, especially D2 binding. These results are consistent with a role for the striatum, as part of the complex corticobasal ganglia-thalamocortical circuitry, in the optimal scheduling and sequencing of responses, and suggest that cognitive manifestations of striatal dysfunction can be evidenced in carriers of the Huntington's disease mutation prior to the onset of overt clinical movement disorder.

Neural Systems Underlying Arousal and Attention: Implications for Drug Abusea.

Abstract: The monoaminergic and cholinergic systems are implicated in different forms of behavioral arousal that can be dissected in terms of their forebrain targets and the nature of the behavioral processes they modulate in distinct regions. Thus, evidence in rats with selective neurochemical manipulations tested behaviorally using an analog of an attentional task developed for human subjects indicates that the coeruleo-cortical noradrenergic system is implicated in divided and selective attention, the basal forebrain cholinergic system in stimulus detection, the mesostriatal and mesolimbic dopaminergic systems in response speed and vigor, and the mesencephalic serotoninergic or 5-HT systems in response inhibition. Our recent studies have focused on fractionating, in the same task, the differential contributions of the dorsal and median raphe 5-HT systems as well as elucidating the functions of the mesocortical dopaminergic system, each of which may be relevant to understanding the behavioral and cognitive sequelae of cocaine administration in human subjects as well as in experimental animals.

Dissociations in dopamine release in medial prefrontal cortex and ventral striatum during the acquisition and extinction of classical aversive conditioning in the rat

Abstract: Dual perfusion in vivo brain microdialysis was used to monitor extracellular levels of dopamine in the medial prefrontal cortex and ventral striatum during the acquisition and extinction of a classical aversive conditioning paradigm in rats. The main finding was a dissociation in the pattern of release in the two brain areas. The first stimulus–footshock pairing elicited large increases in cortical dopamine over baseline levels that were much greater than the increases elicited by different stimuli of equivalent salience that were unpaired with footshock. In contrast, dopamine levels in ventral striatum were unchanged under these conditions. Over the next two pairings, there was a decline in the cortical response and an increase in the response in ventral striatum. The first presentation of the aversive conditioned stimulus in a separate context elicited the largest response in ventral striatum. Post-conditioning, the cortical response to the conditioned stimulus was smaller than that elicited by the initial stimulus–footshock pairing and was equivalent in magnitude to that elicited by stimuli unpaired with footshock. Over the final two conditioned stimuli presentations, in the absence of the footshock reinforcer (extinction), responses declined in both brain areas. Simultaneous monitoring of behaviour indicated that the neurochemical events were accompanied by effective aversive learning, as indexed by conditioned freezing responses. The data are discussed in terms of the hypothesis that medial prefrontal cortex is especially engaged during novel circumstances which may, potentially, require new learning, whilst ventral striatal dopamine more closely follows the expression of conditioned responding during learning and extinction.

Specific Neuropsychological Deficits in Schizophrenic Patients with Preserved Intellectual Function

Abstract: Although a wide range of cognitive deficits have been demonstrated in schizophrenia, it is not clear whether specific deficits stand out from general intellectual decline. Separate cases have been made for selective impairments in mnemonic and in executive function but these remain unconfirmed. A common problem in studies of schizophrenia is heterogeneity of deficits and Shallice, Burgess, and Frith (1991) have addressed this by using a single case study approach. The present study used the CANTAB battery of neuropsychological tests to examine cognitive performance in a small group of schizophrenic patients with preserved intellectual function. This test battery allows a componential analysis of performance, and its neurological validation may enable specific neurobiological hypotheses to be addressed. Twelve schizophrenic patients with current IQ greater than 90 and within 10 points of premorbid IQ were assessed on tests of visuospatial memory, spatial working memory, planning, and attentional set-shifti...

Impaired generation and use of strategy in schizophrenia: evidence from visuospatial and verbal tasks.

Abstract: Background. The aim of this study was to investigate mnemonic strategic deficits in schizophrenic patients. Methods. Analogous tasks were used that required the self-generation of an efficient strategy and its implementation in two domains: visuospatial and verbal. The tasks were given to 20 IQ preserved schizophrenics and 20 matched normal controls. A number of different scores was derived from each task including strategy, short-term memory capacity and perseveration. Results. Overall, the schizophrenic patients were significantly impaired in their ability to generate effective mnemonic strategies on both tasks. In addition, on the visuospatial task there was no difference between the groups on the memory scores, but the schizophrenic patients made significantly more perseverative errors than controls. They were disproportionately worse on the verbal strategy task, showing impairment on memory as well as on strategy scores and were also impaired at semantically classifying the words. Performance was similar to the deficit seen in patients with frontal lobe excisions and Parkinson's disease, in terms of the inability to generate an effective strategy. The deficit on the verbal task was similar to patients with temporal lobe excisions who show impaired verbal memory. However, the pattern differed in the sense that the temporal lobe patients were able to generate effective strategies, unlike the patients with schizophrenia. Conclusions. High functioning schizophrenic patients are impaired in utilizing visuospatial and verbal mnemonic strategies. By comparing the results with those of neurosurgical excision patients, further evidence is provided for both frontal and temporal lobe involvement in schizophrenia.

Homology in behavioural pharmacology: an approach to animal models of human cognition.

Abstract: The distinction in biology between homology and analogy is examined for possible application to studies in behavioural pharmacology. It is argued that the concept of homology is central to understanding the 'construct validity' of animal models of human cognition. It is suggested that we capitalize

Excitotoxic lesions of the mediodorsal thalamic nucleus attenuate intravenous cocaine self-administration

Abstract: The present experiments investigated the effects of excitotoxic, axon-sparing lesions of the mediodorsal nucleus of the thalamus (MD) on locomotor activity and IV cocaine self-administration. Infusion of quinolinic acid into the MD using a glass micropipette produced well-defined neuronal loss restricted to medial and lateral portions of the MD, sparing adjacent areas such as the lateral habenula and paraventricular thalamic nucleus. MD lesions resulted in delayed habituation to activity cages. In addition, lesioned rats self-administered significantly smaller amounts of cocaine than controls during a 14-day acquisition period, and showed attenuated responding for cocaine doses on the descending limb of the dose-effect function. Since typical titrating patterns of responding were maintained in lesioned rats, and responding on the inactive lever did not differ from sham-operated animals, these present results indicate an enhanced sensitivity to the reinforcing effects of response-contingent cocaine in rats with excitotoxic lesions of the MD.

Basal forebrain cholinergic lesions enhance conditioned approach responses to stimuli predictive of food

Abstract: This study examined the effects of lesions to different neuronal populations within the basal forebrain on reward-related learning. Rats received bilateral alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or quinolinate lesions that preferentially destroy the cholinergic nucleus basalis magnocellularis (NBM) or noncholinergic ventral pallidal neurons, respectively. Both lesions enhanced conditioned approach responses to stimuli predictive of food but did not increase the locomotor stimulating effect of d-amphetamine. Although both lesions disrupted the discriminative control over behavior by a conditioned stimulus, they did not impair the subsequent acquisition of instrumental responding with conditioned reinforcement (CR). Indeed, both lesions were associated with an increased responding with CR following intra-accumbens infusions of d-amphetamine (0, 1, 3, 10, and 20 microg). Quinolinate lesions also increased responses on an inactive control lever. Neither lesion altered consummatory responses to food or sucrose. Results suggest that NBM lesions may disrupt the balance between cortical and subcortical dopamine levels, and/or produce a deficit in attentional mechanisms that is manifested as increased responding to specific stimuli.

Effects of lesions of the nucleus basalis magnocellularis on the acquisition of cocaine self-administration in rats

Abstract: The nucleus basalis magnocellularis (NBM) is one element in the limbic cortical-ventral striatal circuitry that has been implicated in reinforcement processes. The present study examined the involvement of the cholinergic neurons of the NBM in mediating aspects of cocaine reinforcement. Lesions of the NBM were made by injecting 0.01 M AMPA into the subpallidal basal forebrain. Following 4 days' recovery, rats were implanted chronically with catheters in the jugular vein. In three separate experiments, rats were trained to acquire cocaine self-administration under a FR1 schedule of reinforcement at doses of 0.25, 0.083 and 0.028 mg/injection. A dose-effect function was also determined at the end of the acquisition experiments using five different doses of cocaine (0.009, 0.028, 0.083, 0.25, 0.50 mg/injection) and saline which were presented once daily in a Latin square design. There were no significant differences between groups in the acquisition of cocaine self-administration at any of the three doses studied (0.028, 0.083 and 0.25 mg/injection), although at the lowest dose, lesioned animals responded at greater levels on both active and inactive levers. However, a shift to the left in the cocaine dose-response function was observed revealing that the lesioned group self-administered significantly higher amounts of low doses of cocaine than control rats. These data suggest that the integrity of the NBM is not a critical determinant of the reinforcing effects of cocaine during the acquisition of self-administration of the drug, but that NBM-dependent cholinergic mechanisms may nevertheless interact with the neural substrates mediating the reinforcing properties of cocaine. The data are relevant to recent hypotheses of functional interactions between the dopaminergic system and the cholinergic NBM.

The cerebral metabolic effects of manipulating glutamatergic systems within the basal forebrain in conscious rats

Abstract: N-methyl-d-aspartate (NMDA) and non-NMDA receptor-mediated manipulations of the cortical cholinergic input arising from the basal forebrain differentially affect cognitive function. We used [14C]-2-deoxyglucose autoradiography in conscious rats to map the effects of excitatory amino acid agonist infusions into the nucleus basalis magnocellularis (NBM) on cerebral functional activity, as reflected by local rates of glucose utilization. Acute stimulation of NBM neurones by local infusion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 15 min before glucose use measurement, resulted in glucose use reductions in nine cortical regions innervated by NBM efferents including prefrontal, frontal, sensorimotor and cingulate cortices. NMDA infusions altered glucose use in two cortical areas. Both AMPA and NMDA markedly increased glucose use in the striatum and globus pallidus, with concomitant perturbations in striato-pallidal projection targets including the substantia nigra, entopeduncular nucleus, subthalamic nucleus and lateral habenular nucleus. In contrast, the GABAA agonist muscimol did not affect glucose use in the NBM or neocortical regions, but induced glucose use increases in several subcortical nuclei including the substantia nigra and entopeduncular nucleus. The delayed effects of excitotoxic lesions were assessed 3 weeks after basal forebrain infusions of AMPA, NMDA, ibotenate or quisqualate. Statistically significant glucose use changes only occurred in the hypothalamus after NMDA, and the NBM after ibotenate infusions, although reduced cortical metabolism was apparent following AMPA-induced lesions of the NBM. Results support a dissociation between the functional sequelae of NMDA and non-NMDA receptor-mediated events in the basal forebrain, and long-term compensatory functional adaptation following cortical denervation.