Showing papers by "Trevor W. Robbins published in 1997"

Central cholinergic systems and cognition

Abstract: The organization and possible functions of basal forebrain and pontine cholinergic systems are reviewed. Whereas the basal forebrain cholinergic neuronal projections likely subserve a common electrophysiological function, e.g. to boost signal-to-noise ratios in cortical target areas, this function has different effects on psychological processes dependent upon the neural network operations within these various cortical domains. Evidence is presented that (a) the nucleus basalis-neocortical cholinergic system contributes greatly to visual attentional function, but not to mnemonic processes per se; (b) the septohippocampal projection is involved in the modulation of short-term spatial (working) memory processes, perhaps by prolonging the neural representation of external stimuli within the hippocampus; and (c) the diagonal band-cingulate cortex cholinergic projection impacts on the ability to utilize response rules through conditional discrimination. We also suggest that nucleus basalis-amygdala cholinergic projections have a role in the retention of affective conditioning while brainstem cholinergic projections to the thalamus and midbrain dopamine neurons affect basic arousal processes (e.g. sleep-wake cycle) and behavioral activation, respectively. The possibilities and limitations of therapeutic interventions with procholinergic drugs in patients with Alzheimer's disease and other neurodegenerative disorders in which basal forebrain cholinergic neurons degenerate are also discussed.

Different types of fear-conditioned behaviour mediated by separate nuclei within amygdala

Abstract: The amygdala has long been thought to be involved in emotional behaviour, and its role in anxiety and conditioned fear has been highlighted. Individual amygdaloid nuclei have been shown to project to various cortical and subcortical regions implicated in affective processing. Here we show that some of these nuclei have separate roles in distinct mechanisms underlying conditioned fear responses. Rats with lesions of the central nucleus exhibited reduction in the suppression of behaviour elicited by a conditioned fear stimulus, but were simultaneously able to direct their actions to avoid further presentations of this aversive stimulus. In contrast, animals with lesions of the basolateral amygdala were unable to avoid the conditioned aversive stimulus by their choice behaviour, but exhibited normal conditioned suppression to this stimulus. This double dissociation demonstrates that distinct neural systems involving separate amygdaloid nuclei mediate different types of conditioned fear behaviour. We suggest that theories of amygdala function should take into account the roles of discrete amygdala subsystems in controlling different components of integrated emotional responses.

Dissociable Forms of Inhibitory Control within Prefrontal Cortex with an Analog of the Wisconsin Card Sort Test: Restriction to Novel Situations and Independence from “On-Line” Processing

Abstract: Attentional set-shifting and discrimination reversal are sensitive to prefrontal damage in the marmoset in a manner qualitatively similar to that seen in man and Old World monkeys, respectively (Dias et al., 1996b). Preliminary findings have demonstrated that although lateral but not orbital prefrontal cortex is the critical locus in shifting an attentional set between perceptual dimensions, orbital but not lateral prefrontal cortex is the critical locus in reversing a stimulus-reward association within a particular perceptual dimension (Dias et al., 1996a). The present study presents this analysis in full and extends the results in three main ways by demonstrating that (1) mechanisms of inhibitory control and "on-line" processing are independent within the prefrontal cortex, (2) impairments in inhibitory control induced by prefrontal damage are restricted to novel situations, and (3) those prefrontal areas involved in the suppression of previously established response sets are not involved in the acquisition of such response sets. These findings suggest that inhibitory control is a general process that operates across functionally distinct regions within the prefrontal cortex. Although damage to lateral prefrontal cortex causes a loss of inhibitory control in attentional selection, damage to orbitofrontal cortex causes a loss of inhibitory control in affective processing. These findings provide an explanation for the apparent discrepancy between human and nonhuman primate studies in which disinhibition as measured on the Wisconsin Card Sort Test is associated with dorsolateral prefrontal damage, whereas disinhibition as measured on discrimination reversal is associated with orbitofrontal damage.

Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms

Abstract: A series of ten experiments examined the effects of profound central 5-HT depletion on attentional performance in the rat in the five-choice serial reaction time task, and also determined the effects of such depletion on responding affected by d-amphetamine and by selective dopamine receptor antagonists. Rats were trained to detect and locate brief visual stimuli randomly presented in one of five spatial locations. When performance had stabilised (>80% correct, <20% omissions), selective central 5-HT depletion was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. The lesioned animals performed the five-choice serial reaction time task with the same degree of accuracy as the sham-operated controls. However, 5-HT depletion reduced the percentage of omitted trials and increased the number of premature/anticipatory responses. This pattern of behaviour following 5-HT depletion could not be attributed to enhanced primary motivation as demonstrated by measures of food intake and latencies to collect food reinforcement. The lesion attenuated the increase of premature responding induced by high doses of systemically administered d-amphetamine. 5-HT depletion also attenuated the dose-dependent decrease in accuracy induced by (–)-sulpiride, a D2 receptor antagonist, although the effects of this drug on response latencies and premature responding were similar in both groups. However, the systemic administration of the D1 receptor antagonist, SCH 23390, blocked the impulsive responding produced by the lesion as indicated by a lack of lesion effects on the percentage of omitted trials and premature responding. The results suggest that central 5-HT depletion results in impulsive, fast responding, which nevertheless does not impair accuracy of visual discrimination performance. The increased impulsivity may be mediated by altered 5-HT-dopamine interactions, with the lesion removing an inhibitory influence over dopamine neurotransmission.

Frontal-striatal cognitive deficits in patients with chronic schizophrenia.

Abstract: Spatial working memory and planning abilities were assessed in 36 hospitalized patients with chronic schizophrenia, using the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB), and compared with those of normal subjects and patients with neurological disorders (frontal lobe lesions; temporal lobe and amygdalohippocampal lesions; Parkinson's disease), matched for age, sex and National Adult Reading Test IQ. The patients in the group with temporal lobe lesions were unimpaired in their performance on these tasks. Patients with schizophrenia were impaired on visuo-spatial memory span compared with all the other groups, while severity of Parkinson's disease was correlated with the degree of impairment on this task. The patients with schizophrenia and those with frontal lobe lesions were impaired on a 'spatial working memory' task, with increased 'between-search errors'. Patients with Parkinson's disease performed this task poorly compared with the younger control subjects. Patients with schizophrenia were unable to develop a systematic strategy to complete this task, relying instead on a limited visuo-spatial memory span. Higher level planning ability was investigated using the CANTAB 'Tower of London'. All groups were equally able to complete the task. However, the groups of patients with schizophrenia and frontal lobe lesions made fewer perfect solutions and required more moves for completion. Movement times were significantly slower in the schizophrenia group, suggesting impairment in the sensorimotor requirements of the task. The patients with schizophrenia were not impaired in their 'initial thinking' (planning) latencies, but had significantly prolonged 'subsequent thinking' (execution) latencies. This pattern resembled that of the group with frontal lobe lesions and contrasted with the prolonged 'initial thinking' time seen in Parkinson's disease. The results of this study are indicative of an overall deficit of executive functioning in schizophrenia, even greater than that seen in patients with frontal lobe lesions. However, the pattern of results in schizophrenia resembled that seen in patients with lesions of the frontal lobe or with basal ganglia dysfunction, providing support for the notion of a disturbance of frontostriatal circuits in schizophrenia. Our findings also indicate that there is a loss of the normal relationships between different domains of executive function in schizophrenia, with implications for impaired functional connectivity between different regions of the neocortex.

Effects of methylphenidate on spatial working memory and planning in healthy young adults

Abstract: Previous studies of the effects of the psychomotor stimulant, methylphenidate, have concentrated on vigilance and reaction time tasks. In this study, the effects of methylphenidate on more complex aspects of cognition were studied using tasks from the CANTAB battery and related tests which have been shown to be sensitive to frontal lobe dysfunction. Twenty-eight young healthy men participated in a counterbalanced, double-blind, placebo-controlled study of the effects of methylphenidate. Cognitive assessment included tests of spatial working memory, planning, verbal fluency, attentional set-shifting and sustained attention. Methylphenidate had significant effects on performance of the tests of spatial working memory and planning but not on the attentional and fluency tests. When the drug was taken on the first test session, performance on the spatial tests was enhanced by the drug compared to placebo. However, when the drug was taken second, performance accuracy was impaired whereas response latencies were decreased. These results are consistent with a hypothesis that methylphenidate influences performance in two conflicting ways; enhancing executive aspects of spatial function on novel tasks but impairing previously established performance. This pattern of effects is discussed within the framework of dual, interacting arousal mechanisms.

Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat.

Abstract: Four experiments examined effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on tests of visual discrimination learning, using a new "touchscreen" testing method for rats. Anterior cingulate cortex lesions impaired acquisition of an 8-pair concurrent discrimination task, whereas posterior cingulate cortex lesions facilitated learning but selectively impaired the late stages of acquisition of a visuospatial conditional discrimination. Medial frontal cortex lesions selectively impaired reversal learning when stimuli were difficult to discriminate; lesions of anterior and posterior cingulate cortex had no effect. These results suggest roles for the anterior cingulate, posterior cingulate, and medial frontal cortex in stimulus-reward learning, stimulus-response learning or response generation, and attention during learning, respectively.

Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats

Abstract: Lesioning the subthalamic nucleus (STN) has been suggested as possible therapy for the treatment of parkinsonism. Previous experiments investigating this hypothesis in rats confirmed that excitotoxic STN lesions alleviate the motor impairment induced by striatal dopamine depletion, which reproduced the degeneration observed in parkinsonism, but elicited presumed non-motor deficits such as premature responding, suggesting that the STN could be involved in other aspects of response control. The aim of the present study was to extend this analysis to choice paradigms. We thus investigated the behavioural effects of bilateral excitotoxic lesions of the STN in rats performing a five-choice test of divided and sustained visual attention, modelled on the human continuous performance task. This task required the animals to detect a brief visual stimulus presented in one of five possible locations and respond by a nose-poke in this illuminated hole within a fixed delay, for food reinforcement. Bilateral lesions of the STN severely impaired several aspects of performance, including discriminative accuracy, but also increased premature, anticipatory responding as well as perseverative panel pushes and nose-poke responses. While increasing the stimulus duration and reducing the waiting period for the stimulus partially alleviated the accuracy deficit and the premature responding deficit respectively, other deficits, such as perseverative panel pushes and nose-poke responses, were sustained under these conditions. Systemic injection of the mixed dopaminergic D1/D2 receptor antagonist, alpha-flupenthixol (0.03-0.18 mg/kg), reduced premature responses and perseverative panel pushing without affecting the perseverative nose-poke responses, suggesting that some of the deficits were independent of striatal dopaminergic transmission. These results suggest that STN lesions have multiple, dissociable effects on attentional performance, including discriminative deficits, impulsivity and perseverative behaviour. They are consistent in part with a hypothesized role of the STN in recent models of basal ganglia function in action selection and inhibition. The results also show that other aspects of behaviour should be monitored when examining the capacity of STN lesions to reverse the parkinsonian deficit induced by striatal dopamine depletion.

Abnormal response to negative feedback in unipolar depression:evidence for a diagnosis specific impairment

Abstract: Objectives—To assess in further detail the specific form of motivational impairment influencing neuropsychological performance in depression—oversensitivity to perceived failure. The present study considers two questions:firstly whether this is specific to depression and secondly how the eVect relates to clinical features. Methods—Unipolar depressed patients and matched controls were assessed on two neuropsychological tests giving explicit performance feedback. The data were analysed in two separate studies to consider the questions above. The first study considered the specificity of the eVect to depressed patients, using data on the same tests collected from other patient groups. The second study was a longitudinal assessment of the depressed patients on clinical recovery to determine whether the eVect is specific to the depressed state. Results—The eVect was not seen in nondepressed patient groups, either neurological or psychiatric groups. The longitudinal study showed a residual abnormal response to negative feedback on clinical recovery. Conclusions—Abnormal response to negative feedback is specific to a primary diagnosis of depression and may be a trait rather than a state factor of the disorder. These results are discussed in relation to the putative neuropathology of depression and also to cognitive and behavioural accounts of the disorder. The findings presented here have important implications for establishing a link between mood and cognition in unipolar depression. (J Neurol Neurosurg Psychiatry 1997;63:74‐82)

Dissociable effects of cingulate and medial frontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure for the rat: implications for the neurobiology of emotion.

Abstract: The effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on stimulus-reward learning were investigated with a novel Pavlovian autoshaping procedure in an apparatus allowing the automated presentation of computer-graphic stimuli to rats (T. J. Bussey, J. L. Muir, & T. W. Robbins, 1994). White vertical rectangles were presented on the left or the right of a computer screen. One of these conditioned stimuli (the CS+) was always followed by the presentation of a sucrose pellet; the other, the CS-, was never followed by reward. With training, rats came to approach the CS+ more often than the CS-. Anterior cingulate cortex-lesioned rats failed to demonstrate normal discriminated approach, making significantly more approaches to the CS- than did sham-operated controls. Medial frontal cortex-lesioned rats acquired the task normally but had longer overall approach latencies. Posterior cingulate cortex lesions did not affect acquisition.

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats

Abstract: Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex.

Effects of scopolamine on delayed-matching-to-sample and paired associates tests of visual memory and learning in human subjects: comparison with diazepam and implications for dementia.

Abstract: Two experiments examined dose-related effects of 200, 400 and 600 μg scopolamine (n = 24, SC) and 5 and 10 mg diazepam (n = 6, PO) on parallel tests of visual memory and learning taken from the CANTAB battery. Scopolamine significantly impaired accuracy of performance on a delayed matching to sample test of visual recognition memory in a dose-and delay-dependent manner, but had only marginal decremental effects on a test of visuospatial paired associates learning. Scopolamine significantly lengthened decision times in a visual search matching to sample task at the 400 and 600 μg doses, without significantly affecting accuracy. The drug also impaired performance on tests of spatial (on accuracy and response time measures) and pattern (on response time only) memory. Most of the deleterious effects on scopolamine were removed by covariance analyses with indices of subjective sedation, but the effects of delayed matching accuracy and latency remained. By contrast, diazepam significantly impaired paired associates learning but affected delayed matching to sample in a delay-independent manner. These results suggest that scopolamine can produce selective deficits in tests of short-term visual recognition memory which do not depend on overall impairments in arousal and which contrast with deficits in visual associative learning produced by diazepam. They have implications for the pharmacological modelling of dementia and memory disorders in man and for the neurochemical substrates of the short-term recognition memory and associative learning for visual stimuli.

Unilateral lesions of the dorsal striatum in rats disrupt responding in egocentric space

Abstract: Rats were trained in a specially designed, multichoice operant chamber on a visual choice reaction time task designed to assess performance on each side of the rat’s body. The task required animals to sustain a nose poke in a central hole, until a brief light stimulus was presented in either of two holes that were located on the same side of the box. Once the rats were trained to perform the task to both sides independently they received unilateral injections of quinolinic acid into the dorsal striatum. Postoperatively, lesioned animals were impaired when performing the task on the side contralateral to the lesion. The time taken to initiate contralateral responses was increased. Contralateral responses were also exclusively biased toward the nearer of the two response locations, regardless of the location of the stimulus. This was interpreted as a specific impairment in generating responses in contralateral space. In contrast, no comparable deficit was seen when the animals performed the task on the side ipsilateral to the lesion. Additional postoperative challenges, in which response options were presented bilaterally, showed this response deficit to be defined in egocentric coordinates, with the severest response deficits for the most contralateral locations.

Symmetrical effects of amphetamine and alpha-flupenthixol on conditioned punishment and conditioned reinforcement: contrasts with midazolam.

Abstract: In a test of conditioned punishment, saline-treated controls showed a moderate bias in responding away from a lever producing a response-contingent auditory conditioned stimulus (CS) that had been paired with mild footshock during training and towards a lever producing a neutral auditory CS. Systemic treatment with the indirect dopamine (DA) agonist amphetamine (0.25–1.0 mg/kg) produced a dose-dependent increase in the punishing effect of the aversive CS, whilst responding on the neutral CS lever was unchanged. Treatment with the dopamine-receptor antagonist α-flupenthixol (0.125, 0.25 mg/kg) decreased the efficacy of the punishing CS, but again left responding on the neutral lever unchanged. The benzodiazepine midazolam (0.1, 0.3 mg/kg) had a similar effect to α-flupenthixol, but treated animals showed a preference for the aversive CS. Parallel results were observed with amphetamine (0.25 mg/kg) and α-flupenthixol (0.125, 0.25 mg/kg) in a matched test of positive conditioned reinforcement, with amphetamine enhancing, and α-flupenthixol reducing, the efficacy of the CS paired with food. Midazolam treatment (0.1–1.0 mg/kg) had no effect on the reinforcing impact of an appetitive CS. Thus dopaminergic agents modulate the behavioural impact of both appetitively and aversively motivated conditioned stimuli on instrumental performance, whilst the benzodiazepine midazolam has a selective impact on aversively-motivated stimuli that is qualitatively distinct from that of the dopaminergic antagonist α-flupenthixol.