Showing papers by "Trevor W. Robbins published in 1992"

Fronto-striatal cognitive deficits at different stages of parkinson's disease

Abstract: Groups of patients with idiopathic Parkinson's disease, either medicated or unmedicated, were compared with matched groups of normal controls on a computerized battery previously shown to be sensitive to frontal lobe dysfunction, including tests of planning, spatial working memory and attentional set-shifting. In a series of problems based on the 'Tower of London' test, medicated patients with Parkinson's disease were shown to be impaired in the amount of time spent thinking about (planning) the solution to each problem. Additionally, an impairment in terms of the accuracy of the solution produced on this test was only evident in those patients with more severe clinical symptoms and was accompanied by deficits in an associated test of spatial short-term memory. Medicated patients with both mild and severe clinical symptoms were also impaired on a related test of spatial working memory. In contrast, a group of patients who were unmedicated and 'early in the course' of the disease were unimpaired in all three of these tests. However, all three Parkinson's disease groups were impaired in the test of attentional set-shifting ability, although unimpaired in a test of pattern recognition which is insensitive to frontal lobe damage. These data are compared with those previously published from a group of young neurosurgical patients with localized excisions of the frontal lobes and are discussed in terms of the specific nature of the cognitive deficit at different stages of Parkinson's disease.

L-dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction

Abstract: A group of ten patients with idiopathic Parkinson's disease (PD) was tested on a series of automated tests of learning, memory, planning and attention whilst either on or off L-dopa medication Controlled withdrawal of L-dopa interfered with aspects of performance on three of the tests that had previously been shown to be sensitive to frontal lobe dysfunction; a spatial working memory task, the Tower of London planning test, and a visual discrimination paradigm that also included intra- and extra-dimensional shift tests of selective attention More specifically, errors were increased in the spatial working memory test, and both the accuracy and latency of thinking were impaired Thinking time was significantly slowed following L-dopa withdrawal, even though the possible contaminating effects on motor slowing were fully controlled by a yoked control procedure Nine out of ten patients reached a further stage of the visual discrimination, set-shifting paradigm when on, rather than off, L-dopa medication Spatial span was also impaired off medication, but there were no effects of L-dopa withdrawal on tests of pattern and spatial recognition memory, simultaneous and delayed matching to sample or visuospatial conditional associative learning Comparisons with a large control group confirmed previous findings that PD is associated with deficits on the majority of these tests The results are discussed in terms of the fronto-striatal, dopamine dependent nature of some of the cognitive deficits found in PD, but the apparent dopamine-independent nature of deficits in other aspects of cognitive functioning, notably in tests of visual recognition memory and associative learning

Dopaminergic and serotonergic function following isolation rearing in rats: study of behavioural responses and postmortem and in vivo neurochemistry.

Abstract: This series of experiments compared isolation-reared and socially reared rats for their locomotor activity, behavioural stereotypy, and monoamine function both postmortem and in vivo using intracerebral dialysis In Experiment 1, isolates showed an altered time course of locomotor activity following d-amphetamine sulphate (AMPH) administration (05, 20, 30, or 50 mg/kg, SC) Isolation-reared rats also showed increased sensitivity to the sedative effects of a low dose of apomorphine hydrochloride (01 mg/kg) but did not differ from social controls following higher doses of the drug (05, 15, or 30 mg/kg, SC) Isolates showed a decrease in the intensity of apomorphine-induced stereotyped behaviours but no change in stereotypy induced by AMPH In Experiment 2, isolates had higher postmortem dopamine (DA) concentrations and an altered asymmetry in DA function in the medial prefrontal cortex (PFC) but not in the nucleus accumbens (NAC) or caudate putamen (CPu) Isolated rats also had a lower 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the NAC (but not in the PFC or CPu) compared to controls Experiment 3 used intracerebral dialysis to examine monoamine function in vivo following isolation rearing Isolates showed greater increases in extracellular DA and greater decreases in DOPAC in response to 2 mg/kg AMPH SC in both the NAC and CPu There were no apparent differences in the perfusate concentrations of either dopamine (DA), dihydroxyphenylacetic acid (DOPAC), or homovanillic acid (HVA) prior to drug administration However, consistent with the results of Experiment 2, isolates had a reduced basal perfusate concentration of 5-HIAA from the NAC but not from the CPu Experiment 4 measured postsynaptic DA function in CPu tissue slices following isolation Isolation rearing did not affect cAMP accumulation in response to stimulation of D1 DA receptors by DA (0, 27, 9, or 30 microM) In addition, isolation rearing did not affect the coupling between D1 and D2 receptors, as measured by the increase in cAMP accumulation with 1 microM 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepin (SK&F 38393) and its reduction by 10 microM quinperole hydrochloride (LY 171555) These results are discussed in terms of the possible relationship between these neurochemical findings and the behavioural disturbances following isolation rearing of rats

Attentional functions of the forebrain cholinergic systems: effects of intraventricular hemicholinium, physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction time task.

Abstract: Degeneration of the cholinergic magnocellular neurons in the basal forebrain and their cortical projections is a major feature of the neuropathology of Alzheimer's disease. In the present study, two experiments examined the disruptive effects on visual attentional performance of two different manipulations that reduce central cholinergic function. In Expt. I, pharmacological manipulation of the cholinergic system was investigated using icv administration of hemicholinium (HC-3), a 9high affinity choline uptake blocker, administered either alone or in conjunction with the anticholinesterase, physostigmine. The results revealed impairments in the ability of the rats to localize brief visual targets in a serial reaction time task, as shown in particular by a reduction in choice accuracy and lengthening of the latency to respond correctly to the visual stimulus. Cholinergic specificity was supported by the reversal of these behavioural impairments by pre-treatment with the anticholinesterase, physostigmine. In Expt. II, quisqualateinduced lesions of the basal forebrain produced behavioural deficits at 3 weeks post-lesion surgery similar to those observed following icv infusion of HC-3. In an attempt to restore the extrinsic cortical cholinergic innervation by reinnervation of the deafferented cortex, embryonic basal forebrain cholinergic cells were transplanted into the cortex of lesioned animals. After three months recovery, impairments in performance on the baseline schedule of the task were no longer apparent in lesioned animals. However, behavioural deficits, observed predominantly as a lengthening of correct response latency, could be reinstated in the lesioned animals by interpolation of distracting bursts of white noise during each trial, and this deficit was ameliorated by the cholinergic grafts. Furthermore, a non-specific effect of both cholinergic and non-cholinergic grafts in controlling the increase in perseverative time-out responses which occurred as a result of the basal forebrain lesion was consistently observed. These results suggest that cholinergic dysfunction can produce deficits in visual attention which can be ameliorated by cholinergic treatments such as physostigmine or cholinergic-rich cortical grafts. These data provide support for a role for the basal forebrain-neocortical cholinergic projection in attentional function.

Cognitive performance in multiple system atrophy

Abstract: The cognitive performance of a group of patients with multiple system atrophy (MSA) of striato-nigral predominance was compared with that of age and IQ matched control subjects, using three tests sensitive to frontal lobe dysfunction and a battery sensitive to memory and learning deficits in Parkinson's disease and dementia of the Alzheimer type. The MSA group showed significant deficits in all three of the tests previously shown to be sensitive to frontal lobe dysfunction. Thus, a significant proportion of patients from the MSA group failed an attentional set-shifting test, specifically at the stage when an extra-dimensional shift was required. They were also impaired in a subject-ordered test of spatial working memory. The MSA group showed deficits mostly confined to measures of speed of thinking, rather than accuracy, on the Tower of London task. These deficits were seen in the absence of consistent impairments in language or visual perception. Moreover, the MSA group showed no significant deficits in tests of spatial and pattern recognition previously shown to be sensitive to patients early in the course of probable Alzheimer's disease and only a few patients exhibited impairment on the Warrington Recognition Memory Test. There were impairments on other tests of visual memory and learning relative to matched controls, but these could not easily be related to fundamental deficits of memory or learning. Thus, on a matching-to-sample task the patients were impaired at simultaneous but not delayed matching to sample, whereas difficulties in a pattern-location learning task were more evident at its initial, easier stages. The MSA group showed no consistent evidence of intellectual deterioration as assessed from their performance on subtests of the Wechsler Adult Intelligence Scale (WAIS) and the National Adult Reading Test (NART). Consideration of individual cases showed that there was some heterogeneity in the pattern of deficits in the MSA group, with one patient showing no impairment, even in the face of considerable physical disability. The results show a distinctive pattern of cognitive deficits, unlike those previously seen using the same tests in patients with Parkinson's and Alzheimer's diseases, and suggesting a prominent frontal-lobe-like component. The implications for concepts of 'subcortical' dementia and 'fronto-striatal' cognitive dysfunction are considered.

The functional role of mesotelencephalic dopamine systems

Abstract: ( I ) Sensorimotor test batteries and neglect . . . . . . . . (2) Sensorimotor interpretations of eating and rotation deficits . . , . V. Cognitive effects of neostriatal and dopaminergic lesions . . . . . . . . . . . ( I ) Response initiation following nigrostriatal lesions . . . . . . (2) Response switching and incentive motivation following ventral striatal lesions . . . . . . . . . . . . . . . . . . IX. References . . . . . . . . . . . . . . 111. Motivational effects of hypothalamic and dopaminergic lesions . . .

Striatal Graft‐Associated Recovery of a Lesion‐Induced Performance Deficit in the Rat Requires Learning to Use The Transplant

Abstract: Peformance in a prelearned choice reaction time task was studied 6 months after surgery in rats with ibotenate-induced lesions of the striatum either with or without striatal grafts, and in sham-operated controls. The long postoperative interval allowed full transplant maturation and the establishment of appropriate connections by the transplants. The animals were trained prior to surgery on a visual choice reaction time task which requires that a movement is made away from stimuli signalling reward. The use of multiple measures allowed a thorough analysis of several aspects of the animals' performance. Whilst sham-operated control animals recovered normal (preoperative) performance rapidly, the lesioned animals had a severe performance deficit. Although the transplanted animals were initially at least as deficient in performance as the lesioned group, repeated testing led to an amelioration of the lesion-induced deficit according to two distinct measures of spatial bias and reaction time. On a third measure, latency to complete the lateralized movement, the grafted group were initially worse than the lesioned group but repeated testing resulted in significant recovery. These results suggest that postoperative training may help to optimize the efficacy of graft-induced recovery, and that animals may need to learn to use a transplant in order for it to confer functional benefit in complex prelearned tasks.

Differential effects of mesocortical, mesolimbic, and mesostriatal dopamine depletion on spontaneous, conditioned, and drug-induced locomotor activity

Abstract: Groups of rats with 6-hydroxydopamine (6-OHDA) lesions of either the medial prefrontal cortex (PFC), nucleus accumbens (NAC), or caudate putamen (CPu) were given daily tests for locomotor activity in photocell cages while food deprived. Two separate groups of NAC-lesioned rats were prepared with either large [NACT (90% NAC dopamine depletion)] or partial [NACP (67% NAC dopamine depletion)] lesions. NACT rats were spontaneously hypoactive whereas NACP rats were hyperactive compared with sham-operated controls. PFC-lesioned rats were also hyperactive compared to their respective controls. Spontaneous locomotor activity in CPu-lesioned rats did not differ from shams. When daily food supplements were paired with the photocell cages, all subjects developed a conditioned locomotor response. During the first few days of conditioning, the response to this conditioning procedure was markedly greater in the NACP group whereas the response in the NACT group was unaffected initially and actually enhanced during the latter days of testing. the locomotor response to the conditioning procedure was unaffected in either the PFC- or CPu-lesioned groups. Both the NACT and NACP lesions attenuated the locomotor response to 1.5 mg/kg d -amphetamine sulphate IP, and the NACT group showed a supersensitive response to 0.1 mg/kg apomorphine HCl SC. PFC or CPu 6-OHDA lesions did not alter the response to either drug. These results differentiate the role of PFC, NAC, and CPu dopamine in spontaneous, conditioned, and drug-induced locomotor activity and further implicate dopaminergic mechanisms of the NAC in the magnitude of the behavioral response to incentive stimuli.

Disruptive effects of muscimol infused into the basal forebrain on conditional discrimination and visual attention: differential interactions with cholinergic mechanisms

Abstract: The behavioural effects of GABAergic manipulation of the basal forebrain were investigated using two behavioural tasks, which previous studies have shown to yield dissociable effects following quisqualate-induced lesions of the basal forebrain: a five-choice serial reaction time task, involving approaching the location of a brief visual stimulus that is associated with reward; and a conditional visual discrimination task, requiring retrieval of information about a discriminative stimulus that stays constant over time. Following acquisition of the tasks, chronic guide cannulae were stereotaxically implanted into the basal forebrain. Those animals trained on the conditional visual discrimination task showed a dose-dependent reduction in choice accuracy and a lengthening of latency to respond correctly to the visual stimulus following administration of the GABA-A agonist, muscimol (1, 2, 3 ng/µl/hem). While certain of these deficits, for example response latency, could be restored to control levels by co-administration of the GABA-A antagonist, bicuculline, none of the behavioural impairments could be significantly attenuated by systemic co-administration of the cholinesterase inhibitor, physostigmine (0.05, 0.1, 0.2 mg/kg, IP). Similarly, a dose dependent effect of muscimol (1, 1.5, 2 ng/µl/hem) on choice accuracy and correct response latency was observed on performance of the five-choice attentional task. However, in contrast to the conditional task, significant attenuation of the impairment in choice accuracy was obtained following administration of physostigmine (0.05 and 0.1 mg/kg). Attenuation of muscimol-induced deficits by administration of bicuculline was also observed. It is therefore evident that although manipulation of GABAergic activity in the region of the basal forebrain produces profound deficits in different tasks of cognitive function, only some of these may be due to modulation of the magnocellular cholinergic projection to the neocortex.

Does visuospatial memory in senile dementia of the Alzheimer type depend on the severity of the disorder

Abstract: Visuospatial memory was studied in patients suffering from senile dementia of the Alzheimer type (SDAT). They had been allocated into one of two groups depending on the severity of their disorder (mild or moderate), and a control group of healthy elderly subjects was included. Three different microcomputer-controlled tasks were used. The spatial span task was able to distinguish between the two SDAT groups. Both groups were impaired, relative to control, on spatial recognition. The deficit in spatial working memory was also equivalent in the mild and moderate groups and was accompanied by evidence of an intact strategic approach to the task. The normal positive relationship between spatial memory performance and strategy was in fact reversed in the SDAT groups, suggesting a pure spatial memory deficit. These results show that spatial memory processes are impaired in the early stages of SDAT and get worse as the disease progresses. They also suggest that the neuroanatomical foci of the deficits may be predominantly in posterior cortical regions (including hippocampus), rather than the frontal cortex.

Diencephalic Noradrenaline Depletion Impairs the Corticosterone Response to Footshock but does not Affect Conditioned Fear

Abstract: This study tested the hypothesis that hypothalamic noradrenaline (NA) depletion induced by 6-hydroxydopamine alters neuroendocrine, but not behavioural, responses to aversive stimuli. Sham-operated and NA depleted rats were exposed to pairings of an auditory (clicker) CS and (footshock) US in a distinctive environment. Subjects were tested for preference of a 'safe' environment over the one in which they were shocked, as a measure of effective conditioning to the contextual stimuli present in the distinctive environment. Subjects were also tested, in a separate operant chamber, for the suppression of drinking in the presence of the auditory stimulus, as a measure of effective conditioning to the explicit auditory CS. Blood samples were collected immediately following each phase of the behavioural experiment and were later analysed for plasma Corticosterone concentration. Behavioural and Corticosterone responses of individual control animals to the CS were positively correlated, consistent with previous results. This correlation was not present in the NA depleted group. The lesioned rats also showed a severely attenuated Corticosterone response to the footshock US. By contrast, NA depletion had no effect on any behavioural measure of CS or contextual conditioning. Together with previous experiments, these results suggest that diencephalic NA projections are more likely to mediate neuroendocrine, and coeruleo-cortical NA projections are more likely to mediate behavioural responses to conditioned and unconditioned aversive stimuli.

Visuell-räumliches Gedächtnis bei Alzheimer-Demenz und Parkinson-Krankheit

Abstract: Die Alzheimer-Demenz ist durch eine globale Beeintrachtigung verschiedener kogniti-ver Funktionen gekennzeichnet (Rossor 1982). Auch ein betrachtlicher Teil der Patien-ten mit Parkinson-Krankheit zeigt kognitive Defizite in unterschiedlichem Ausmas und Demenz (Brown u. Marsden 1984). Es besteht eine bemerkenswerte Uberlappung hinsichtlich der neuropathologischen und neurochemischen Veranderungen bei Alzheimer- und Parkinson-Krankheit (Whitehouse 1986). Das legt einen systemati-schen Vergleich der kognitiven Veranderungen bei diesen Erkrankungen nahe. In der vorliegenden Studie wurden visuell-raumliche Gedachtnisdefizite bei Alzheimer- und Parkinson-Patienten untersucht.