Cross-modal matching and the primate frontal cortex.

Rhesus monkeys with selective lesions of the prefrontal system were tested on a tactile-visual cross-modal matching task. Monkeys with lesions in the banks and depths of the arcuate sulcus were impaired, while normal controls and monkeys with lesions in the banks and depths of the sulcus principalis and in the anterodorsal part of the head of the caudate nucleus were not.

Postponement of satiety by blockade of brain cholecystokinin (CCK-B) receptors.

Exogenous cholecystokinin (CCK) decreases food intake and causes satiety in animals and man. However, it has not been established that endogenous CCK causes satiety or whether the response is mediated by peripheral-type (CCK-A) or brain-type (CCK-B) receptors. The development of potent and selective antagonists for CCK-A (MK-329) and CCK-B (L-365,260) receptors now allows these issues to be addressed. The CCK-A antagonist MK-329 and the CCK-B antagonist L-365,260 increased food intake in partially satiated rats and postponed the onset of satiety; however, L-365,260 was 100 times more potent than MK-329 in increasing feeding and preventing satiety. These results suggest that endogenous CCK causes satiety by an agonist action on CCK-B receptors in the brain.

Tail-pinch stimulation: sufficient motivation for learning.

A paper clip applied to the tails of rats induced gnawing and eating, which decreased in latency and increased in duration with experience. With sustained pressure to the tail, rats learned a new habit in order to gain access to wood chips on which to gnaw. That these are also properties of behavior elicited by electrical brain stimulation suggests that both manipulations may act through the same mechanism. These results support the hypothesis that a nonspecific arousing stimulus can be a sufficient condition for establishing learned habits.

Selective extraction of small and large molecules from the cerebrospinal fluid by Purkinje neurons.

Cerebellar Purkinje neurons accumulated propidium iodide, granular blue, and horseradish peroxidase conjugated to wheat germ agglutinin but not unconjugated horseradish peroxidase, bisbenzimide, or Evans blue when these compounds were infused into the lateral cerebral ventricles of awake, unrestrained rats. Accumulation of propidium iodide by Purkinje neurons of the vermis was associated with a reproducible behavioral abnormality characterized by truncal tremor, ataxia, and nystagmus. Both the accumulation of propidium iodide in Purkinje cells and the behavioral abnormality were prevented by prior intracerebroventricular administration of ouabain or colchicine, drugs that block neuronal transport processes. The ability of cerebellar Purkinje neurons to extract small and large molecules from the cerebrospinal fluid has important implications for their physiology and pathology.

Nigral transplants reinnervating the dopamine-depleted neostriatum can sustain intracranial self-stimulation.

Transplants of embryonic substantia nigra reinnervated the striatum and were able to sustain intracranial self-stimulation in rats with brain lesions induced by 6-hydroxydopamine. Dopaminergic drugs and alterations in current intensity produced typical changes in response rates. Animals with electrodes implanted into cortical grafts or into the denervated striatum failed to exhibit self-stimulation. These findings suggest that transplanted dopamine neurons convey specific, temporally organized information axonally to the striatum.

Substance P analog, DiMe-C7: evidence for stability in rat brain and prolonged central actions.

A metabolically protected analog of substance P, [pGlu5-MePhe8-MeGly9]SP(5-11) (DiMe-C7), was approximately equipotent with substance P in causing increased locomotor activity after microinfusion into the ventral tegmental area of rat brain, but the effects of DiMe-C7 on behavior were considerably prolonged. There was little metabolic degradation of tritiated DiMe-C7 for up to 1 hour after infusion, whereas tritiated substance P was completely degraded within 10 minutes.

Activation of auditory cortex during silent lipreading.

Watching a speaker's lips during face-to-face conversation (lipreading) markedly improves speech perception, particularly in noisy conditions. With functional magnetic resonance imaging it was found that these linguistic visual cues are sufficient to activate auditory cortex in normal hearing individuals in the absence of auditory speech sounds. Two further experiments suggest that these auditory cortical areas are not engaged when an individual is viewing nonlinguistic facial movements but appear to be activated by silent meaningless speechlike movements (pseudospeech). This supports psycholinguistic evidence that seen speech influences the perception of heard speech at a prelexical stage.

Crossmodal identification.

Everyday experience involves the continuous integration of information from multiple sensory inputs. Such crossmodal interactions are advantageous since the combined action of different sensory cues can provide information unavailable from their individual operation, reducing perceptual ambiguity and enhancing responsiveness. The behavioural consequences of such multimodal processes and their putative neural mechanisms have been investigated extensively with respect to orienting behaviour and, to a lesser extent, the crossmodal coordination of spatial attention. These operations are concerned mainly with the determination of stimulus location. However, information from different sensory streams can also be combined to assist stimulus identification. Psychophysical and physiological data indicate that these two crossmodal processes are subject to different temporal and spatial constraints both at the behavioural and neuronal level and involve the participation of distinct neural substrates. Here we review the evidence for such a dissociation and discuss recent neurophysiological, neuroanatomical and neuroimaging findings that shed light on the mechanisms underlying crossmodal identification, with specific reference to audio-visual speech perception.

Direct comparison of cognitive facilitation by physostigmine and tetrahydroaminoacridine in two primate models.

Cognitive facilitation by physostigmine and tetrahydroaminoacridine (THA) was compared in two primate models. Disruption of spatial delayed response performance by scopolamine (0.03 mg/kg) was fully reversed by coadministration of 5 doses of physostigmine in the range 0.03-0.08 mg/kg, but by only one dose (4.0 mg/kg) of THA; partial reversal of some effects of scopolamine was observed at 1 and 3 mg/kg of THA. Visual recognition memory was enhanced following treatment with 4 doses of physostigmine in the range 0.001-0.03 mg/kg. The effect of THA across the group of animals was not significant but performance tended to improve using a dose of 0.8 mg/kg. Our findings indicate that THA does not have a superior profile to physostigmine as a cognitive enhancer in primates.

A neuropsychological investigation of prefrontal cortex involvement in acute mania.

OBJECTIVE: Mania has received little attention from a contemporary neuropsychological perspective despite its clear resemblance to the disinhibition syndrome sometimes seen after frontal brain injury, particularly injury to the inferior aspect of the prefrontal cortex. The purpose of this investigation was to describe the neuropsychological profile of severe acute mania by using a range of tasks selected primarily for the detection of localized neural disruption within the prefrontal cortex. METHOD: Fifteen acutely manic inpatients were compared with 30 nonpsychiatric subjects on tasks from the Cambridge Automated Neuropsychological Test Battery (Tower of London, spatial working memory, intradimensional-extradimensional attentional shift, and rapid visual information processing tasks) and on the Iowa Gambling Task, Stroop Color and Word Test, a verbal fluency task, and the California Verbal Learning Test. RESULTS: Discriminant function analysis identified deficits in sustained attention (on the rapid visual information processing task) and verbal learning (on the California Verbal Learning Test) as the best indicators of manic performance, rather than deficits on any of the tests of executive functioning. The model correctly classified 91% of subjects overall and 87% of manic subjects. Manic patients did not resemble patients with ventromedial prefrontal cortex damage in their performance on the Iowa Gambling Task. CONCLUSIONS: Acute mania is characterized by core deficits in verbal memory and sustained attention against a background of milder impairments in functions that are traditional measures of prefrontal cortex integrity (attentional set shifting, planning, working memory). The data do not implicate ventral prefrontal cortex disruption as a locus of pathology in acute mania. Verbal memory and sustained attention deficits may relate differentially to the state and trait characteristics of bipolar disorder.

Differential effects of D1 and D2 agonists in MPTP-treated primates: functional implications for Parkinson's disease.

Administration of the indirect agonist L-dopa, the nonselective direct agonist apomorphine, or the selective D2 agonist (+)-PHNO, reversed parkinsonism and induced locomotor activation in MPTP-treated squirrel monkeys. In contrast, administration of the selective partial D1 agonist SKF38393 did not induce locomotor activity, but rather decreased activity. Choreiform movements were observed only following treatment with L-dopa. Coadministration of the D1 antagonist SCH23390 prevented L-dopa-induced chorea at the time of peak effect. However, a rebound exaggeration of chorea was observed following SCH 23390 at the time when chorea induced by L-dopa alone would normally be subsiding. Unlike chorea, dystonia could be induced by treatment with either L-dopa or (+)-PHNO. Administration of apomorphine failed to significantly induce dystonia, although a small increase was observed with the highest dose. Treatment with SKF38393 actually decreased dystonia. Our findings clearly indicate that D2 receptor stimulation appears essential for antiparkinsonian activity, and also implicate D2 receptors in the genesis of dystonia, but not chorea. D1 receptor stimulation appears to be involved in the genesis of chorea and possibly also dystonia.

CCK-8S inhibits L-dopa-induced dyskinesias in parkinsonian squirrel monkeys.

Systemic administration of CCK-8S (1 or 10 micrograms/kg IP) markedly inhibited L-dopa-induced dyskinesias in parkinsonian monkeys, but did not interfere with locomotor stimulation by L-dopa. CCK analogues may be useful antidyskinetic agents for improved control of Parkinson's disease.

Antiparkinsonian efficacy of a novel transdermal delivery system for (+)-PHNO in MPTP-treated squirrel monkeys.

We examined the ability of the antiparkinsonian agent (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) to enter the systemic circulation in therapeutic concentrations after continuous transdermal absorption in squirrel monkeys rendered parkinsonian by MPTP. Direct subcutaneous administration of (+)-PHNO in the dose range of 2.5 to 20 micrograms/kg restored locomotor activity to levels seen in normal monkeys for approximately 1 hour. Application of transdermal patches capable of delivering, into an infinite sink, an estimated 2.6 micrograms/cm2/h of (+)-PHNO over a skin surface area of 4.78 to 19.12 cm2 also restored locomotor activity to the normal range during a 24-hour period. We suggest the use of transdermal application of PHNO as a novel drug delivery system for the improved management of Parkinson's disease.

Functional organization of striatum as studied with neural grafts.

The function of the striatum has proved elusive. A structure which, at the gross microscopic level, appears homogeneous is now revealed to be heterogeneous in terms of its afferent and efferent relationships with cortex, limbic system and mid brain. Cerebral cortex projects topographically to caudate/putamen. Lesions to different cortical areas result in different behavioural impairments which are mirrored by selective neuronal or neurochemical lesions to the sectors of striatum receiving input from the cortex. Foetal neurones prepared from substantia nigra or striatum grafted to a damaged area of adult striatum reverse the lesion-induced behavioural impairments. Within different sectors of striatum the neurones and their afferent and efferent connections are defined to striosomes and matrix representing a finer grain of intrastriatal organization, the functional significance of which is unclear. It remains a challenge within such complex anatomical circuitry to discover the full extent of anatomical reintegration and functional compensation that can be achieved with grafts of foetal neurones.

Cognitive impairment in schizophrenia: how experimental models using nonhuman primates may assist improved drug therapy for negative symptoms.

Antipsychotic drugs provide effective relief from hallucinations but do not improve, and may even induce, other symptoms of schizophrenia. Tardive dyskinesia, which is often associated with intellectual impairment, is generally attributed to chronic therapy with antipsychotic drugs. However, the possible contribution of medication to cognitive impairment is not easily dissociated from the underlying progression of the disease. Recently evidence has accumulated from studies performed in patients and experimental monkeys that augmentation of catecholamine function may improve performance on certain cognitive tasks. Further investigation of the role of catecholamines in cognition is warranted in order to assist development of antipsychotic drugs with fewer undesirable effects and entirely new approaches to therapy for cognitive impairment in schizophrenia.

Hemifield-specific visual recognition memory impairments in patients with unilateral temporal lobe removals.

Recent evidence on visual neglect suggests that each hemisphere maintains a retinotopically organized representation of the visual world contralateral to the current fixation point and that this representation is based not only on analysis of the current retinal input but, equally importantly, on information retrieved from memory. This idea predicts that unilateral damage to memory systems should produce a lateralized impairment of memory for the retinotopically contralateral visual world. To test this prediction we examined visual recognition memory performance in the left and right visual hemifields of patients who had undergone partial unilateral temporal lobe removals for the relief of epilepsy, either in the left hemisphere (n = 5) or the right (n = 5). The patients were given complex artificial scenes to remember, constructed of independent left and right halves, and were then tested for recognition of the left and the right halves separately. Stimuli were exposed tachistoscopically throughout and fixation was maintained on a central position. Patients made significantly more errors with half-scenes in the hemifield contralateral to their removal than in the ipsilateral hemifield, an increase of 50% in the error rate on average. The effect was seen equally in patients with left and right removals. This finding supports the idea that visual memory retrieval is retinotopically organized.

Substance-P antagonists: effect on spontaneous and drug-induced locomotor activity in the rat.

The substance P (SP) antagonists (D-Pro4, D-Trp7,9, Leu11) SP(4-11), (D-Pro4, D-Trp7,9, Phe11)SP(4-11) and (D-Pro4, D-Trp7,9,10, Leu11) SP (4-11) were infused into the lateral ventricles (i.c.v.) and their effects on spontaneous and drug-induced locomotor activity were investigated. The drug DiMeC7, the stable substance P agonist, was used to stimulate locomotor activity because of its prolonged action. Only (D-Pro4, D-Trp7,9,10) SP (4-11) was found to attenuate the drug-induced increases in motor activity, indicating that it is a substance P antagonist with activity in the CNS.

Spontaneous and drug-induced rotation following localized 6-hydroxydopamine and kainic acid-induced lesions of the neostriatum.

Twelve groups of rats received small localized lesions produced by either 6-hydroxydopamine (6-OHDA) or kainic acid (KA) in one of six placements in the right neostriatum. All groups lesioned with 6-OHDA showed ipsilateral spontaneous and amphetamine-induced rotation and contralateral apomorphine-induced rotation. All groups lesioned with kainic acid showed ipsilateral spontaneous rotation on day 1 following the lesion but contralateral rotation by day 8, and no significant rotation to injections of either amphetamine or apomorphine. The histology suggested that the lesions were topographically specific, and it is therefore concluded that the neostriatum is topographically homogeneous in the mediation of rotational behaviour as measured in automated rotometers.

An interactive 24-channel event-logging system based on the AIM 65 single-board microcomputer.

Measures of the spontaneous behaviour of animals commonly involve the repetitive counting of behavioural events over successive periods of time following some experimental treatment. An automated event-logging system has been designed for such applications. The system is based on an AIM 65 microcomputer with 4 Kbytes of random-access memory and facilities for manual event-logging through the keyboard, or automatic logging via a signal-conditioning buffer, connected to the backplane connector of the computer. The control program is written in 6500 machine code and stored in an onboard, read-only, memory chip. The software generates a simple interactive dialogue for the selection of operating options which include manual or automatic modes, configuration of active channels, duration and number of logging cycles, and the choice of printed or transmitted output. The microcomputer can also be instructed to pause and then to restart, to print out its current status, or to abort. The system has been used over a period of 18 months in numerous experiments in this laboratory, and has proved to be reliable, accurate and entirely suited to its application.

Effect of injections of 6-OHDA into either nucleus accumbens septi or frontal cortex on spontaneous and drug-induced activity.

The effect of injections of 6-hydroxydopamine (6-OHDA) into either frontal cortex (FCx) or nucleus accumbens (NAS) on spontaneous, amphetamine and apomorphine photocell cage activity was studied. Both lesions groups had significant noradrenaline depletion in frontal cortex but only the FCx group had significant dopamine depletion in frontal cortex. Whereas NAS 6-OHDA rats exhibited enhanced apomorphine- and decreased amphetamine-activity there were no differences in activity of the FCx group. 6-OHDA NAS rats also exhibited spontaneous hypoactivity on the third but not the seventh post-operative day; there were no differences in spontaneous activity on either days in the FCx group. In 1975 Kelly, Seviour and Iversen demonstrated that destruction of forebrain dopaminergic terminals induced with injection sof 6-hydroxydopamine (6-OHDA) into the nucleus accumbens septi (NAS) attenuated the locomotor response to 1.5 mg/kg d-amphetamine without affecting stereotypy seen at 5.0 mg/kg. In addition, these rats exhibited an enhanced locomotor response to the dopamine receptor agonist apomorphine, an effect thought to reflect receptor supersensitivity induced by dopamine denervation (Ungerstedt, 1971). Biochemical assay data revealed that dopamine levels were significantly reduced both in nucleus accumbens septi (NAS) and olfactory tubercle (OT) but not neostriatum; thus it was concluded that amphetamine- and apomorphine-induced locomotor activity is mediated by the mesolimbic dopamine system. Since then it has become clear that the A10 group of dopamine (DA) cells bodies in the ventral tegmental area (VTA), give rise to dopamine fibres which innervate not only NAS and OT, but also frontal cortex (Bjorklund and Lindvall, 1978).(ABSTRACT TRUNCATED AT 250 WORDS)