Update on narcolepsy.

The last two decades have seen an explosion in our understanding of the clinical nature of narcolepsy and its pathogenesis, fuelling new approaches to potentially effective treatments. It is now recognised that the full narcoleptic syndrome has significant adverse effects on sleep regulation across the full 24-h period and is often associated with clinical features outside the sleep-wake domain. The discovery that most narcoleptic subjects specifically lack a hypothalamic neuropeptide (hypocretin, also called orexin) was a truly original and landmark observation in 1999, greatly furthering our understanding both of the syndrome itself and sleep biology in general. An autoimmune pathophysiology has long been suggested by the tight association with specific histocompatibility antigens and very recently partly confirmed by detailed analysis of T-cell immunological function in affected subjects. Drug treatments remain symptomatic but may soon become more focussed by restoring central hypocretin signalling with replacement therapy. Potentially disease-modifying, immunological approaches have yet to be studied systematically, although the interval between disease onset and development of the full clinical syndrome may be longer than previously appreciated, affording a realistic window of opportunity for limiting neuronal damage in this disabling condition.

Rivastigmine in the treatment of parkinsonian psychosis and cognitive impairment: preliminary findings from an open trial.

This open study assessed the ability of rivastigmine to treat the neuropsychiatric complications of advanced Parkinson's disease. In a group of 12 patients, hallucinations, sleep disturbance, and carer distress were all improved and cognitive performance significantly enhanced by the drug.

CSF antigliadin antibodies and the Ramsay Hunt syndrome.

Although the association between celiac disease and progressive myoclonic ataxia is well recognized, in each of the reported cases the neurologic features began in middle adult life and usually in patients who had clinical or laboratory evidence of malabsorption. We report a case of progressive myoclonic ataxia and epilepsy (Ramsay Hunt syndrome) that began in childhood. In this patient there were no features suggestive of gluten intolerance. The presence of antigliadin antibodies in the serum and CSF suggested celiac disease was the cause of the patient's neurologic syndrome. Duodenal morphologic abnormalities reversed with treatment but no major changes were noted in the patient. Celiac disease should be considered in the differential diagnosis of myoclonic ataxia at any age, even in the absence of clinical evidence of gluten-sensitive enteropathy.

Embryonic striatal grafts reverse the disinhibitory effects of ibotenic acid lesions of the ventral striatum.

Bilateral damage to the ventral striatum induced by the excitotoxin ibotenic acid was found to have profound disinhibitory effects on rats' behaviour. Lesioned animals were unable to acquire efficient levels of performance on an operant schedule (differential reinforcement of low rates of responding, DRL) that required them to inhibit a previously rewarded response. In addition, lesioned subjects were relatively resistant to the disruptive effects of amphetamine on performance of the DRL schedule and were slower to cease responding under conditions of non-reward. A measure of unconditioned behaviour, overnight locomotor activity, was also disinhibited by the presence of the lesion. Grafts of embryonic striatal tissue transplanted to the lesioned ventral striatum were found to survive well. Moreover, the presence of the grafts reversed the effects of the lesion on measures of conditioned and unconditioned behaviour. The nature of the lesion-induced behavioural deficit and the ability of the embryonic transplants to reverse it are discussed in terms of the possible restoration of limbi-subcortical circuitry.

Conditioning versus priming of dopaminergic grafts by amphetamine.

Previous treatment with amphetamine can influence the rotational response induced by amphetamine in rats with dopaminergic grafts. In order to distinguish whether this is due to graft "priming" or conditioning effects of the drug, groups of adult rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra, or with the lesion plus grafts of embryonic mesencephalic tissue in the striatum, were exposed to either: (1) amphetamine in the test environment and saline in the home cage; (2) saline in the test environment and amphetamine in the home cage; or (3) saline in the test environment and saline in the home cage. During this conditioning stage of the experiment, rats with the lesion alone rotated ipsilaterally and rats with the lesion plus grafts contralaterally when tested after administration of amphetamine. The rotation sensitized, i.e. the rats with lesions made more ipsilateral and the rats with grafts more contralateral turns, with repeated injections of the drug. On a subsequent no-drug test, only the rats with grafts which had previously experienced amphetamine in the test environment (1) showed conditioned contralateral rotation. Rats with grafts which had received the same number of amphetamine injections, but experienced the effects of the drug in the home cage (2), rotated ipsilaterally on the no-drug test to the same extent as rats with grafts which had received only saline (3). Thus, amphetamine treatment per se did not "prime" grafts. Rather, the response of the rats with grafts was the result of formation of a conditioned association between the amphetamine and the environment with which it had been paired.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrastriatal dopamine-rich grafts induce a hyperexpression of Fos protein when challenged with amphetamine.

The aim of the present experiment was to characterize the effect of intrastriatal grafts of embryonic dopaminergic neurones on the expression of Fos protein in the striatum when challenged with amphetamine. Unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway were made in adult rats and grafting was performed 3 weeks later. The numbers of Fos-positive nuclei in the ipsi- and contralateral striata were counted on coronal sections following immunohistochemical staining 5 months after grafting. Administration of d-amphetamine induced an increase in the density of Fos-positive nuclei in the intact striatum. This stimulatory effect of amphetamine on c-fos expression was blocked by 6-hydroxydopamine hydrobromide lesions and was restored in the striata bearing transplants. However, an overshoot was observed as the density of Fos-positive cells within the grafted striatum was larger than that observed within the intact striatum. This hyperexpression of Fos-positive nuclei was correlated with the exaggerated compensation of amphetamine-induced rotation in the same animals.

The effects of excitotoxic lesions of the nucleus accumbens on a matching to position task.

The effects of bilateral ibotenic acid lesions of the nucleus accumbens in the rat were examined on a delayed matching to position task. The lesion induced a stable delay-dependent performance deficit suggestive of a short-term memory problem. Following analysis of the impaired performance on trials with long delays, using measures akin to signal detection indices, the deficit was interpreted as being largely due to the intrusion of a side-dependent response bias. Low-dose amphetamine (0.75 mg/kg) produced a similar disruption in the sham-operated rats, both in terms of accuracy impairment and degree of strategical bias. As well as mimicking the effects of low-dose amphetamine in sham-operated rats, the lesion also protected against the disruptive effects of the drug at low doses. Whilst exhibiting no performance deficit when the matching schedule lacked a delay component, the lesioned rats were very significantly impaired in switching their response strategies when exposed to a series of reversals. In addition, the lesioned rats were remarkably resistant to an extinction procedure. Both these findings indicate that the lesioned rats were unable to exhibit flexibility in their response patterns. These results, taken together with those of the delayed matching procedure, imply that one of the functions of the intact nucleus accumbens is to inhibit habitual responding under conditions of non-reward and low stimulus control, possibly via its connections to the dorsal striatal system.

Dissociable roles of the ventral, medial and lateral striatum on the acquisition and performance of a complex visual stimulus-response habit.

The effects of discrete bilateral ibotenic acid lesions to 3 areas of striatum were examined on a conditional visual discrimination task involving temporal frequency (SLOW vs FAST flashes) that had previously been shown to be sensitive to the effects of dorsal striatal dopamine depletion. Two of the groups, namely, those with nucleus accumbens (ACC) and lateral caudate-putamen (LCP) lesions, were very disrupted in the acquisition of the task. The nature of the respective impairments of the 2 groups was dissociable, however. The performance of the ACC group could be improved either by manipulations of stimulus duration or inter-stimulus interval, implying an attentional deficit. In contrast, the rats with lesions of the LCP were not significantly improved by any of the behavioural challenges. Their performance was characterised by a bias to respond to the SLOW discriminandum. Under conditions of non-reward, the LCP group extinguished their responding at a similar rate to control rats whereas the ACC group were very much more persistent. Lesions of the medial caudate-putamen failed to affect any index of performance significantly. These data suggest that the LCP is necessary for the acquisition of arbitrary stimulus-response rules and that damage to an equivalent area in humans, such as in Huntington's disease, may explain deficits of procedural memory. The second part of the experiment investigated the effects of ACC lesions on established performance of the schedule. The lesioned group behaved identically to the ACC group that had been lesioned prior to acquisition, both in terms of accuracy and degree of persistence in extinction, further implying the role of attentional factors and inflexibility in the lesion-induced deficit.

Frontal lobe dysfunction in schizophrenia and Parkinson's disease--a meeting point for neurology, psychology and psychiatry: discussion paper.

The psychotic features of schizophrenia and the motor problems of Parkinson's disease, respectively, allow striking contrasts to be made between the two disorders. However, it has recently become apparent that the two groups of patients share problems of mentation that are best explained by some dysfunction of the prefrontal cortical areas of the brain. These commonalities are addressed in terms of neurobiological fact and psychological theory, providing possible insight into the neuropsychology of schizophrenia and its dichotomous nature. In particular, the putative role of abnormal frontostriatal interactions in the two disease states is emphasized.