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A computational model of programmed cell death (PCD) in the nervous system is described. A neurobiologically realisable method for identifying and removing the least useful cells from a network is developed, and it is shown by simulation that an artificial neural network can solve difficult problems efficiently if it is given more neurons initially than it needs subsequently. The least useful neurons die off gradually after learning is complete, and the learned solution can then be maintained with a smaller number of units than were needed for initial learning. The research suggests a functional role for PCD, and how self-limiting PCD could be achieved in real neural systems.

Throughout the 1980s there has been a remarkable rise in the retention rate of Australian students in secondary education. Although the absolute numbers of students undertaking the traditional upper secondary school preparatory subjects for Engineering courses has been increasing, their proportion as a percentage of the whole Year 12 group has simultaneously been decreasing. In the face of this situation, the Faculty of Engineering at Monash decided in 1989 to ask the Faculty of Education to offer special bridging courses in chemistry and physics to students who had the appropriate high entry scores, but who had not studied either one or the other of these subjects during their Year 12 program. After an initial period of data collection involving researching the chemistry and physics courses, two intensive special bridging courses to be taken over one semester were designed to meet the needs of these students. The first four years of the program have produced very encouraging results. The paper d...

(1994). Metacognition and the Quality of Learning. Studies in Science Education: Vol. 23, No. 1, pp. 21-37.

Introduction. Tourette syndrome (TS) is thought to be associated with striatal dysfunction. Changes within frontostriatal pathways in TS could lead to changes in abilities reliant on the frontal cortex. Such abilities include executive functions and aspects of social reasoning. Methods. This study aimed to investigate executive functioning and Theory of Mind (ToM; the ability to reason about mental states, e.g., beliefs and emotions), in 18 patients with TS and 20 controls. A range of tasks involving ToM were used. These required participants to make judgements about mental states based on pictures of whole faces or the eyes alone, reason about humour in cartoons that featured sarcasm, irony or slapstick style humour, and make economic decisions. The executive measures assessed inhibition and verbal fluency. Results. Patients with TS exhibited significantly poorer performance than controls on all four tasks involving ToM, even when patients with comorbid obsessive-compulsive disorder were excluded. These difficulties were despite no inhibitory deficits. Patients with TS exhibited impairment on the verbal fluency task but their performance on executive and ToM tasks was not related. Conclusions. We propose that TS is associated with changes in ToM. The observed deficits could reflect dysfunction in frontostriatal pathways involving ventromedial prefrontal cortex.

Deep brain stimulation (DBS) is an emerging therapeutic option for severe, treatment-resistant Tourette Syndrome (TS), with about 40 cases reported in the scientific literature over the last decade. Despite the production of clinical guidelines for this procedure from both European and USA centres, a number of unresolved issues still persist, mainly in relation to eligibility criteria and brain targets. The present article illustrates the UK perspective on DBS in TS and proposes consensus-based recommendations for double-blind controlled trials.

Acute alcohol consumption is associated with socially inappropriate behaviour. Such behaviour could in part reflect the potential of alcohol to interfere with social cognition. In this experiment we tested the hypothesis that acute alcohol consumption by regular heavy social drinking young adults would compromise an aspect of social cognition, namely theory of mind (understanding intentions, emotions and beliefs). Participants who had consumed 6–8 units of alcohol showed specific impairments on two theory of mind tests: identification of faux pas and emotion recognition. This result suggests that alcohol consumption could lead to social problems secondary to difficulties in interpreting the behaviour of others due to theory of mind impairments.

Patients with Huntington’s disease (HD) have been shown to exhibit impairment in the recognition of facial expressions such as disgust, as well as deficits in disgust responses to olfactory and gustatory stimuli. The present study investigated whether HD is associated with changes in emotional responses to a variety of visual and verbal stimuli selected to elicit core disgust, moral disgust, fear and happiness. Thirteen patients with HD and twelve controls provided emotional ratings after both reading emotion eliciting scenarios and viewing pictures from the International Affective Picture System database. Patients with HD exhibited executive dysfunction. In comparison to controls, they gave similar ratings for happy stimuli and did not differ significantly in response to core disgust or moral disgust stimuli. However, they did exhibit lower fear ratings in response to both sets of fear stimuli (pictures and scenarios), and higher anger ratings than controls in response to fear pictures. These differences in fear response could reflect dysfunction within frontostriatal pathways involving the amygdala. Changes to fear responses in HD may impair decision making and lead to increased risk-taking behaviour with significant personal or social consequences.

Pilot study of nabilone in Huntington's disease (HD). Double-blind, placebo-controlled, cross-over study of nabilone versus placebo. Primary outcome, Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Secondary measures: UHDRS subsections for chorea, cognition and behavior, and neuropsychiatric inventory (NPI). 44 randomized patients received either nabilone (1 or 2 mg) followed by placebo (n = 22), or placebo followed by nabilone (n = 22). Recruiting was straightforward. Nabilone safe and well tolerated, no psychotic episodes. Assessment of either dose of nabilone versus placebo showed a treatment difference of 0.86 (95% CI: -1.8 to 3.52) for total motor score; 1.68 (95% CI: 0.44 to 2.92) for chorea; 3.57 (95% CI: -3.41 to 10.55) for UHDRS cognition; 4.01 (95% CI: -0.11 to 8.13) for UHDRS behavior, and 6.43 (95% CI: 0.2 to 12.66) for the NPI. Larger longer RCT of nabilone in HD is feasible and warranted.

In this paper we consider how disturbances in the neurobiological/neurochemical processes at a young age lead to problematic attachment styles in later life, and which can potentiate probability of offending behavior. In particular, we will contrast attachment and offending patterns of the more generalist type of offender (i.e., those who have a varied criminal career, committing both violent and non-violent offenses, in extremis the psychopathic type of offender), with the more specialist sexual offender (prototypically, the fixated pedophile), in the light of a preliminary neurobiological model. Here, we will argue that these two extremes of offenders show, or are predicted to show, differential patterns of neurochemical/neurobiological functioning.

Patients with Huntington's disease show deficits in recognizing disgust in the facial expressions and vocal intonations of others. In this study, the authors demonstrate that these disgust-related deficits extend to foul-smelling olfactory stimuli and inappropriate combinations of taste stimuli.

Dexamethasone, a synthetic corticosteroid, which can induce a range of mood disorders including depression and affective psychosis, is toxic to specific hippocampal and striatal neuronal populations. Chronic administration of antidepressants can induce neuroprotective effects, potentially by raising cellular levels of brain-derived neurotrophic factor (BDNF). We accordingly tested the hypothesis that chronic pretreatment of rats (Sprague-Dawley, male) with antidepressants would attenuate dexamethasone-induced neuronal damage as revealed by reductions in the level of neuronal death and in sublethal neuronal damage shown by the increase in the number of MAP-2 immunoreactive neurons. In support of this hypothesis, we demonstrate that chronic treatment with a range of antidepressants prior to dexamethasone administration (0.7 mg/kg, i.p.) attenuated the levels of neuronal death and loss of MAP-2 immunoreactivity in both the hippocampus and striatum. The antidepressants used were: desipramine (8 mg/kg, i.p., tricyclic), fluoxetine (8 mg/kg, i.p., selective serotonin reuptake inhibitor) and tranylcypromine (10 mg/kg, i.p., monoamine oxidase inhibitor) with each drug being injected once per day for 10 days. In contrast, acute injection of none of the antidepressants exerted a protective effect from dexamethasone-associated neuronal damage. Similarly, injection of neither cocaine nor chlordiazepoxide (benzodiazepine) exerted protective effects when injected either chronically or acutely. The observed protection from dexamethasone-induced neuronal damage is in keeping with the potential of chronic antidepressant medication to increase BDNF levels. The potential for dexamethasone to induce disorders of mood by damaging specific neuronal populations in the hippocampus and dorsomedial striatum is discussed.

Abnormal corticosteroid release is extensively associated with mood disorders. This association may result from the toxic actions of endogenous corticosteroids which can induce apoptosis of hippocampal neurons. Similarly, dexamethasone, a synthetic corticosteroid, can induce lethal and sublethal damage to rat hippocampal and striatal neurons and can result in steroid-induced psychoses in humans. The experiments reported here tested the hypothesis that pre-treatment with oestrogen would also attenuate dexamethasone-induced neuronal damage as oestrogens have neuroprotective actions against a variety of insults and falling levels of oestrogen are associated with increased vulnerability to mood disorders. Male Sprague-Dawley rats received three systemic injections which were a combination of vehicle, 17-beta-oestradiol (0.2 mg/kg, s.c.), the oestrogen receptor antagonist tamoxifen (10 mg/kg, s.c.) and dexamethasone (0.7 mg/kg, i.p.) and were killed 24 h after the final injection. Injections of dexamethasone (when preceded by vehicle injections) resulted in elevated levels of apoptosis and sub-lethal damage, as demonstrated by reduced levels of microtubule-associated protein-2-immunopositive neurons, in the striatum and hippocampus. This damage was regional with the dorsomedial caudate putamen and the dentate gyrus and CA1 and CA3 hippocampal sub-fields being particularly affected. Pretreatment with oestrogen substantially attenuated the dexamethasone-induced neuronal damage. This oestrogen-induced neuronal protection was in turn virtually eliminated by giving an initial injection of tamoxifen. These results suggest, therefore, that oestrogens can protect from corticosteroid-induced neuronal damage via an oestrogen receptor-mediated process.

It has been shown previously that the synthetic corticosteroid dexamethasone induces apoptosis of granule cells in the dentate gyrus and striatopallidal neurons in the dorsomedial caudate–putamen. We investigated whether or not dexamethasone can induce damage to other neuronal populations. This issue was addressed using OX42 immunohistochemistry to visualise activated microglia and thereby gauge the extent of dexamethasone-induced neuronal death. A single dose of dexamethasone (20 mg/kg, i.p.) administered to young male Sprague–Dawley rats induced a strong microglial reaction which was restricted to the striatum, the dentate gyrus and all of the CA subfields of the hippocampus. Some OX42-immunoreactive cells were also seen in the lateral septal nucleus. Subsequent quantitative analysis of silver/methenamine-stained sections confirmed that acute administration of dexamethasone induced apoptosis in the striatum and all regions of the hippocampus at doses as low as 0.7 mg/kg. In contrast, dexamethasone failed to induce apoptosis in the lateral septal nucleus at doses up to 20 mg/kg. The levels of dexamethasone-induced striatal and hippocampal apoptosis were attenuated by pretreatment with the corticosteroid receptor antagonist RU38486 (Mifepristone), which implies that the cell death was mediated by a corticosteroid receptor-dependent process. We further determined whether dexamethasone induced sublethal damage to neurons by quantifying reductions in the number of microtubule-associated protein-2-immunoreactive striatal and hippocampal cells following injection of the corticosteroid. Dexamethasone induced dramatic decreases in the striatum, with the dorsomedial caudate–putamen being particularly affected. Similar damage was seen in the hippocampus, with the dentate gyrus and CA1 and CA3 subfields being particularly vulnerable. Equivalent corticosteroid-induced neuronal damage may occur in mood disorders, where the levels of endogenous corticosteroids are often raised. Corticosteroid-induced damage of striatal and hippocampal neurons may also account for some of the cognitive deficits seen following administration of the drugs to healthy volunteers.

Aims In Tourette Syndrome (TS), striatal dysfunction could affect the functioning of the frontal cortex, leading to changes in cognition and social behaviour. This study investigated social and economic reasoning in patients with TS. Methods 16 patients with TS and 20 neurologically intact controls completed three reasoning tasks that involved making judgements about mental states (Theory of Mind) and an economic decision making task. The tasks used were the “Eyes Test”, a “socially competitive emotions” task, a humourous cartoons task featuring sarcasm and irony, and a version of the Ultimatum Game. Executive functions were assessed using the FAS verbal fluency test and a black and white Stroop task. Results Patients with TS exhibited significant impairments on all four of the tasks selected to assess social and economic reasoning. These difficulties were evident despite the finding that patients did not exhibit significant executive deficits on the verbal fluency or inhibitory measures. Conclusions TS is associated with deficits on a range of tasks involving social and economic reasoning. Impairments on similar tasks have been reported in patients who have dysfunction of ventromedial prefrontal cortex. The observed deficits could imply that patients with TS exhibit dysfunction within frontostriatal pathways involving this region.

The different types of striatal neuron show a range of vulnerabilities to a variety of insults. This can be clearly seen in Huntington's disease where a well mapped pattern of pathological events occurs. Medium spiny projection (MSP) neurons are the first striatal cells to be affected as the disease progresses whilst interneurons, in particular the NADPH diaphorase positive ones, are spared even in the late stages of the disease. The MSP neurons themselves are also differentially affected. The death of MSP neurons in the patch compartment of the striatum precedes that in the matrix compartment and the MSP neurons of the dorsomedial caudate nucleus degenerate before those in the ventral lateral putamen. The enkephalin positive striatopallidal MSP neurons are also more vulnerable than the substance P/dynorphin MSP neurons. We review the potential causes of this selective vulnerability of striatopallidal neurons and discuss the roles of endogenous glutamate, nitric oxide and calcium binding proteins. It is concluded that MSP neurons in general are especially susceptible to disruptions of cellular respiration due to the enormous amount of energy they expend on maintaining unusually high transmembrane potentials. We go on to consider a subpopulation of enkephalinergic striatopallidal neurons in the rat which are particularly vulnerable. This subpopulation of neurons readily undergo apoptosis in response to experimental manipulations which affect dopamine and/or corticosteroid levels. We speculate that the cellular mechanisms underlying this cell death may also operate in degenerative disorders such as Huntington's disease thereby imposing an additional level of selectivity on the pattern of degeneration. The possible contribution of the selective death of striatopallidal neurons to a number of clinically important psychiatric conditions including obsessive compulsive disorders and Tourette's syndrome is also discussed.

Pharmacological depletion of dopaminergic neurotransmission can result in an elevation in striatal Fos levels. This elevation may occur as a direct result of decreased dopaminergic neurotransmission or indirectly via elevated corticostriatal glutamatergic neurotransmission which occurs secondary to dopamine depletion. To test the hypothesis that elevated N -methyl- d -aspartic acid (NMDA)-mediated corticostriatal transmission may underlie the increase in striatal Fos levels upon dopamine depletion, rats were unilaterally 6-hydroxydopamine lesioned under anaesthesia induced by either barbiturate or the NMDA antagonist, ketamine. Following surgery the animals remained under light anaesthesia for 6 h prior to sacrifice and quantification of striatal Fos immunoreactivity. The results demonstrate that dopamine depletion following 6-hydroxydopamine lesioning can result in elevated striatal Fos levels which can be attenuated by contiguous treatment with an NMDA antagonist. This suggests that the increase in striatal Fos levels observed following dopamine depletion may occur as a result of elevated cytoplasmic calcium levels in the striatal cells.

Experiments were conducted to characterise the Fos-immunopositive neurons that are observed in the dorsal rim of the striatum following monoamine depletion by the systemic administration of reserpine. Using a retrograde tract-tracer, some of these neurons could be shown to project to the globus pallidus but none were seen to project to the entopeduncular nucleus. In addition, these neurons were located in a region of both poor calbindin immunoreactivity and cholinesterase activity. It can be concluded that Fos levels are increased only in a subset of striatopallidal neurons following monoamine depletion. This subset of neurons is located in the dorsal region of the striatum where it has previously been shown that neurons can preferentially be induced to undergo apoptosis upon monoamine depletion.

Aims Studies have shown that patients with Huntington9s disease (HD) can exhibit impairment in the recognition of emotional facial expressions such as disgust. It is likely that the same neural substrates are involved in experiencing an emotion and recognising that emotion in another. However, few studies have investigated emotional experience in HD. We investigated whether HD is associated with changes in emotional responses to a variety of visual and verbal stimuli selected to elicit core disgust, moral disgust, fear and happiness. Methods Thirteen patients with HD and 12controls provided emotional ratings after reading emotion eliciting scenarios and viewing pictures from the International Affective Picture System database. Results Patients with HD did not differ to controls for happiness ratings for stimuli selected to elicit happiness, and small differences in disgust ratings for core and moral disgust stimuli failed to reach significance. However, patients did exhibit significantly lower fear ratings in response to both sets of fear stimuli (pictures and scenarios), and significantly higher anger ratings than controls in response to fear pictures. Conclusions These differences in fear response could reflect dysfunction within frontostriatal pathways involving the amygdala. Changes in fear experience in HD could affect decision making and social interaction.