Much evidence suggests that lesions of the prefrontal cortex (PFC) produce marked impairments in the ability of subjects to shift cognitive set, as exemplified by performance of the Wisconsin Card Sorting Test (WCST). However, studies with humans and experimental primates have suggested that damage to different regions of PFC induce dissociable impairments in two forms of shift learning implicit in the WCST (that is, extradimensional (ED) shift learning and reversal shift learning), with similar deficits also being apparent after damage to basal ganglia structures, especially the caudate nucleus. In this study, we used the same visual discrimination learning paradigm over multidimensional stimuli, and the H215O positron emission tomography (PET) technique, to examine regional cerebral blood flow (rCBF) changes associated with these subcomponent processes of the WCST. In three conditions, subjects were scanned while acquiring visual discriminations involving either (i) the same stimulus dimension as preceding discriminations (intradimensional (ID) shifts); (ii) different stimulus dimensions from previous discriminations (ED shifts) or (iii) reversed stimulus-reward contingencies (reversal shifts). Additionally, subjects were scanned while responding to already learnt discriminations ('performance baseline'). ED shift learning, relative to ID shift learning, produced activations in prefrontal regions, including left anterior PFC and right dorsolateral PFC (BA 10 and 9⁄46). By contrast, reversal learning, relative to ID shift learning, produced activations of the left caudate nucleus. Additionally, compared to reversal and ID shift learning, ED shift learning was associated with relative deactivations in occipito-temporal pathways (for example, BA 17 and 37). These results confirm that, in the context of visual discrimination learning over multidimensional stimuli, the control of an acquired attentional bias or'set', and the control of previously acquired stimulus-reinforcement associations, activate distinct cortical and subcortical neural stations. Moreover, we propose that the PFC may contribute to the control of attentional-set by modulating attentional processes mediated by occipito-temporal pathways.

BackgroundHuntington's disease (HD) is a fatal inherited neurodegenerative disease, caused by a

We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.

Seventeen individuals at risk for Huntington's disease and five symptomatic patients, who had previously undergone [11C]SCH23390 and [11C]raclopride PET to assess in vivo levels of striatal dopamine D1 and D2 receptor binding, had neuropsychological assessment on a series of tests known to be sensitive to symptomatic Huntington's disease, including tests of verbal fluency, memory, attention and planning. Compared with age- and IQ-matched healthy volunteers, clinically symptomatic carriers of the Huntington's disease mutation were found to be impaired on tests of verbal fluency, spatial span, planning and sequence generation, as were clinically asymptomatic Huntington's disease mutation carriers. In asymptomatic individuals, both striatal dopamine receptor levels and cognitive performance were lower in subjects approaching their estimated age of onset. In addition, performance on these tasks was found to correlate with PET measures of striatal D1 and D2 receptor binding levels, especially D2 binding. These results are consistent with a role for the striatum, as part of the complex corticobasal ganglia-thalamocortical circuitry, in the optimal scheduling and sequencing of responses, and suggest that cognitive manifestations of striatal dysfunction can be evidenced in carriers of the Huntington's disease mutation prior to the onset of overt clinical movement disorder.