Impaired dimensional selection but intact use of reward feedback during visual discrimination learning in Parkinson's disease.

It has been suggested that Parkinson's disease (PD) impairs the ability to learn on the basis of reward or reinforcing feedback i.e., by trial-and-error. In many learning tasks, particular 'dimensions' of stimulus information are relevant whilst others are irrelevant; therefore, efficient performance depends on identifying the dimensions of these 'compound' stimuli and selecting the relevant dimension for further processing. We investigated the ability of patients with PD, as well as patients with Huntington's disease and patients with frontal or temporal lobe lesions, to learn visual discriminations which required either a number of associations to be learned concurrently (the 'eight-pair' task) or the selection of information from compound stimuli (the 'five-dimension' task), both tasks being learned by trial-and-error. None of the basal ganglia disorder patient groups was impaired on the eight-pair task, militating against a crucial role for these brain structures in trial-and-error learning per se. Patients with mild, medicated PD, but not unmedicated PD patients, were impaired at identifying all five feature dimensions in the five-dimension task, implying dopaminergic 'overdosing' of the ability to analyse compound stimuli in terms of their component dimensions. Temporal lobe lesion patients performed similarly, suggesting that the temporal lobe may be the site of the medication overdose effect. Patients with severe, medicated PD were impaired at compound discrimination learning on the five-dimension task in the absence of an underlying impairment in identifying component stimulus dimensions; this pattern resembled that seen in Huntington's disease and frontal lobe lesion patients, implying that fronto-striatal circuitry is involved in the formation of rules based upon selected stimulus dimensions.

Impaired planning but intact decision making in early Huntington's disease: implications for specific fronto-striatal pathology.

Previous neuropsychological data have suggested that deficits in early Huntington's disease (HD) include executive impairments, which often are linked with frontal-lobe dysfunction. This study sought to investigate the profile of cognitive deficits using two computerised tasks whose performance is known to rely on intact functions of separate areas of the prefrontal cortex. Twenty patients with early HD and 20 matched controls were given the one-touch Tower of London, a stringent measure of visuo-spatial planning, and a decision making task, which involved selecting and gambling on outcomes on the basis of their differing probabilities. Patients were significantly less accurate than controls on the planning test, which is sensitive to frontal lobe lesions and is strongly associated with the dorsolateral prefrontal cortex in functional imaging studies. On the decision making task, patients were unimpaired on the quality of their decision making, in contrast to previous reports of impairment on this task in patients with ventromedial prefrontal cortex lesions. This dissociation of performance is discussed in terms of the usual path of progression of HD through the striatum and the resultant pattern of disruption of the functioning of the different cortico-striatal functional loops.

Visual object and visuospatial cognition in Huntington's disease: implications for information processing in corticostriatal circuits.

The primate visual system contains two major streams of visual information processing. The ventral stream is directed into the inferior temporal cortex and is concerned with visual object cognition, whereas the dorsal stream is directed into the posterior parietal cortex and is concerned with visuospatial cognition. Both of these processing streams send projections to the basal ganglia, and the ventral stream may also receive reciprocal connections from the basal ganglia. Although a role for the basal ganglia in visual object and visuospatial cognition has been suggested, little work has been carried out in this area in humans. The primary site of neuropathology in Huntington's disease is the basal ganglia, and hence Huntington's disease provides an important model for the role of the human basal ganglia in visual object and visuospatial cognition, and its breakdown in disease. We examined performance on a wide battery of tests of both visual object and visuospatial recognition memory, working memory, attention, associative learning and perception, enabling us to specify more fully the role of the basal ganglia in visual object and visuospatial cognition, and the disruption of these processes in Huntington's disease. Huntington's disease patients exhibited deficits on tests of pattern and spatial recognition memory; showed impaired simultaneous matching and delay-independent delayed matching-to-sample deficits; showed spared accuracy but impaired reaction times in visual search; were impaired in spatial but not visual object working memory; and showed impaired pattern-location associative learning. The results of our investigations suggest a particular role for the striatum in context-dependent action selection, in line with current computational theories of basal ganglia function.

Huntington's disease progression. PET and clinical observations.

Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months in nine asymptomatic adult Huntington's disease mutation carriers, four patients with symptomatic disease, seven mutation-negative controls and three subjects at risk for the disease. Eight of the nine asymptomatic Huntington's disease mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of striatal D2 binding of 4.0%. Only five of these eight, however, showed active progression, and they had a mean annual loss of D2 binding of 6.5%. All nine asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated active progression and they had a mean annual loss of 4.5%. Our four symptomatic Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly greater in the known mutation carriers than in the combined at-risk and gene-negative groups (P < 0.05). At follow-up PET all subjects were clinically assessed using the Unified Huntington's Disease Rating Scale. Scores for motor function and total functional capacity correlated with PET measures of striatal dopamine receptor binding both in the asymptomatic mutation carriers (D1, P < 0.01) and across the combined asymptomatic and clinically affected Huntington's disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET measures of striatal D1 and D2 dopamine binding can be used to identify asymptomatic Huntington's disease mutation carriers who are actively progressing and who would thus be suitable for putative neuroprotective therapies. Measures of disease progression rates in Huntington's disease patients and asymptomatic mutation carriers will be of critical importance in future trials of experimental restorative treatments.

The relationship between striatal dopamine receptor binding and cognitive performance in Huntington's disease.

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.