Patients sustaining lesions of the orbital prefrontal cortex (PFC) exhibit marked impairments in the performance of laboratory-based gambling, or risk-taking, tasks, suggesting that this part of the human PFC contributes to decision-making cognition. However, to date, little is known about the particular regions of the orbital cortex that participate in this function. In the present study, eight healthy volunteers were scanned, using H(2)(15)0 PET technology, while performing a novel computerized risk-taking task. The task involved predicting which of two mutually exclusive outcomes would occur, but critically, the larger reward (and penalty) was associated with choice of the least likely outcome, whereas the smallest reward (and penalty) was associated with choice of the most likely outcome. Resolving these "conflicting" decisions was associated with three distinct foci of regional cerebral blood flow increase within the right inferior and orbital PFC: laterally, in the anterior part of the middle frontal gyrus [Brodmann area 10 (BA 10)], medially, in the orbital gyrus (BA 11), and posteriorly, in the anterior portion of the inferior frontal gyrus (BA 47). By contrast, increases in the degree of conflict inherent in these decisions was associated with only limited changes in activity within orbital PFC and the anterior cingulate cortex. These results suggest that decision making recruits neural activity from multiple regions of the inferior PFC that receive information from a diverse set of cortical and limbic inputs, and that the contribution of the orbitofrontal regions may involve processing changes in reward-related information.

The indirect catecholamine agonist methylphenidate (Ritalin) is the drug treatment of choice in attention deficit/hyperactivity disorder (AD/HD), one of the most common behavioral disorders of childhood (DSM-IV), although symptoms may persist into adulthood. Methylphenidate can enhance cognitive performance in adults and children diagnosed with AD/HD (Kempton et al., 1999; Riordan et al., 1999) and also in normal human volunteers on tasks sensitive to frontal lobe damage, including aspects of spatial working memory (SWM) performance (Elliott et al., 1997). The present study investigated changes in regional cerebral blood flow (rCBF) induced by methylphenidate during performance of a self-ordered SWM task to define the neuroanatomical loci of the beneficial effect of the drug. The results show that the methylphenidate-induced improvements in working memory performance occur with task-related reductions in rCBF in the dorsolateral prefrontal cortex and posterior parietal cortex. The beneficial effects of methylphenidate on working memory were greatest in the subjects with lower baseline working memory capacity. This is to our knowledge the first demonstration of a localization of a drug-induced improvement in SWM performance in humans and has relevance for understanding the treatment of AD/HD.

SynopsisThe CANTAB battery of neuropsychological tests was used to compare the performance of 28 patients with unipolar depression with that of 22 age and IQ matched controls. The patients were impaired on almost all tests studied with deficits in pattern and spatial recognition memory, matching to sample, spatial span, spatial working memory and planning. Most of the patients showed at least some impairment and deficits were seen across cognitive domains. An important finding was the detrimental effect of failure on subsequent performance; having solved one problem incorrectly, patients were far more likely than controls to fail the subsequent problem. Superimposed on the general deficits, there were also specific deficits in executive tasks characteristic of frontostriatal dysfunction and deficits in mnemonic tasks characteristic of temporal lobe dysfunction. This combination of a specific form of motivational deficit, resulting in oversensitivity to negative feedback, and superimposed specific neuropsychological deficits were correlated with severity of depression. The most significant correlations were seen between mnemonic deficits and clinical rating scores. Comparisons of the deficits seen in the depressed patients in this study with other patient groups assessed with the CANTAB neuropsychological battery, showed that one of the hypotheses of the neuropsychological deficits in depression, that of ‘frontosubcortical’ or ‘frontostriatal’ dysfunction, was not supported. These findings are discussed in relation to the likely neural substrates of depression.

SynopsisThe paper reports the profile of impairment across a variety of cognitive functions with special emphasis on tests sensitive to frontal lobe dysfunction, in 24 elderly depressed patients during and on recovery from mood disorder, compared with 15 age- and sex-matched controls. Traditional neuropsychological tests and a recently developed battery of computerized tests (CANTAB) were used. Impairments were found in the depressed group compared to controls and to themselves on recovery across all domains examined. The depressed group showed deficits on visuospatial recognition memory, attentional shifting at the extra-dimensional shift stage and in measures of both processing and motor speed without impaired accuracy in a visual search task. Impairments were also found on a planning task with disproportionately increased numbers of moves needed for more difficult problems and evidence of both slowed motor response and increased processing time once the task was commenced.Performance on recovery improved across all tasks. Comparisons were made with the performance of patients suffering from dementia of the Alzheimer type (DAT) and Parkinson's disease on similar tests. Response latencies in test performance were found to correlate with the number of episodes of depression suffered and with ventricular size on CT scan, as measured by computerized planimetry. On recovery, residual depression scores correlated with latency of test performance and with ventricular brain ratio. The results, thus, show that depression in the elderly is associated with a significant degree of deficit on tests sensitive to frontostriatal dysfunction. Some of the deficits appear specific to depression and some do not remit following clinical recovery. However, these impairments have to be interpreted in the context of a broad profile of cognitive deficit.