No abstract

Event-related functional magnetic resonance imaging was used to measure blood oxygenation level-dependent responses in 13 young healthy human volunteers during performance of a probabilistic reversal-learning task. The task allowed the separate investigation of the relearning of stimulus-reward associations and the reception of negative feedback. Significant signal change in the right ventrolateral prefrontal cortex was demonstrated on trials when subjects stopped responding to the previously relevant stimulus and shifted responding to the newly relevant stimulus. Significant signal change in the region of the ventral striatum was also observed on such reversal errors, from a region of interest analysis. The ventrolateral prefrontal cortex and ventral striatum were not significantly activated by the other, preceding reversal errors, or when subjects received negative feedback for correct responses. Moreover, the response on the final reversal error, before shifting, was not modulated by the number of preceding reversal errors, indicating that error-related activity does not simply accumulate in this network. The signal change in this ventral frontostriatal circuit is therefore associated with reversal learning and is uncontaminated by negative feedback. Overall, these data concur with findings in rodents and nonhuman primates of reversal-learning deficits after damage to ventral frontostriatal circuitry, and also support recent clinical findings using this task.

Recent work has suggested an association between the orbitofrontal cortex in humans and practical decision making. The aim of this study was to investigate the profile of cognitive deficits, with particular emphasis on decision-making processes, following damage to different sectors of the human prefrontal cortex. Patients with discrete orbitofrontal (OBF) lesions, dorsolateral (DL) lesions, dorsomedial (DM) lesions and large frontal lesions (Large) were compared with matched controls on three different decision-making tasks: the Iowa Gambling Task and two recently developed tasks that attempt to fractionate some of the cognitive components of the Iowa task. A comprehensive battery including the assessment of recognition memory, working memory, planning ability and attentional set-shifting was also administered. Whilst combined frontal patients were impaired on several of the tasks employed, distinct profiles emerged for each patient group. In contrast to previous data, patients with focal OBF lesions performed at control levels on the three decision-making tasks (and the executive tasks), but showed some evidence of prolonged deliberation. DL patients showed pronounced impairment on working memory, planning, attentional shifting and the Iowa Gambling Task. DM patients were impaired at the Iowa Gambling Task and also at planning. The Large group displayed diffuse impairment, but were the only group to exhibit risky decision making. Methodological differences from previous studies of OBF patient groups are discussed, with particular attention to lesion laterality, lesion size and psychiatric presentation. Ventral and dorsal aspects of prefrontal cortex must interact in the maintenance of rational and 'non-risky' decision making.

Sustained attention deficit may represent a neuropsychological vulnerability marker for bipolar disorder, providing a focus for further understanding of the phenotype and analysis of the neuronal networks involved.

Cognitive functions dependent on the prefrontal cortex, such as the ability to suppress behavior (response inhibition) and to learn from complex feedback (probabilistic learning), play critical roles in activities of daily life. To what extent do different neurochemical systems modulate these two cognitive functions? Here, using stop-signal and probabilistic learning tasks, we show a double dissociation for the involvement of noradrenaline and serotonin in human cognition. In healthy volunteers, inhibition of central noradrenaline reuptake improved response inhibition but had no effect on probabilistic learning, whereas inhibition of central serotonin reuptake impaired probabilistic learning with no effect on response inhibition.Ascending monoamine projections play important neuromodulatory roles in high-level cognition through actions upon the prefrontal cortex (PFC), a major brain structure with considerable functional heterogeneity in humans (1). Dysfunction in these neurochemical systems is implicated in the etiology and psychopathology of psychiatric illnesses associated with cognitive deficits and PFC abnormalities, including depression, attention deficithyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and drug addiction (2-7). Dopamine regulates executive functions dependent on the dorsolateral PFC, including working memory and attentional set-shifting, but the role of noradrenaline (NA) and serotonin [5-hydroxytryptamine (5-HT)] in cognition is less well characterized (8). The orbitofrontal cortex (OFC) is involved in emotion-cognition interactions, and 5-HT drugs modulate response to feedback and decision-making within this region (9-15). 5-HT and NA have both been implicated in response inhibition (16,17), a function that has been linked to the right inferior frontal gyrus (RIFG) (18).We investigated the differential involvement of NA and 5-HT transmitter systems in these processes in humans, using the selective NA reuptake inhibitor (SNRI) atomoxetine and the selective 5-HT reuptake inhibitor (SSRI) citalopram. These agents are among the most selective inhibitors for brain NA and 5-HT reuptake transporters available for human use,