Angela C. Roberts

Cognitive inflexibility after prefrontal serotonin depletion.

Serotonergic dysregulation within the prefrontal cortex (PFC) is implicated in many neuropsychiatric disorders, but the precise role of serotonin within the PFC is poorly understood. Using a serial discrimination reversal paradigm, we showed that upon reversal, selective serotonin depletion of the marmoset PFC produced perseverative responding to the previously rewarded stimulus without any significant effects on either retention of a discrimination learned preoperatively or acquisition of a novel discrimination postoperatively. These results highlight the importance of prefrontal serotonin in behavioral flexibility and are highly relevant to obsessive-compulsive disorder, schizophrenia, and the cognitive sequelae of drug abuse in which perseveration is prominent.

Serotoninergic regulation of emotional and behavioural control processes

5-Hydroxytryptamine (5-HT, serotonin) has long been implicated in a wide variety of emotional, cognitive and behavioural control processes. However, its precise contribution is still not well understood. Depletion of 5-HT enhances behavioural and brain responsiveness to punishment or other aversive signals, while disinhibiting previously rewarded but now punished behaviours. Findings suggest that 5-HT modulates the impact of punishment-related signals on learning and emotion (aversion), but also promotes response inhibition. Exaggerated aversive processing and deficient response inhibition could underlie distinct symptoms of a range of affective disorders, namely stress- or threat-vulnerability and compulsive behaviour, respectively. We review evidence from studies with human volunteers and experimental animals that begins to elucidate the neurobiological systems underlying these different effects.

6-Hydroxydopamine Lesions of the Prefrontal Cortex in Monkeys Enhance Performance on an Analog of the Wisconsin Card Sort Test: Possible Interactions with Subcortical Dopamine

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinsons disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.

Primate analogue of the Wisconsin Card Sorting Test : Effects of excitotoxic lesions of the prefrontal cortex in the marmoset

Using a primate analogue of the Wisconsin Card Sort Test, this study demonstrated, for the first time, that lesions of the prefrontal cortex in monkeys produce a qualitatively similar impairment in attentional set-shifting to that seen following prefrontal cortical damage in humans. Although damage to the prefrontal cortex did not disrupt the ability of marmosets, a New World monkey, to maintain an attentional set, it did disrupt their ability to shift an attentional set. It also impaired their performance on discrimination reversal, object retrieval, and spatial delayed response, consistent with the effects of prefrontal damage in Old World monkeys. Comparison of the cognitive processes underlying discrimination reversal, object retrieval, and attentional set-shifting reveals the various types of inhibitory control provided by the prefrontal cortex.

Prefrontal Serotonin Depletion Affects Reversal Learning But Not Attentional Set Shifting

Recently, we have shown that serotonin (5-HT) depletion from the prefrontal cortex (PFC) of the marmoset monkey impairs performance on a serial discrimination reversal (SDR) task, resulting in perseverative responding to the previously correct stimulus (Clarke et al., 2004). This pattern of impairment is just one example of inflexible responding seen after damage to the PFC, with performance on the SDR task being dependent on the integrity of the orbitofrontal cortex. However, the contribution of 5-HT to other forms of flexible responding, such as attentional set shifting, an ability dependent on lateral PFC (Dias et al., 1996a), is unknown. The present study addresses this issue by examining the effects of 5,7-dihydroxytryptamine-induced PFC 5-HT depletions on the ability to shift attention between two perceptual dimensions of a compound visual stimulus (extradimensional shift). Monkeys with selective PFC 5-HT lesions, despite being impaired in their ability to reverse a stimulus-reward association, were unimpaired in their ability to make an extradimensional shift when compared with sham-operated controls. These findings suggest that 5-HT is critical for flexible responding at the level of changing stimulus-reward contingencies but is not essential for the higher-order shifting of attentional set. Thus, psychological functions dependent on different loci within the PFC are differentially sensitive to serotonergic modulation, a finding of relevance to our understanding of cognitive inflexibility apparent in disorders such as obsessive-compulsive disorder and schizophrenia.

Lesions of the Medial Striatum in Monkeys Produce Perseverative Impairments during Reversal Learning Similar to Those Produced by Lesions of the Orbitofrontal Cortex

The ability to switch responding between two visual stimuli based on their changing relationship with reward is dependent on the orbitofrontal cortex (OFC). OFC lesions in humans, monkeys, and rats disrupt performance on a common test of this ability, the visual serial discrimination reversal task. This finding is of particular significance to our understanding of psychiatric disorders such as obsessive–compulsive disorder (OCD) and schizophrenia, in which behavioral inflexibility is a prominent symptom. Although OFC dysfunction can occur in these disorders, there is considerable evidence for more widespread dysfunction within frontostriatal and frontoamygdalar circuitry. Because the contribution of these subcortical structures to behavioral flexibility is poorly understood, the present study compared the effects of excitotoxic lesions of the medial striatum (MS), amygdala, and OFC in the marmoset monkey on performance of the serial reversal task. All monkeys were able to learn a novel stimulus–reward association but, compared with both control and amygdala-lesioned monkeys, those with MS or OFC lesions showed a perseverative impairment in their ability to reverse this association. However, whereas both MS and OFC groups showed insensitivity to negative feedback, only OFC-lesioned monkeys showed insensitivity to positive feedback. These findings suggest that, for different reasons, both the MS and OFC support behavioral flexibility after changes in reward contingencies, and are consistent with the hypothesis that striatal and OFC dysfunction can contribute to pathological perseveration.

Perseveration and Strategy in a Novel Spatial Self-Ordered Sequencing Task for Nonhuman Primates: Effects of Excitotoxic Lesions and Dopamine Depletions of the Prefrontal Cortex

Damage to the prefrontal cortex disrupts the performance of self-ordered sequencing tasks, although the precise mechanisms by which this effect occurs is unclear. Active working memory, inhibitory control, and the ability to generate and perform a sequence of responses are all putative cognitive abilities that may be responsible for the impaired performance that results from disruption of prefrontal processing. In addition, the neurochemical substrates underlying prefrontal cognitive function are not well understood, although active working memory appears to depend upon an intact mesocortical dopamine system. The present experiments were therefore designed to evaluate explicitly the contribution of each of these abilities to successful performance of a novel spatial self-ordered sequencing task and to examine the contribution of the prefrontal cortex and its dopamine innervation to each ability in turn. Excitotoxic lesions of the prefrontal cortex of the common marmoset profoundly impaired the performance of the self-ordered sequencing task and induced robust perseverative responding. Task manipulations that precluded perseveration ameliorated the effect of this lesion and revealed that the ability to generate and perform sequences of responses was unaffected by excitotoxic damage to prefrontal cortex. In contrast, large dopamine and noradrenaline depletions within the same areas of prefrontal cortex had no effect on any aspect of the self-ordered task but did impair the acquisition of an active working memory task, spatial delayed response, to the same degree as the excitotoxic lesion. These results demonstrate that a lesion of the ascending monoamine projections to the pre-frontal cortex is not always synonymous with a lesion of the prefrontal cortex itself and thereby challenge existing concepts concerning the neuromodulation of prefrontal cognitive function.

Neural contributions to the motivational control of appetite in humans

The motivation to eat in humans is a complex process influenced by intrinsic mechanisms relating to the hunger and satiety cascade, and extrinsic mechanisms based on the appetitive incentive value of individual foods, which can themselves induce desire. This study was designed to investigate the neural basis of these two factors contributing to the control of motivation to eat within the same experimental design using positron emission tomography. Using a novel counterbalanced approach, participants were scanned in two separate sessions, once after fasting and once after food intake, in which they imagined themselves in a restaurant and considered a number of items on a menu, and were asked to choose their most preferred. All items were tailored to each individual and varied in their incentive value. No actual foods were presented. In response to a hungry state, increased activation was shown in the hypothalamus, amygdala and insula cortex as predicted, as well as the medulla, striatum and anterior cingulate cortex. Satiety, in contrast, was associated with increased activation in the lateral orbitofrontal and temporal cortex. Only activity in the vicinity of the amygdala and orbitofrontal cortex was observed in response to the processing of extrinsic appetitive incentive information. These results suggest that the contributions of intrinsic homeostatic influences, and extrinsic incentive factors to the motivation to eat, are somewhat dissociable neurally, with areas of convergence in the amygdala and orbitofrontal cortex. The findings of this study have implications for research into the underlying mechanisms of eating disorders.

Performance norms for a rhesus monkey neuropsychological testing battery : acquisition and long-term performance

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.

A specific form of cognitive rigidity following excitotoxic lesions of the basal forebrain in marmosets

The effects of N-methyl-D-aspartate-induced lesions of the basal forebrain were studied on performance of a series of visual discrimination tests that examined a range of cognitive functions in the marmoset. These included the ability to attend to the various dimensional properties of stimuli and to use just one of these properties in order to solve a discrimination (intra-dimensional shift); to switch attention from one dimension to another (extra-dimensional shift); to learn the reinforcement value of specific exemplars within a dimension (new learning); and to relearn their reinforcement value following reversal of the reward contingencies (serial reversals). Lesions of the basal forebrain did not impair the ability either to attend selectively to the dimensional properties of the stimuli or to switch attention from one dimension to the other. However, the lesion did affect various aspects of associative learning including a transient impairment of new learning and a marked disruption of serial reversal learning. The reversal deficit could be characterised as a tendency to perseverate on the previously correct stimulus and as a failure to to show the formation of a reversal learning set. In addition, the lesion prevented disruption of performance of a well-learned discrimination when novel exemplars from the irrelevant dimension were introduced (probe test). It is suggested that the functional effects of the basal forebrain lesion reflect impaired learning of stimulus-reward associations and behavioural rigidity. The finding, however, that there was no effect of the lesion on attentional set-shifting suggests that any loss of inhibitory control was specific to the level of stimulus-response or stimulus-reward associations, inhibitory control at the level of attentional selection remaining intact. The similarity of the effects of damage to the basal forebrain to those seen following damage to the orbitofrontal cortex and the amygdala are discussed in the context of the close anatomical and functional relationships that exist among these three structures.