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Biomedical subjects

B J Sahakian

Publications and source records attributed to B J Sahakian.

At least 19 recordsLinked to original sources
PubMed2003

Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance.

BACKGROUND: Recent evidence suggests that an abnormal response to performance feedback may contribute to the wide-ranging neuropsychological deficits typically associated with depressive illness. The present research sought to determine whether the inability of depressed patients to utilize performance feedback advantageously is equally true for accurate and misleading feedback. METHOD: Patients with major depression and matched controls completed: (1) a visual discrimination and reversal task that featured intermittent and misleading negative feedback; and (2) feedback and no-feedback versions of a computerised test of spatial working memory. In the feedback version, negative feedback was accurate, highly informative, and could be used as a mnemonic aid. RESULTS: On the Probability Reversal task, depressed patients were impaired in their ability to maintain response set in the face of misleading negative feedback as shown by their increased tendency to switch responding to the 'incorrect' stimulus following negative reinforcement, relative to that of controls. Patients' ability to acquire and reverse the necessary visual discrimination was unimpaired. On the Spatial Working Memory task, depressed patients made significantly more between-search errors than controls on the most difficult trials, but their ability to use negative feedback to facilitate performance remained intact. CONCLUSIONS: The present results suggest that feedback can have different effects in different contexts. Misleading, negative feedback appears to disrupt the performance of depressed patients, whereas negative but accurate feedback does not. These findings are considered in the context of recent studies on reinforcement systems and their associated neurobiological substrates.

Adult↗
PubMed2003

Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory.

We investigated the effects of subdissociative dose ketamine on executive processes during a working memory task. A total of 11 healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. They attended on three occasions, receiving intravenous infusions of placebo, a lower ketamine dose, and a higher ketamine dose. On each occasion, they underwent a series of tasks engaging working memory function in verbal and visuo-spatial domains. Further tasks explored aspects of long-term memory, planning, attention, and perceptual processing. With respect to working memory/executive function, a highly specific pattern of impairment was observed. Impairments were seen only at the higher dose of ketamine and restricted to a subgroup of the verbal working memory tasks: While visuo-spatial working memory showed no evidence of impairment, and while simple maintenance processes during verbal working memory were also unimpaired, higher dose ketamine produced a significant impairment in the manipulation of information within working memory. This process-specific effect of ketamine was reflected in a drug-by-task interaction. The specificity of this ketamine effect suggests that the earliest effect of NMDA receptor blockade is in higher order control of executive function rather than in more basic maintenance processes.

Adolescent↗
PubMed2003

Inhibition of subliminally primed responses is mediated by the caudate and thalamus: evidence from functional MRI and Huntington's disease.

Masked prime tasks have shown that sensory information that has not been consciously perceived can nevertheless trigger the preactivation of a motor response. Automatic inhibitory control processes prevent such response tendencies from interfering with behaviour. The present study investigated the possibility that these inhibitory control processes are mediated by a cortico-striatal-pallidal-thalamic pathway by using a masked prime task with Huntington's disease patients (Experiment 1) and with healthy volunteers in a functional MRI (fMRI) study (Experiment 2). In the masked prime task, clearly visible left- or right-pointing target arrows are preceded by briefly presented and subsequently masked prime arrows. Participants respond quickly with a left or right key-press to each target. Trials are either compatible (prime and target pointing in the same direction) or incompatible (prime and target pointing in different directions). Prior behavioural and electrophysiological results show that automatic inhibition of the initially primed response tendency is reflected in a 'negative compatibility effect' (faster reaction times for incompatible trials than for compatible trials), and is shown to consist of three distinct processes (prime activation, response inhibition and response conflict) occurring within 300 ms. Experiment 1 tested the hypothesis that lesions of the striatum would interrupt automatic inhibitory control by studying early-stage Huntington's disease patients. Findings supported the hypothesis: there was a bimodal distribution for patients, with one-third (choreic) showing disinhibition, manifested as an absent negative compatibility effect, and two-thirds (non-choreic) showing excessive inhibition, manifested as a significantly greater negative compatibility effect than that in controls. Experiment 2 used fMRI and a region of interest (ROI) template-based method to further test the hypothesis that structures of the striatal-pallidal-thalamic pathway mediate one or more of the processes of automatic inhibitory control. Neither prime activation nor response conflict significantly engaged any ROIs, but the response inhibition process led to significant modulation of both the caudate and thalamus. Taken together, these experiments indicate a causal role for the caudate nucleus and thalamus in automatic inhibitory motor control, and the results are consistent with performance of the task requiring both direct and indirect striatal-pallidal-thalamic pathways. The finding that Huntington's disease patients with greater chorea were disinhibited is consistent with the theory that chorea arises from selective degeneration of striatal projections to the lateral globus pallidus, while the exaggerated inhibitory effect for patients with little or no chorea may be due to additional degeneration of projections to the medial globus pallidus.

Adult↗
PubMed2002

The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers.

RATIONALE: Cognitive impairment is a common feature of depressive illness. While accumulating evidence suggests that brain serotonin (5-HT) pathways play an important role in the neurobiology of depression, the extent to which altered 5-HT function is responsible for the associated changes in cognition and emotion remains unclear. OBJECTIVE: The present study examined the effects of acute dietary depletion of tryptophan (TRP) on cognitive and affective processing in healthy volunteers and explored the putative role of 5-HT in the neuropsychology of depression. METHODS: We administered computerised cognitive tests to healthy control participants following ingestion of TRP-free and nutritionally balanced amino acid drinks in a double-blind, placebo-controlled, crossover design. RESULTS: The TRP-free amino acid mixture significantly lowered plasma total and free TRP concentrations relative to baseline values and produced selective deficits similar to those observed previously in cases of clinical depression. In particular, TRP depletion increased response times for happy but not sad targets in an affective go/no-go task and slowed responding in a visual discrimination and reversal learning task. These deficits were not due to a global sedative effect, as planning ability was unimpaired. CONCLUSIONS: The present data indicate that serotonergic factors may be more involved in the disrupted inhibitory and emotional processing characteristic of depression than in other aspects of executive function, such as planning ability. These findings support the recent proposal that serotonergic manipulation may have greater effects on tasks mediated by frontal circuitry that includes the orbitofrontal cortex than by dorsolateral prefrontal cortex circuitry.

Adult↗
PubMed2002

Decision making deficits in patients with first-episode and chronic schizophrenia.

A considerable body of evidence suggests that the dorsolateral prefrontal cortex is dysfunctional in schizophrenia. However, relatively few studies have explored the involvement of other areas of the frontal cortex. Research suggests that the orbitofrontal cortex (OFC) plays an important role in decision making processes. We assessed the decision making cognition of first-episode and chronic schizophrenic patients with a novel task sensitive to orbitofrontal dysfunction. Both first-episode and chronic patients with schizophrenia took longer than matched controls to make decisions, and both groups were also impaired on a measure of risk adjustment. The impairment in these measures was more severe in the chronic patients than in the first-episode patients, and only the chronic patients made significantly fewer optimal decisions than controls. These results contribute to increasing evidence of orbitofrontal dysfunction in schizophrenia, and suggest that disease progression or the effects of long term antipsychotic medication may influence performance on this task.

Analysis of Variance↗
PubMed2002

Neuropsychological evidence of a relatively selective profile of temporal dysfunction in drug-free MDMA ("ecstasy") polydrug users.

RATIONALE: Experimental evidence has shown that 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") can act as a serotonergic neurotoxin in laboratory animals. The serotonin system predominantly innervates frontal and limbic regions of the brain and has been associated with consolidatory learning and mnemonic processes in humans. OBJECTIVES: The aim of the present study was to investigate the cognitive neuropsychological profile of drug-free ecstasy users by employing a selection of tasks previously associated with lesion or neurodegenerative damage to the temporal lobe or fronto-striatal regions. METHODS: The study comprised 40 participants: 20 ecstasy polydrug users and 20 polydrug users who had never taken ecstasy. RESULTS: Ecstasy users were significantly impaired on a recognition task for complex visual patterns and spatial working memory, as a function of task difficulty rather than systematic search strategy. They also showed a trend towards impairment on several learning paradigms. Ecstasy users remained relatively unimpaired on most measures associated with prefrontal functioning, with the exception of verbal fluency "letter" generation. CONCLUSIONS: Initial cognitive deficits in ecstasy polydrug users may be more apparent in tasks known to be sensitive to temporal functioning.

Adolescent↗
PubMed2002

Neurocognitive deficits in decision-making and planning of patients with DSM-III-R borderline personality disorder.

BACKGROUND: Repeated, self-damaging behaviour occurring in the context of borderline personality disorder (BPD) may reflect impairments in decision-making and planning cognition. However, there has been no systematic neuropsychological examination of these particular cognitive functions in patients diagnosed with BPD. Such investigations may improve our understanding of the possible role of brain dysfunction in BPD and improve the characterization of the psychological difficulties associated with this disorder. METHOD: Forty-two psychiatric patients with a diagnosis of DSM-III-R BPD (41 of whom gave a history of self-harm), without a history of specified 'psychoses' or current major affective disorder, were clinically assessed before completing computerized tasks of decision-making and planning previously shown to be sensitive to frontal lobe dysfunction, and tests of spatial and pattern visual recognition memory previously shown to be sensitive to frontal lobe damage and temporal lobe damage respectively. The performance of the BPD patient group was compared with that of a non-clinical control group consisting of 42 subjects. RESULTS: The performance of the BPD patients on the decision-making task was characterized by a pattern of delayed and maladaptive choices when choosing between competing actions, and by impulsive, disinhibited responding when gambling on the outcome of their decisions. BPD patients also showed impairments on the planning task. There was no evidence of impaired visual recognition memory. Additional analyses suggested only limited effects of current medication and history of previous substance use disorder. CONCLUSIONS: These findings suggest that BPD is associated with complex impairments in dissociable cognitive processes mediated by circuitry encompassing the frontal lobes. These impairments may mediate some of the behavioural changes evident in BPD. Further work is needed to examine the specificity of these findings.

Adolescent↗
PubMed2001

Differing patterns of temporal atrophy in Alzheimer's disease and semantic dementia.

OBJECTIVE: To characterize and quantify the patterns of temporal lobe atrophy in AD vs semantic dementia and to relate the findings to the cognitive profiles. Medial temporal lobe atrophy is well described in AD. In temporal variant frontotemporal dementia (semantic dementia), clinical studies suggest polar and inferolateral temporal atrophy with hippocampal sparing, but quantification is largely lacking. METHODS: A volumetric method for quantifying multiple temporal structures was applied to 26 patients with probable AD, 18 patients with semantic dementia, and 21 matched control subjects. RESULTS: The authors confirmed the expected bilateral hippocampal atrophy in AD relative to controls, with involvement of the amygdala bilaterally and the right parahippocampal gyrus. Contrary to expectations, patients with semantic dementia had asymmetric hippocampal atrophy, more extensive than AD on the left. As predicted, the semantic dementia group showed more severe involvement of the temporal pole bilaterally and the left amygdala, parahippocampal gyrus (including the entorhinal cortex), fusiform gyrus, and the inferior and middle temporal gyri. Performance on semantic association tasks correlated with the size of the left fusiform gyrus, whereas naming appeared to depend upon a wider left temporal network. Episodic memory measures, with the exception of recognition memory for faces, did not correlate with temporal measures. CONCLUSIONS: Hippocampal atrophy is not specific for AD but is also seen in semantic dementia. Distinguishing the patients with semantic dementia was the severe global but asymmetric (left > right) atrophy of the amygdala, temporal pole, and fusiform and inferolateral temporal gyri. These findings have implications for diagnosis and understanding of the cognitive deficits in AD and semantic dementia.

Aged↗
PubMed2001

Acute dietary tryptophan depletion impairs maintenance of "affective set" and delayed visual recognition in healthy volunteers.

RATIONALE: Altered serotonergic transmission in affective disorders and Alzheimer's disease has prompted research aimed at defining the precise cognitive effects of depleting central serotonin in humans, using acute dietary tryptophan depletion. OBJECTIVE: We examined the effects of tryptophan depletion on mood and cognition in healthy volunteers. Cognitive tests of memory and attentional processing were employed to test hypotheses of central 5-hydroxytryptamine (5-HT) function related to cortical processing. METHODS: A double-blind, parallel design, placebo control study was employed with 15 subjects in each group. Mood rating scales were performed at the start and 5 h after ingestion of the drink. Cognitive tests were also performed at 5 h, after completion of the subjective rating scales. RESULTS: A robust reduction in total tryptophan was achieved in the test group. Subjects receiving the placebo drink showed the expected effect of shift on the affective shifting task, that is, more errors in the more difficult shift versus the non-shift condition. The tryptophan-depleted group made a similar number of errors in the shift trials but failed to reduce the number of errors in the non-shift trials. The tryptophan-depleted group showed a significant impairment on the delayed pattern recognition task. No significant effects on the subjective mood measures were found. CONCLUSIONS: Tryptophan depletion abolished the normal tendency to improve error scores on non-shift trials in response to affective cues on a go/no-go task. We suggest that this inability to "maintain set" in the non-shift condition may be due to a disruption of semantic retrieval processes concerned with affect. The novel finding of impairment on a delayed visual pattern recognition task confirms and extends previous studies where selective effects on memory and learning have been found following acute tryptophan depletion.

Adult↗
PubMed2001

Decision-making cognition in mania and depression.

BACKGROUND: Despite markedly different clinical presentations, few studies have reported differences in neuropsychological functioning between mania and depression. Recent work has suggested that differences may emerge on cognitive tasks requiring affective processing, such as decision-making. The present study sought to compare decision-making cognition in mania and depression in order to clarify the current profiles of impairment for these disorders and to contribute to our more general understanding of the relationship between mood and cognition. METHODS: Medicated manic patients, depressed patients, and normal healthy controls completed a computerized decision-making task. All subjects were asked to win as many points as possible by choosing outcomes based on variably-weighted probabilities and by placing 'bets' on each decision. RESULTS: Both patient groups were impaired on this task, as evidenced by slower deliberation times, a failure to accumulate as many points as controls and suboptimal betting strategies. Manic, but not depressed, patients made suboptimal decisions--an impairment that correlated with the severity of their illness. CONCLUSIONS: These findings are consistent with a growing consensus that manic and depressed patients are characterized by significant impairments in cognitive and particularly executive, functioning. Furthermore, the distinct patterns of observed impairment in manic and depressed patients suggests that the nature and extent of cognitive impairment differ between these two groups. Viewed in the context of other recent studies, these findings are consistent with a role for the ventromedial prefrontal cortex in mediating mood-cognition relationships.

Adult↗
PubMed2001

Mechanisms of cognitive set flexibility in Parkinson's disease.

Previous research on cognitive set shifting in patients with Parkinson's disease has often been confounded by concept formation, rule learning, working memory and/or general slowing of cognitive processes. To circumvent this problem, the present study used the task-set switching procedure in which good performance was independent of rule learning, and in which working memory load was reduced by explicitly cueing the task switches. Our results provide strong evidence for a specific cognitive set shifting deficit in patients with mild Parkinson's disease in a non-learning context, which also cannot be explained by general slowing of cognitive processes. Moreover, the deficit was robust in a small sample of patients at the earliest stages of the disease. Finally, the impairment in task-set switching was only apparent when competing information was present, i.e. when the load on selection mechanisms was increased.

Cognition↗
PubMed2001

Decision-making in mania: a PET study.

Poor decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania.

Adult↗
PubMed2001

Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands.

We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson's disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex- ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry.

Attention↗
PubMed2001

Temporal lobe rating scale: application to Alzheimer's disease and frontotemporal dementia.

OBJECTIVES: Temporal lobe atrophy as assessed by MRI can be measured in several ways. Volumetric measurements are quantitative but very time consuming and require extensive training to perform, so are not easily transferable to clinical practice. Visual rating scales, by contrast, are quick and widely applicable. Although medial temporal lobe atrophy is well described in Alzheimer's disease (AD), it is uncertain how early these changes can be detected and whether they discriminate AD from other neurodegenerative diseases, most notably frontotemporal dementia (FTD). The objectives were (1) to develop a widely applicable temporal lobe rating scale, and (2) to characterise and quantify the patterns of temporal lobe atrophy in AD versus temporal and frontal variants of FTD. METHODS: The temporal lobe assessments were made using an established hippocampal rating scale extended to incorporate additional temporal regions. This was firstly validated with volumetric analysis and then applied to 30 probable AD, 30 FTD (consisting of 17 temporal variant (semantic dementia) and 13 frontal variant) and 18 control coronal MRI images. RESULTS: Bilateral hippocampal atrophy was found in 50% of the patients with AD. Contrary to expectations, patients with semantic dementia also had hippocampal atrophy, which for the left side exceeded that seen in AD; other regions (temporal pole, parahippocampal gyrus, and lateral temporal lobe), spared in AD, were severely atrophied in this group. The patients with frontal variant FTD occupied an intermediate position and were largely indistinguishable from AD. CONCLUSIONS: Hippocampal atrophy is, therefore, not specific for AD. Semantic dementia can be distinguished from AD, by the presence of severe bilateral atrophy of the temporal pole, parahippocampal and lateral regions. These findings have implications for the differential diagnosis of dementias.

Aged↗
PubMed2001

Neuropsychology of bipolar disorder.

Background Although the presence of wide-ranging neuropsychological deficits in individuals with major depression is well established, few studies have investigated the nature of cognitive impairment in patients with bipolar disorder. Aims To review research of the neuropsychology of bipolar disorder, with special attention to the relationship between mood and cognitive functioning. Method Literature review. Results Findings generally demonstrate mania-related impairments on conventional neuropsychological tests, with direct comparisons of patients with mania and patients with depression failing to find group differences. More recent work has sought to differentiate these disorders by employing tasks with affective components. This research has demonstrated biases for processing positive and negative stimuli in patients with mania and depression, respectively. Conclusions Future studies, employing tasks that require cognitive and emotional processing, should improve our understanding of the deficits observed in depression and mania. Neuroimaging studies of the neural regions that underlie cognitive processing of affective meaning suggest that the medial and orbitofrontal prefrontal cortex may be particularly involved.

Journal Article↗
PubMed2001

Neuropsychology of bipolar disorder.

BACKGROUND: Although the presence of wide-ranging neuropsychological deficits in individuals with major depression is well established, few studies have investigated the nature of cognitive impairment in patients with bipolar disorder. AIMS: To review research of the neuropsychology of bipolar disorder, with special attention to the relationship between mood and cognitive functioning. METHOD: Literature review. RESULTS: Findings generally demonstrate mania-related impairments on conventional neuropsychological tests, with direct comparisons of patients with mania and patients with depression failing to find group differences. More recent work has sought to differentiate these disorders by employing tasks with affective components. This research has demonstrated biases for processing positive and negative stimuli in patients with mania and depression, respectively. CONCLUSIONS: Future studies, employing tasks that require cognitive and emotional processing, should improve our understanding of the deficits observed in depression and mania. Neuroimaging studies of the neural regions that underlie cognitive processing of affective meaning suggest that the medial and orbitofrontal prefrontal cortex may be particularly involved.

Bipolar Disorder↗