Biomedical subjects

Luke Clark

Publications and source records attributed to Luke Clark.

34 records · Page 2Linked to original sources

PubMed2005

Mood-congruent bias in affective go/no-go performance of unmedicated patients with major depressive disorder.

OBJECTIVE: Neuropsychological studies of major depressive disorder have described attentional biases for affectively laden stimuli, but these reports were based on measures obtained from medicated subjects. This study investigated performance of unmedicated depressed patients on the Affective Go/No-Go Task. METHOD: Twenty depressed patients and 20 healthy comparison subjects, matched for age, gender, and IQ, performed the Affective Go/No-Go Task as well as tests of attention and memory for nonaffective stimuli. RESULTS: Depressed patients did not differ from healthy subjects on memory task performance, but they made more omission errors on the attention task. On the Affective Go/No-Go Task, depressed patients made more omission errors during happy than sad word blocks and required more time to respond to happy than to sad words. In contrast, healthy subjects required more time to respond to sad than to happy words. CONCLUSIONS: Unmedicated depressed patients do not show a pattern of generalized cognitive impairment but, rather, specifically display an attentional deficit and a mood-congruent bias toward salient stimuli.

Adult↗

PubMed2004

Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder.

BACKGROUND: Modafinil, a novel cognitive enhancer, has a clinical profile similar to conventional stimulants such as methylphenidate, despite a seemingly different mechanism of action. Modafinil selectively improves neuropsychological task performance in healthy volunteers, possibly through improved inhibitory control. We examined whether modafinil induced similar improvements in adults with attention-deficit/hyperactivity disorder. METHODS: Twenty patients with a DSM-IV diagnosis of attention-deficit/hyperactivity disorder were entered into a double-blind, randomized, placebo-controlled crossover study using a single 200 mg dose of modafinil. RESULTS: Modafinil produced a similar pattern of cognitive enhancement to that observed in healthy adults, with improvements on tests of short-term memory span, visual memory, spatial planning, and stop-signal motor inhibition. On several measures, increased accuracy was accompanied by slowed response latency. This alteration in the speed-accuracy trade-off may indicate that modafinil increases the ability to "reflect" on problems coupled with decreased impulsive responding. Improvements were also seen in sustained attention, which was unaffected in healthy subjects. CONCLUSIONS: If these benefits are shown to be maintained with chronic administration, modafinil may have potential as an important therapy for attention-deficit/hyperactivity disorder with a similar effect to stimulants such as methylphenidate in improving stop-signal response inhibition but without the side effects commonly experienced with amphetamine-like drugs.

Adult↗

PubMed2004

Differential responses in human striatum and prefrontal cortex to changes in object and rule relevance.

Event-related functional magnetic resonance imaging was used to measure blood oxygenation level-dependent responses in 16 young healthy human volunteers during performance of an attentional switching task. The task allowed the separate investigation of lower-order switching between concrete objects and higher-order switching between abstract task rules. Significant signal change in the ventral striatum was demonstrated on trials when subjects switched between objects but not when subjects switched between abstract task rules. In contrast, signal change in the lateral prefrontal cortex (PFC) was observed during all switch trials. The switch-related responses were not contaminated by task difficulty, because the greatest signal change was observed during the relatively easy switch trials, which required both lower-order and higher-order switching at the same time. The present data suggest that mechanisms of inhibitory response control in frontostriatal systems are organized according to distinct levels of abstraction. Specifically, the response selection computation carried by the ventral striatum, which projects to the orbitofrontal cortex and the medial PFC, is restricted to the transformation of concrete stimulus exemplar information into motor responses, whereas the adaptive function of the lateral PFC extends to the transformation of abstract task-rule representations into action.

Adolescent↗

PubMed2004

State- and trait-related deficits in sustained attention in bipolar disorder.

Investigation of neuropsychological functioning in bipolar disorder provides a potential link from the prominent cognitive symptoms of the disorder to the underlying neural mechanisms. Continuous performance measures of sustained attention have yielded consistent findings in bipolar disorder patients. There are impairments that appear to be both state- and trait-related. Impaired target detection may represent one of the most sensitive markers of illness course in bipolardisorder. It is unrelated to residual mood symptomatology and medication status, and is present in patients with good functional recovery. The impairment in target detection is exacerbated in the manic state, and is accompanied by an increased rate of false responding. Sustained attention deficit is present early in the course of the disorder, but becomes more pronounced with repeated episodes. This cognitive profile, of an early-onset, state-modulated, trait marker, is distinct from the profile of attentional disruption seen in schizophrenia or unipolar depression. The state- and trait-related impairments may be differentially associated with the ascending dopamine and noradrenaline projections.

Attention↗

PubMed2004

Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia.

Modafinil, a novel cognitive enhancer, selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder (ADHD). It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission. The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia. Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind, randomized, placebo-controlled crossover study using a 200 mg dose of modafinil. Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD. Improvement was seen on short-term verbal memory span, with trends towards improved visual memory and spatial planning. This was accompanied by slowed response latency on the spatial planning task. No effect on stop-signal performance was seen. Importantly, significant improvement in attentional set shifting was seen, despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.

Adult↗

PubMed2004

Social and emotional decision-making following frontal lobe injury.

Neuropsychological, psychophysiological and functional imaging research has begun to offer insights into the everyday difficulties in decision-making experienced by some patients with frontal lobe damage. It is widely accepted that the ventral prefrontal cortex plays a pivotal role in social and emotional decision-making. This article will review experimental findings using the Iowa Gambling Task and the Cambridge Gamble Task that explore the brain mechanisms of decision-making. Convergent evidence from the two tasks confirms the importance of ventral PFC, but also highlights the relevance of lesion laterality, lesion aetiology, and the contribution of other brain regions (including the dorsal prefrontal cortex and amygdala) to decision-making abilities. The extent to which disrupted decision-making can be separated from the broader domain of executive function is discussed.

Brain Injuries↗

PubMed2004

Episodic memory impairment in bipolar disorder and obsessive-compulsive disorder: the role of memory strategies.

BACKGROUND: There is evidence that individuals with bipolar disorder exhibit neuropsychological impairments not only during mood episodes but also when they are euthymic. One of the most consistently reported cognitive problems in euthymic individuals with bipolar disorder is an impairment in verbal episodic memory. Verbal learning and memory depend on individuals' ability to organize verbal information appropriately during learning. The purpose of the present study was (i) to determine whether episodic memory impairment in euthymic individuals with bipolar disorder is mediated by impairments in organization of verbal information during learning and (ii) to compare the characteristics of memory impairment in bipolar disorder with that previously found in obsessive-compulsive disorder (OCD). METHODS: Study participants were 30 individuals with DSM-IV bipolar I disorder (BP-I), 30 individuals with DSM-IV OCD and 30 normal control participants matched for age, gender and education. Participants completed the California Verbal Learning Test (CVLT), a well-established measure of verbal learning and memory that enables assessment of verbal organization strategies during learning. RESULTS: Compared with control subjects, both BP-I and OCD participants showed impaired performance in long-delayed free recall and verbal organization strategies during learning. BP-I participants showed greater long-delay free recall difficulties but not greater verbal organization difficulties during learning than OCD participants. For OCD participants, the long-delay recall impairment was mediated by difficulties using verbal organizational strategies during learning. In contrast, the group difference in long-delayed free recall between BP-I and control participants remained significant even when semantic clustering was introduced as a mediator. This indicated that BP-I participants' long-delayed free recall difficulties were mediated to a lesser extent by difficulties using verbal organizational strategies than for OCD participants. CONCLUSIONS: Verbal episodic memory problems in individuals with bipolar I disorder and OCD are mediated to different degrees by difficulties using semantic clustering encoding strategies compared with control participants.

Adult↗

PubMed2003

Relative lack of cognitive effects of methylphenidate in elderly male volunteers.

RATIONALE: Methylphenidate, a dopaminergic and noradrenergic reuptake inhibitor, has been shown in young, healthy adult volunteers to produce pronounced effects on working memory and sustained attention. We were interested in assessing whether similar improvements could be conferred upon elderly volunteers in order to gain a more complete understanding of the effects of age on monoaminergic manipulations of working memory and attention, as well as to explore the potential for pharmacological intervention in attention and executive dysfunction disorders in this age group. OBJECTIVES: The main aim of the study was to characterise the dose-related effects of methylphenidate on a range of neuropsychological functions in elderly healthy volunteers. METHODS: Sixty healthy elderly adult male volunteers received either a single oral dose of placebo, 20 mg or 40 mg methylphenidate prior to performing a variety of tasks designed to assess memory, attention and executive function. A randomised double-blind, between-subjects design was used. RESULTS: Methylphenidate had significant cardiovascular and subjective effects. However, unlike in younger volunteers, no significant effects of drug on working memory (spatial span and spatial working memory), response inhibition (stop-signal) or sustained attention (rapid visual information processing) were seen. Subtle effects on latency similar to those in younger volunteers were identified: both doses of methylphenidate resulted in a slowing in response time during set-shifting and decision-making. CONCLUSIONS: The results of this study demonstrate that, in elderly subjects, the cognitive effects of methylphenidate are grossly attenuated and distinct from the profile previously described in younger volunteers. It is suggested that methylphenidate may not be appropriate as a pharmacological intervention in elderly patient groups, such as those reporting age-related cognitive decline.

Administration, Oral↗

PubMed2003

The contributions of lesion laterality and lesion volume to decision-making impairment following frontal lobe damage.

Lesions to prefrontal cortex (PFC) in humans can severely disrupt everyday decision-making, with concomitant effects on social and occupational functioning. Forty-six patients with unilateral lesions to prefrontal cortex and 21 healthy control subjects were administered three neuropsychological measures of decision-making: the Iowa Gambling Task, the Cambridge Gamble Task, and the Risk Task. Magnetic resonance imaging (MRI) scans were acquired from 40 patients, with region of interest (ROI) mapping of prefrontal subregions. The frontal patients showed only limited damage in medial and orbital prefrontal cortex, but greater damage in lateral prefrontal regions of interest. Patients with right frontal lesions preferred the risky decks on the Iowa Gambling Task, and differed significantly from left frontal and control subjects. Within the right frontal group, the preference for the risky decks was correlated with the total lesion volume and the volume of damage outside of the ventromedial prefrontal region. Right and left frontal groups did not differ significantly on the Cambridge Gamble Task or the Risk Task, and performance was not associated with lesion volume. The results indicate a laterality effect on the Iowa Gambling Task, and the contribution of prefrontal regions outside the ventromedial region to task performance. The Cambridge Gamble Task and Risk Task were less sensitive to the effects of unilateral frontal lobe lesions, and may be more selectively associated with ventral prefrontal damage.

Adult↗

PubMed2002

Cognitive enhancing effects of modafinil in healthy volunteers.

RATIONALE: Modafinil, a novel wake-promoting agent, has been shown to have a similar clinical profile to that of conventional stimulants such as methylphenidate. We were therefore interested in assessing whether modafinil, with its unique pharmacological mode of action, might offer similar potential as a cognitive enhancer, without the side effects commonly experienced with amphetamine-like drugs. OBJECTIVES: The main aim of this study was to evaluate the cognitive enhancing potential of this novel agent using a comprehensive battery of neuropsychological tests. METHODS: Sixty healthy young adult male volunteers received either a single oral dose of placebo, or 100 mg or 200 mg modafinil prior to performing a variety of tasks designed to test memory and attention. A randomised double-blind, between-subjects design was used. RESULTS: Modafinil significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time. These performance improvements were complemented by a slowing in latency on three tests: delayed matching to sample, a decision-making task and the spatial planning task. Subjects reported feeling more alert, attentive and energetic on drug. The effects were not clearly dose dependent, except for those seen with the stop-signal paradigm. In contrast to previous findings with methylphenidate, there were no significant effects of drug on spatial memory span, spatial working memory, rapid visual information processing or attentional set-shifting. Additionally, no effects on paired associates learning were identified. CONCLUSIONS: These data indicate that modafinil selectively improves neuropsychological task performance. This improvement may be attributable to an enhanced ability to inhibit pre-potent responses. This effect appears to reduce impulsive responding, suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder.

Adult↗

PubMed2002

Decision-making deficits in drug addiction.

Core aspects of addictive behaviour can be explained in terms of abnormal decision-making. Using recording of autonomic function during performance of two gambling tasks, Bechara et al. have recently identified three distinct neuropsychological subtypes in individuals with substance dependence. These subtypes may reflect dissociable patterns of disruption in limbic brain circuitry.

Journal Article↗

PubMed2002

Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging.

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.

Adult↗

PubMed2002

Sustained attention deficit in bipolar disorder is not a working memory impairment in disguise.

Euthymic patients with bipolar disorder have been reported to show persistent deficits in sustained attention. However, the sustained attention task which was used also placed demands on working memory. Bipolar disorder patients in the euthymic state were therefore compared with healthy controls on two measures of sustained attention with and without a working memory component. Signal detection methodology was applied to the results. Euthymic patients with bipolar disorder were particularly impaired at detecting targets in the sustained attention task without a working memory component. This deficit was still apparent in a sub-group of patients who were not currently receiving lithium medication. By contrast, performance in the sustained attention task involving working memory task was not significantly different in the two groups. Sustained attention deficits apparent during the euthymic period of bipolar disorder cannot be explained in terms of working memory impairment and represents a reduced inherent capacity rather than a change in response bias. Deficits in sustaining attention may help explain the difficulties in psychological and occupational functioning in bipolar disorder patients during remission.

Adult↗

PubMed2002

Decision-making processes following damage to the prefrontal cortex.

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.

Adult↗

PubMed2002

Sustained attention deficit in bipolar disorder.

BACKGROUND: Recovery in bipolar disorder is central to its definition but is rarely complete. Previous work has suggested that neuropsychological impairment persists during the euthymic state but has been confounded partly by mild affective symptoms in remitted patients. AIMS: To characterise neuropsychological functioning in the euthymic phase of bipolar disorder with an emphasis on tasks of executive functioning. METHOD: Thirty euthymic patients with bipolar disorder were compared with thirty healthy controls on neuropsychological tasks differentially sensitive to damage within prefrontal cortex. RESULTS: Bipolar I patients were impaired on tasks of attentional set shifting, verbal memory and sustained attention. Only sustained attention deficit survived controlling for mild affective symptoms. This deficit was related to progression of illness, but was none the less present in a subgroup of patients near illness onset. CONCLUSIONS: 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.

Adolescent↗

PubMed2000

Repetitive transcranial magnetic stimulation to right prefrontal cortex does not modulate the psychostimulant effects of amphetamine.

Preliminary evidence indicates lateralized efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of mood disorders. Right-sided prefrontal cortex (PFC) stimulation has been reported to treat symptoms of mania. The acute effect of amphetamine serves as a model of mania in healthy individuals, hence rTMS to right PFC was hypothesized to attenuate the psychostimulant action of amphetamine in healthy volunteers. Eighteen subjects received rTMS to right PFC or right parietal cortex (PAR), or sham stimulation, in a randomized between-subjects design. Following rTMS subjects received i.v. amphetamine (0.15 mg/kg). Intravenous amphetamine induced robust subjective (visual analogue scales) and objective (blood pressure, sustained attention) effects, but the extent of the effects was not modulated by right PFC stimulation. Though this dose cannot refute the efficacy of rTMS in treating mania, it indicates that any therapeutic mechanism of action is unlikely to be through modulation of dopamine function.

Journal Article↗