Biomedical subjects

Luke Clark

Publications and source records attributed to Luke Clark.

At least 19 recordsLinked to original sources

PubMed2006

Association between response inhibition and working memory in adult ADHD: a link to right frontal cortex pathology?

BACKGROUND: We sought to assess the relationship between response inhibition and working memory in adult patients with attention-deficit/hyperactivity disorder (ADHD) and neurosurgical patients with frontal lobe damage. METHODS: The stop-signal reaction time (SSRT) test and a spatial working memory (SWM) task were administered to 20 adult patients with ADHD and a group of matched controls. The same tasks were administered to 21 patients with lesions to right frontal cortex and 19 patients with left frontal lesions. RESULTS: The SSRT test, but not choice reaction time, was significantly associated with search errors on the SWM task in both the adult ADHD and right frontal patients. In the right frontal patients, impaired performance on both variables was correlated with the volume of damage to the inferior frontal gyrus. CONCLUSIONS: Response inhibition and working memory impairments in ADHD may stem from a common pathologic process rather than being distinct deficits. Such pathology could relate to right frontal-cortex abnormalities in ADHD, consistent with prior reports, as well as with the demonstration here of a significant association between SSRT and SWM in right frontal patients.

Adult↗

PubMed2006

A neuropsychological comparison of obsessive-compulsive disorder and trichotillomania.

BACKGROUND: Obsessive-compulsive disorder (OCD) and trichotillomania (compulsive hair-pulling) share overlapping co-morbidity, familial transmission, and phenomenology. However, the extent to which these disorders share a common cognitive phenotype has yet to be elucidated using patients without confounding co-morbidities. AIM: To compare neurocognitive functioning in co-morbidity-free patients with OCD and trichotillomania, focusing on domains of learning and memory, executive function, affective processing, reflection-impulsivity and decision-making. METHOD: Twenty patients with OCD, 20 patients with trichotillomania, and 20 matched controls undertook neuropsychological assessment after meeting stringent inclusion criteria. RESULTS: Groups were matched for age, education, verbal IQ, and gender. The OCD and trichotillomania groups were impaired on spatial working memory. Only OCD patients showed additional impairments on executive planning and visual pattern recognition memory, and missed more responses to sad target words than other groups on an affective go/no-go task. Furthermore, OCD patients failed to modulate their behaviour between conditions on the reflection-impulsivity test, suggestive of cognitive inflexibility. Both clinical groups showed intact decision-making and probabilistic reversal learning. CONCLUSIONS: OCD and trichotillomania shared overlapping spatial working memory problems, but neuropsychological dysfunction in OCD spanned additional domains that were intact in trichotillomania. Findings are discussed in relation to likely fronto-striatal neural substrates and future research directions.

Adult↗

PubMed2006

The relationship between affective decision-making and theory of mind in the frontal variant of fronto-temporal dementia.

Structural brain imaging and neuropsychological data implicate the orbital aspects of prefrontal cortex in the developing neuropathology of fvFTD. Damage to this region is associated with deficient performance on laboratory tasks assessing theory of mind (ToM) and affective decision-making (DM), but the relationship between these two capacities in patients with prefrontal cortex dysfunction is unclear. We studied a group of patients with early/mild fvFTD (n=20) and a group of matched normal controls (n=10) on the Iowa gambling task (IGT) of affective decision-making, and the "reading the mind in the eyes" (MIE) and "faux pas" (FP) tests of ToM. The fvFTD group was impaired in both ToM tasks and the IGT. While performance measures from the two ToM tasks were significantly correlated, they were not associated with IGT performance. This suggests that whilst similar prefrontal circuitry is implicated in ToM and DM tasks, these cognitive domains may be independent. In clinical settings, the IGT may be useful as a complementary tool to the frontal test battery for patients with early/mild fvFTD. Deficits in decision-making and ToM observed in this study have distinct but additive effects upon the development of social behaviour in patients with prefrontal dysfunction.

Aged↗

PubMed2006

The effects of acute tryptophan depletion and serotonin transporter polymorphism on emotional processing in memory and attention.

Polymorphism at the serotonin transporter linked polymorphic region (5-HTTLPR) has been associated with neuroticism, increased risk for affective disorders and greater vulnerability to mood change following serotonin (5-HT) depletion. The aim of the present study was to investigate whether the cognitive effects of 5-HT depletion were differentially affected by genotype at the 5-HTTLPR polymorphism, using neuropsychological measures of memory and attention. We utilized the acute tryptophan depletion (ATD) technique to temporarily reduce 5-HT synthesis in two groups of healthy volunteers pre-selected on the basis of 5-HTTLPR genotype, 15 of the ll genotype and 15 of the ss genotype, in a double-blind, placebo-controlled crossover design. As expected, ATD resulted in a robust reduction in plasma tryptophan concentration in both genotype groups. However, the genotype groups differed in terms of the effect of ATD on cognitive performance. The ss genotype group showed impaired verbal recall following depletion, while episodic memory was unimpaired by ATD in the ll genotype group. Averaging across depletion condition, the ss genotype group outperformed the ll genotype group on tests of episodic memory and attention. Neither group was significantly affected by ATD on measures of emotional state. These data confirm previous reports that ss individuals are particularly vulnerable to 5-HT depletion, but extend these findings to the cognitive domain. The unexpected finding that ss volunteers showed improved memory and attention relative to ll volunteers suggests a possible evolutionary advantage to possession of the s allele, which may offset the disadvantage of vulnerability to depression following stressful life events.

Adult↗

PubMed2006

L-DOPA disrupts activity in the nucleus accumbens during reversal learning in Parkinson's disease.

Evidence indicates that dopaminergic medication in Parkinson's disease may impair certain aspects of cognitive function, such as reversal learning. We used functional magnetic resonance imaging in patients with mild Parkinson's disease to investigate the neural site at which L-DOPA acts during reversal learning. Patients were scanned both ON and OFF their normal dopamine-enhancing L-DOPA medication during the performance of a probabilistic reversal learning task. We demonstrate that L-DOPA modulated reversal-related activity in the nucleus accumbens, but not in the dorsal striatum or the prefrontal cortex. These data concur with evidence from studies with experimental animals and indicate an important role for the human nucleus accumbens in the dopaminergic modulation of reversal learning.

Aged↗

PubMed2006

Serotonin transporter polymorphism mediates vulnerability to loss of incentive motivation following acute tryptophan depletion.

The serotonin (5-HT) system is implicated in incentive motivational processes. The present study utilized the acute tryptophan depletion (ATD) procedure to investigate the effect of temporarily lowering 5-HT synthesis on motivation in healthy volunteers, stratifying the results by allelic variation at the serotonin transporter gene (5-HTTLPR). ATD resulted in a robust reduction in plasma tryptophan concentration. Consistent with a previous study, ATD attenuated motivationally speeded action on the Cued-Reinforcement Reaction Time task. The present investigation revealed that this effect was restricted to volunteers of the ss genotype, whereas ll volunteers exhibited intact motivationally speeded action following ATD (treatment x reinforcement probability x genotype interaction: F1,26=5.8, p=0.024). Furthermore, tryptophan availability to the brain was correlated positively with motivationally speeded action following ATD in the ss genotype group (rho13=0.71, p=0.006), whereas this correlation was negative in the ll genotype group (rho14=-0.60, p=0.023). This is the first study to suggest that allelic variation at the 5-HTTLPR mediates motivational responses to ATD in healthy volunteers. These data indicate that the s allele at the 5-HTTLPR may confer risk for depression via its effect on incentive motivational processing, and highlight the importance of genetic variation in determining individual responses to pharmacological treatments.

Adult↗

PubMed2006

Neurochemical modulation of response inhibition and probabilistic learning in humans.

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.

Adult↗

PubMed2006

Reflection impulsivity in current and former substance users.

BACKGROUND: Chronic drug use is associated with increased impulsivity, risky decision making, and impaired behavioral control, but the underlying mechanisms of this neurocognitive profile remain unclear. We investigated impulsive responding in the context of decision making, using a novel behavioral measure of reflection impulsivity: the tendency to gather and evaluate information before making a decision. METHODS: The Information Sampling Task was administered to current substance users dependent on amphetamines (n = 24) or opiates (n = 40), former users of amphetamines or opiates abstinent for at least 1 year (n = 24), and non-drug-using control subjects (n = 26). RESULTS: Current users of amphetamines and opiates sampled less information than control subjects and responded at a lower probability of making a correct response. Amphetamine- and opiate-dependent subjects did not differ. Reduced reflection was also apparent in the former substance users, who did not differ from the current users. Questionnaire ratings of impulsivity (on the Barratt Impulsivity Scale, version 11) were also inflated in three groups of substance users but were not significantly correlated with performance on the behavioral task. CONCLUSIONS: Reduced reflection is suggested to represent a cognitive marker for substance dependence that does not recover with prolonged abstinence and is associated with multiple drugs of abuse.

Adult↗

PubMed2006

Impulsivity, reward sensitivity, and decision-making in subarachnoid hemorrhage survivors.

Subarachnoid hemorrhage (SAH) survivors often report psychosocial and emotional changes, including a diminished capacity for decision making. However, systematic investigations into the nature of the changes have been limited to those patients surviving SAH secondary to aneurysms of the anterior communicating artery. This study aimed to explore the nature of decision making in survivors of SAH secondary to aneurysms of the middle cerebral or posterior communicating artery using a series of computerized tasks. Twenty SAH survivors and 20 matched controls completed a battery of computerized decision-making tasks. These included tasks examining an individual's ability to make probabilistic choices and risk-taking behavior, as well as tasks examining aspects of impulsivity. The results revealed two key patterns of abnormal decision-making behavior in the SAH survivors: altered sensitivity to both reward and punishment, and impulsive responding. These complex deficits may contribute to difficulties in daily living resulting from apathy, poor judgment, or inhibition in SAH survivors.

Case-Control Studies↗

PubMed2006

Methylphenidate ('Ritalin') can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia.

The frontal variant of frontotemporal dementia is a significant neurological condition worldwide. There exist few treatments available for the cognitive and behavioural sequelae of fvFTD. Previous research has shown that these patients display risky decision-making, and numerous studies have now demonstrated pathology affecting the orbitofrontal cortex. The present study uses a within-subjects, double-blind, placebo-controlled procedure to investigate the effects of a single dose of methylphenidate (40 mg) upon a range of different cognitive processes including those assessing prefrontal cortex integrity. Methylphenidate was effective in 'normalizing' the decision-making behavior of patients, such that they became less risk taking on medication, although there were no significant effects on other aspects of cognitive function, including working memory, attentional set shifting, and reversal learning. Moreover, there was an absence of the normal subjective and autonomic responses to methylphenidate seen in elderly subjects. The results are discussed in terms of the 'somatic marker' hypothesis of impaired decision-making following orbitofrontal dysfunction.

Aged↗

PubMed2006

Profile of executive and memory function associated with amphetamine and opiate dependence.

Cognitive function was assessed in chronic drug users on neurocognitive measures of executive and memory function. Current amphetamine users were contrasted with current opiate users, and these two groups were compared with former users of these substances (abstinent for at least one year). Four groups of participants were recruited: amphetamine-dependent individuals, opiate-dependent individuals, former users of amphetamines, and/or opiates and healthy non-drug taking controls. Participants were administered the Tower of London (TOL) planning task and the 3D-IDED attentional set-shifting task to assess executive function, and Paired Associates Learning and Delayed Pattern Recognition Memory tasks to assess visual memory function. The three groups of substance users showed significant impairments on TOL planning, Pattern Recognition Memory and Paired Associates Learning. Current amphetamine users displayed a greater degree of impairment than current opiate users. Consistent with previous research showing that healthy men are performing better on visuo-spatial tests than women, our male controls remembered significantly more paired associates than their female counterparts. This relationship was reversed in drug users. While performance of female drug users was normal, male drug users showed significant impairment compared to both their female counterparts and male controls. There was no difference in performance between current and former drug users. Neither years of drug abuse nor years of drug abstinence were associated with performance. Chronic drug users display pronounced neuropsychological impairment in the domains of executive and memory function. Impairment persists after several years of drug abstinence and may reflect neuropathology in frontal and temporal cortices.

Adult↗

PubMed2005

Lack of effects of guanfacine on executive and memory functions in healthy male volunteers.

RATIONALE: Guanfacine is an alpha2-adrenergic receptor agonist that has been shown to have beneficial effects on working memory and attentional functions in monkeys and in patients with attention deficit hyperactivity disorder. OBJECTIVES: The aim of this study was to further investigate the cognitive-enhancing properties of guanfacine using an established battery of tasks measuring executive and memory functions. METHODS: Sixty healthy male volunteers were randomised into three groups. Cognitive testing was performed from +2 to +4 h after double-blind administration of a single oral dose of 1 or 2 mg of guanfacine or placebo. RESULTS: Systolic blood pressure was significantly reduced by both doses of guanfacine at the end of the testing session. There were no statistically significant effects on any of the cognitive measures. Two trend effects were observed with poorer performance on digit span backward and slower 'Go' reaction times after guanfacine. CONCLUSION: This study found no improvement of prefrontal memory or executive functions after guanfacine. Negative effects on blood pressure and trend effects on digit span backward and go reaction time indicate a mild sedative effect of guanfacine at these doses, possibly via mechanisms of autoreceptor down-regulation.

Adult↗

PubMed2005

Individual differences in threat sensitivity predict serotonergic modulation of amygdala response to fearful faces.

RATIONALE: In this study we used functional magnetic resonance imaging (fMRI) to examine the effects of acute tryptophan depletion (ATD), a well-recognised method for inducing transient cerebral serotonin depletion, on brain activation to fearful faces. OBJECTIVES: We predicted that ATD would increase the responsiveness of the amygdala to fearful faces as a function of individual variation in threat sensitivity. METHODS: Twelve healthy male volunteers received a tryptophan depleting drink or a tryptophan balancing amino acid drink (placebo) in a double-blind crossover design. Five hours after drink ingestion participants were scanned whilst viewing fearful, happy and neutral faces. RESULTS: Consistent with previous findings, fearful faces induced significant signal change in the bilateral amygdala/hippocampus as well as the fusiform face area and the right dorsolateral prefrontal cortex. Furthermore, ATD modulated amygdala/hippocampus activation in response to fearful relative to happy faces as a function of self-reported threat sensitivity (as measured with the Behavioral Inhibition Scale; Carver CS, White TL (1994) Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: the BIS/BAS scales. J Pers Soc Psychol 67:319-333). CONCLUSION: The data support the hypothesis that individual variation in threat sensitivity interacts with manipulation of 5-HT function to bias the processing of amygdala-dependent threat-relevant stimuli.

Adolescent↗

PubMed2005

Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression.

BACKGROUND: Cognitive dysfunction persists in the euthymic phase of bipolar disorder and may provide a marker of underlying neuropathology and disease vulnerability. This study aimed to replicate a deficit in sustained attention in euthymic bipolar patients and investigate sustained attention in first-degree relatives of bipolar probands and in remitted patients with major depressive disorder. METHODS: The rapid visual information processing (RVIP) task was used to measure sustained attention in 15 euthymic patients with bipolar disorder and 15 control subjects in experiment 1 and in 27 first-degree relatives of bipolar probands, 15 remitted patients with major depressive disorder, and 46 control subjects in experiment 2. RESULTS: Sustained attention deficit was confirmed in the euthymic bipolar patients in experiment 1, but the deficit was not statistically significant in remitted major depressed patients or in the relatives of bipolar probands. CONCLUSIONS: A deficit of sustained attention is not present in patients with recurrent major depression tested during remission nor is it discriminable in the first-degree relatives of bipolar probands. Thus, the confirmed abnormality in euthymic bipolar patients may be acquired as a consequence of bipolar illness. However, future studies of relatives will require larger sample sizes to exclude or utilize small genetic effects.

Adult↗

PubMed2005

Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning.

This study used functional magnetic resonance imaging to examine the effects of acute tryptophan (TRP) depletion (ATD), a well-recognized method for inducing transient cerebral serotonin depletion, on brain activity during probabilistic reversal learning. Twelve healthy male volunteers received a TRP-depleting drink or a balanced amino-acid drink (placebo) in a double-blind crossover design. At 5 h after drink ingestion, subjects were scanned while performing a probabilistic reversal learning task and while viewing a flashing checkerboard. The probabilistic reversal learning task enabled the separate examination of the effects of ATD on behavioral reversal following negative feedback and negative feedback per se that was not followed by behavioral adaptation. Consistent with previous findings, behavioral reversal was accompanied by significant signal change in the right ventrolateral prefrontal cortex (PFC) and the dorsomedial prefrontal cortex. ATD enhanced reversal-related signal change in the dorsomedial PFC, but did not modulate the ventrolateral PFC response. The ATD-induced signal change in the dorsomedial PFC during behavioral reversal learning extended to trials where subjects received negative feedback but did not change their behavior. These data suggest that ATD affects reversal learning and the processing of aversive signals by modulation of the dorsomedial PFC.

Adolescent↗

PubMed2005

Tryptophan depletion disrupts the motivational guidance of goal-directed behavior as a function of trait impulsivity.

Serotonin (5-HT) is well known to affect the motivational properties of stimuli predictive of rewards as well as the inhibitory control of behavior. Here, central 5-HT depletion was induced by the acute tryptophan (TRP) depletion (ATD) procedure in young healthy volunteers to examine the role of 5-HT in motivated action and prepotent response inhibition. A novel reaction-time task, tailored to individual differences in general cognitive speed, was employed to measure the guidance of behavior by motivationally relevant signals predictive of reinforcement likelihood, while the stop-signal reaction-time task was used to measure response inhibition. Following the TRP-balancing control drink, cues predictive of high-reinforcement certainty induced faster, but less accurate responses compared with cues predictive of lower reinforcement certainty. Depletion of central 5-HT modulated this coupling between motivation and action by slowing responses and increasing accuracy as a function of incentive certainty. These effects of ATD on motivated action correlated highly with individual differences in the personality trait of Nonplanning Impulsiveness (Barratt Impulsivity Scale (BIS-11)), so that strongest effects on motivated action were observed in high-impulsive individuals. By contrast, ATD left unaltered the ability to inhibit prepotent responses. Our findings may have implications for a variety of neuropsychiatric disorders including impulsive aggressive disorders and depression.

Adult↗

PubMed2005

Punishment induces risky decision-making in methadone-maintained opiate users but not in heroin users or healthy volunteers.

Reinforcing properties of psychoactive substances are considered to be critically involved in the development and maintenance of substance dependence. While accumulating evidence suggests that the sensitivity to reinforcement values may generally be altered in chronic substance users, relatively little is known about the influence reinforcing feedback exerts on ongoing decision-making in these individuals. Decision-making was investigated using the Cambridge Risk Task, in which there is a conflict between an unlikely large reward option and a likely small reward option. Responses on a given trial were analyzed with respect to the outcome on the previous trial, providing a measure of the impact of prior feedback in modulating behavior. Five different groups were compared: (i) chronic amphetamine users, (ii) chronic opiate users in methadone maintenance treatment (MMT), (iii) chronic users of illicit heroin, (iv) ex-drug users who had been long-term amphetamine / opiate users but were abstinent from all drugs of abuse for at least 1 year and (v) matched controls without a history of illicit substance use. Contrary to our predictions, choice preference was modified in response to feedback only in opiate users enrolled in MMT. Following a loss, the MMT opiate group chose the likely small reward option significantly less frequently than controls and heroin users. Our results suggest that different opiates are associated with distinctive behavioral responses to feedback. These findings are discussed with respect to the different mechanisms of action of heroin and methadone. Neuropsychopharmacology (2005) 30, 2115-2124. doi:10.1038/sj.npp.1300812; published online 6 July 2005.

Adult↗

PubMed2005

Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression.

OBJECTIVE: The authors' goal was to characterize cognitive flexibility and verbal learning in relatives of patients with bipolar disorder and in euthymic patients with recurrent major depression. METHOD: The intradimensional/extradimensional shift task and California Verbal Learning Test were administered to 27 first-degree relatives of probands with bipolar I disorder, 15 euthymic outpatients with recurrent unipolar depression, and 47 healthy comparison subjects. RESULTS: The relatives of patients with bipolar I disorder and the euthymic patients with unipolar depression were more likely to fail the intradimensional/extradimensional shift task than the healthy comparison subjects. The impairments at the extradimensional shift stage were pronounced. Verbal learning, delayed recall, and recognition were unimpaired in all groups. CONCLUSIONS: Attentional set shifting may represent an endophenotype in mood disorder, related to underlying vulnerability rather than the actual disease phenotype.

Adolescent↗