Little is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5-5/week) completed a decision-making task. First, participants stated how much they were willing-to-pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision-making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and "value signals" where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness-to-pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision-related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain.

Elaborated Intrusion (EI) theory posits a key role for visuospatial working memory (WM) in craving. In line with the predictions of EI theory, several studies have found that WM and craving show mutually interfering effects - for example, performance of visuospatial WM tasks has been found to attenuate naturally occurring cravings. However, the extent to which these effects are driven specifically by visuospatial processing remains unclear. We conducted two experiments to investigate the effects of WM on naturally occurring cravings in more detail. In experiment 1, we examined whether such effects are driven specifically by visuospatial WM processes or can also be induced by a verbal WM task. Subjective craving ratings were attenuated equally by performance of visuospatial and verbal WM tasks, suggesting that craving is not dependent specifically on visuospatial processing. In experiment 2, we examined whether effects of visuospatial WM on craving could be driven by simple distraction. Naturally occurring cravings were attenuated in a control condition with minimal WM demands (watching a video). However, the magnitude of attenuation was significantly greater in a visuospatial WM condition. Taken together, these findings highlight a key role for WM in the attenuation of naturally occurring craving, but do not support the hypothesis that such effects are dependent specifically on visuospatial processing.

OBJECTIVE: This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. METHODS: Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. RESULTS: the most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma β-hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory-related neuronal activity were observed. CONCLUSION: over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.

BACKGROUND: There is evidence of executive function impairment in obsessive compulsive disorder (OCD) that potentially contributes to symptom development and maintenance. Nevertheless, the precise nature of these executive impairments and their neural basis remains to be defined. METHOD: We compared stopping and shifting, two key executive functions previously implicated in OCD, in the same task using functional magnetic resonance imaging, in patients with virtually no co-morbidities and age-, verbal IQ- and gender-matched healthy volunteers. The combined task allowed direct comparison of neural activity in stopping and shifting independent of patient sample characteristics and state variables such as arousal, learning, or current symptom expression. RESULTS: Both OCD patients and controls exhibited right inferior frontal cortex activation during stopping, and left inferior parietal cortex activation during shifting. However, widespread under-activation across frontal-parietal areas was found in OCD patients compared to controls for shifting but not stopping. Conservative, whole-brain analyses also indicated marked divergent abnormal activation in OCD in the caudate and thalamus for these two cognitive functions, with stopping-related over-activation contrasting with shift-related under-activation. CONCLUSIONS: OCD is associated with selective components of executive function, which engage similar common elements of cortico-striatal regions in different abnormal ways. The results implicate altered neural activation of subcortical origin in executive function abnormalities in OCD that are dependent on the precise cognitive and contextual requirements, informing current theories of symptom expression.

The A118G single-nucleotide polymorphism (SNP rs1799971) in the μ-opioid receptor gene, OPRM1, has been much studied in relation to alcohol use disorders. The reported effects of allelic variation at this SNP on alcohol-related behaviors, and on opioid receptor antagonist treatments, have been inconsistent. We investigated the pharmacogenetic interaction between A118G variation and the effects of two μ-opioid receptor antagonists in a clinical lab setting. Fifty-six overweight and moderate-heavy drinkers were prospectively stratified by genotype (29 AA homozygotes, 27 carriers of at least 1 G allele) in a double-blind placebo-controlled, three-period crossover design with naltrexone (NTX; 25 mg OD for 2 days, then 50 mg OD for 3 days) and GSK1521498 (10 mg OD for 5 days). The primary end point was regional brain activation by the contrast between alcohol and neutral tastes measured using functional magnetic resonance imaging (fMRI). Secondary end points included other fMRI contrasts, subjective responses to intravenous alcohol challenge, and food intake. GSK1521498 (but not NTX) significantly attenuated fMRI activation by appetitive tastes in the midbrain and amygdala. GSK1521498 (and NTX to a lesser extent) significantly affected self-reported responses to alcohol infusion. Both drugs reduced food intake. Across all end points, there was less robust evidence for significant effects of OPRM1 allelic variation, or for pharmacogenetic interactions between genotype and drug treatment. These results do not support strong modulatory effects of OPRM1 genetic variation on opioid receptor antagonist attenuation of alcohol- and food-related behaviors. However, they do support further investigation of GSK1521498 as a potential therapeutic for alcohol use and eating disorders.

Background: Gray and white matter brain changes have been found in schizophrenia but the anatomical organizing process underlying these changes remains unknown. We aimed to identify gray and white matter volumetric changes in a group of patients with schizophrenia and to quantify the distribution of white matter tract changes using a novel approach which applied three complementary analyses to diffusion imaging data.Methods: 21 patients with schizophrenia and 21 matched control subjects underwent brain magnetic resonance imaging. Gray and white matter volume differences were investigated using Voxel-based Morphometry (VBM). White matter diffusion changes were located using Tract Based Spatial Statistics (TBSS) and quantified within a standard atlas. Tracts where significant regional differences were located were examined using fiber tractography.Results: No significant differences in gray or white matter volumetry were found between the two groups. Using TBSS the schizophrenia group showed significantly lower fractional anisotropy (FA) compared to the controls in regions (false discovery rate

Adult ADHD has been linked to impaired motor response inhibition and reduced associated activation in the right inferior frontal cortex (IFC). However, it is unclear whether abnormal inferior frontal activation in adult ADHD is specifically related to a response inhibition deficit or reflects a more general deficit in attentional processing. Using functional magnetic resonance imaging, we tested a group of 19 ADHD patients with no comorbidities and a group of 19 healthy control volunteers on a modified go/no-go task that has been shown previously to distinguish between cortical responses related to response inhibition and attentional shifting. Relative to the healthy controls, ADHD patients showed increased commission errors and reduced activation in inferior frontal cortex during response inhibition. Crucially, this reduced activation was observed when controlling for attentional processing, suggesting that hypoactivation in right IFC in ADHD is specifically related to impaired response inhibition. The results are consistent with the notion of a selective neurocognitive deficit in response inhibition in adult ADHD associated with abnormal functional activation in the prefrontal cortex, whilst ruling out likely group differences in attentional orienting, arousal and motivation.

Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such "synaptogenic" therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.

The brain-derived neurotropic factor (BDNF) Val66Met polymorphism has been associated with abnormalities of synaptic plasticity in animal models, and abnormalities in motor cortical plasticity have also been described in humans using transcranial direct current stimulation. No study has yet been done on plasticity in non-motor regions, and the effect of two Met alleles (i.e. 'Met dose') is not well understood. We studied the effect of the BDNF Val66Met polymorphism on the after-effects of transcranial direct current stimulation and tetanic auditory stimulation in 65 subjects (23; Val66Val, 22; Val66Met and 20; Met66Met genotypes). In the first session, motor evoked potentials (MEP) were recorded under stereotaxic guidance for 90 min after 9 min of anodal transcranial direct current stimulation (TDCS). In the second session, auditory-evoked potentials (AEP) were recorded before and after 2 min of auditory 13 Hz tetanic stimulation. There was a difference in MEP facilitation post-TDCS comparing Met carriers with non-Met carriers, with Met carriers having a modest late facilitation at 30-90 min. There was no difference in responses between Val66Met genotype and Met66Met genotype subjects. Tetanic auditory stimulation also produced late facilitation of N1-P2 AEP at 25 min, but there was no apparent effect of genetic status. This study indicates that Met66Met carriers behave like Val66Met carriers for TDCS-induced plasticity, and produce a late facilitation of MEPs. Auditory cortical plasticity was not affected by the BDNF Val66Met polymorphism. This study sheds light on the differences between auditory and motor cortical plasticity and the role of the BDNF Val66Met polymorphism.

Ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 polydrug controls, matched for IQ, age, years in education. We used fMRI utilising an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users.

Background Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, yet the search for genes with a definitive role in its etiology has been elusive. Deconstructing the disorder in its endophenotypic traits, where the variance is thought to be associated with a fewer number of genes, should boost the statistical power of molecular genetic studies and clarify the pathophysiology of ADHD. In this study, we tested for neuroanatomical and cognitive endophenotypes in a group of adults with ADHD, their unaffected first-degree relatives, and typically developing control subjects. Methods Sixty participants, comprising 20 adults with ADHD, 20 unaffected first-degree relatives, and 20 typically developing control subjects matched for age and gender undertook structural magnetic resonance imaging scans. Voxel-based morphometry with DARTEL was performed to obtain regional gray and white matter volumes. General linear analyses of the volumes of brain regions, adjusting for age and total intracranial volume, were used to compare groups. Sustained attention and response inhibition were also investigated as cognitive endophenotypes. Results Neuroanatomical abnormalities in gray matter volume in the right inferior frontal gyrus and white matter volume in the caudal portion of the right inferior fronto-occipital fasciculus were shared between ADHD probands and their unaffected first-degree relatives. In addition, impairments in sustained attention were also found to be shared between ADHD patients and their relatives. Conclusions Cognitive impairments in sustained attention and neuroanatomical abnormalities in the right inferior frontal gyrus and the posterior part of right inferior fronto-occipital fasciculus are putative neurocognitive endophenotypes in adult ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, yet the search for genes with a definitive role in its etiology has been elusive. Deconstructing the disorder in its endophenotypic traits, where the variance is thought to be associated with a fewer number of genes, should boost the statistical power of molecular genetic studies and clarify the pathophysiology of ADHD. In this study, we tested for neuroanatomical and cognitive endophenotypes in a group of adults with ADHD, their unaffected first-degree relatives, and typically developing control subjects. METHODS: Sixty participants, comprising 20 adults with ADHD, 20 unaffected first-degree relatives, and 20 typically developing control subjects matched for age and gender undertook structural magnetic resonance imaging scans. Voxel-based morphometry with DARTEL was performed to obtain regional gray and white matter volumes. General linear analyses of the volumes of brain regions, adjusting for age and total intracranial volume, were used to compare groups. Sustained attention and response inhibition were also investigated as cognitive endophenotypes. RESULTS: Neuroanatomical abnormalities in gray matter volume in the right inferior frontal gyrus and white matter volume in the caudal portion of the right inferior fronto-occipital fasciculus were shared between ADHD probands and their unaffected first-degree relatives. In addition, impairments in sustained attention were also found to be shared between ADHD patients and their relatives. CONCLUSIONS: Cognitive impairments in sustained attention and neuroanatomical abnormalities in the right inferior frontal gyrus and the posterior part of right inferior fronto-occipital fasciculus are putative neurocognitive endophenotypes in adult ADHD.

BACKGROUND: the brain-derived neurotrophic factor (BDNF) val66met polymorphism is associated with altered activity dependent secretion of BDNF and a variable influence on brain morphology and cognition. Although a met-dose effect is generally assumed, to date the paucity of met-homozygotes have limited our understanding of the role of the met-allele on brain structure. METHODS: to investigate this phenomenon, we recruited sixty normal healthy subjects, twenty in each genotypic group (val/val, val/met and met/met). Global and local morphology were assessed using voxel based morphometry and surface reconstruction methods. White matter organisation was also investigated using tract-based spatial statistics and constrained spherical deconvolution tractography. RESULTS: Morphological analysis revealed an "inverted-U" shaped profile of cortical changes, with val/met heterozygotes most different relative to the two homozygous groups. These results were evident at a global and local level as well as in tractography analysis of white matter fibre bundles. CONCLUSION: in contrast to our expectations, we found no evidence of a linear met-dose effect on brain structure, rather our results support the view that the heterozygotic BDNF val66met genotype is associated with cortical morphology that is more distinct from the BDNF val66met homozygotes. These results may prove significant in furthering our understanding of the role of the BDNF met-allele in disorders such as Alzheimer's disease and depression.

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

The dopamine D(3) receptor is thought to be a potential target for treating compulsive disorders such as drug addiction and obesity. Here, we used functional Magnetic Resonance Imaging (fMRI) to investigate the effects the selective dopamine D(3) receptor antagonist GSK598809 on brain activation to food images in a sample of overweight and obese binge-eating subjects. Consistent with previous studies, processing of food images was associated with activation of a network of reward areas including the amygdala, striatum and insula. However, brain activation to food images was not modulated by GSK598809. The results demonstrate that D(3) receptor manipulation does not modulate brain responses to food images in overweight and obese subjects.

RATIONALE: Translational research implicates the mu opioid neurochemical system in hedonic processing, but its role in dissociable high-level cognitive functions is not well understood. Binge-eating represents a useful model of 'behavioural addiction' for exploring this issue. OBJECTIVE: the aim of this study was to objectively assess the cognitive effects of a mu opioid receptor antagonist in obese individuals with binge-eating symptoms. METHODS: Adults with moderate to severe binge-eating and body mass index ≥30 kg/m² received 4 weeks of treatment with a mu opioid receptor antagonist (GSK1521498) 2 or 5 mg per day, or placebo, in a double-blind randomised parallel design. Neuropsychological assessment was undertaken at baseline and endpoint to quantify processing bias for food stimuli (visual dot probe with 500- and 2,000-ms stimulus presentations and food Stroop tasks) and other distinct cognitive functions (N-back working memory, sustained attention, and power of attention tasks). RESULTS: GSK1521498 5 mg/day significantly reduced attentional bias for food cues on the visual dot probe task versus placebo (p = 0.042), with no effects detected on other cognitive tasks (all p > 0.10). The effect on attentional bias was limited to the longer stimulus duration condition in the higher dose cohort alone. CONCLUSIONS: These findings support a central role for mu opioid receptors in aspects of attentional processing of food cues but militate against the notion of major modulatory influences of mu opioid receptors in working memory and sustained attention. The findings have implications for novel therapeutic directions and suggest that the role of different opioid receptors in cognition merits further research.

The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from pre-clinical studies suggests that D₃ receptor antagonists may attenuate the motivational impact of rewarding cues. In this study we examined the acute effects of the D₃ receptor antagonist GSK598809 on attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7±3.7, range 27-40 kg/m²) who reported binge and emotional eating. We also determined whether individual differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on both visual probe and food Stroop attentional bias scores was inversely correlated with a measure of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters. Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo, and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to food cues generated by individual differences in eating traits can be modulated by D₃ receptor antagonists, warranting further investigation with measures of eating behaviour and weight loss.

Behavioural and psychological factors related to eating have been associated with obesity, although their relationship to anthropometric measures, more specifically fat mass, has not been fully examined. This study examined the relationship between fat mass (n=98; 75M, 23 F) and behavioural measures of eating and obesity related psychological traits (n=337; 226M, 111 F) in overweight and obese individuals (Mean BMI 30.5±4.0; BMI range 25-46kg/m(2)). Two sets of principal component analyses (PCA) were performed: one on validated questionnaires of eating behaviour and psychological traits and a second on fat mass and body weight related anthropometric measures (BMI, weight) and the aforementioned questionnaire measures. From the initial PCA (n=337), the primary principal component, P1 (R(2) value of 0.33), represented a latent variable associated with overeating or binge eating behaviour. In a second PCA (questionnaire measures augmented by anthropometric variables, n=98), a single component was identified, P1(+) (R(2) of 0.28), similar to that identified as P1 in the previous analysis and this component was highly correlated with fat mass (ρ=0.68). These findings suggest that levels of body fat and eating behaviour (namely, binging or overeating) are strongly related and, at least in a subgroup of individuals, obesity may be driven by behavioural factors associated with eating in combination with pre-existing environmental and genetic factors.

Evidence suggests that the right inferior frontal cortex (IFC) plays a specialized role in response inhibition. However, more recent findings indicate a broader role for this region in attentional control. Here, we used functional magnetic resonance imaging to examine the functional role of the right IFC in attention, inhibition, and response control in 2 experiments that employed novel variations of the go/no-go task. Across the 2 experiments, we observed a graded response in the right insula/IFC, whereby increasing response control demands led to an increase in activation. The results are consistent with the hypothesis that this region plays a key role in the integration of bottom-up, sensory information with top-down, response-related information to facilitate flexible, goal-directed behavior. © the Author 2010. Published by Oxford University Press. All rights reserved.

OBJECTIVES: to identify tasks that were sensitive to a temporary decline in cognitive performance after sleep deprivation and to investigate the ability of the acetylcholinesterase inhibitor donepezil to reverse any sleep deprivation-induced impairment. METHODS: Thirty healthy volunteers were administered either a 5-mg daily dose of donepezil or placebo for 14-17 days, in a double-blind parallel group design, then underwent either 24 h sleep deprivation or a normal night of sleep in non-blinded crossover, and were subsequently tested on a battery of cognitive tasks designed to measure different components of memory and executive function. RESULTS: Sleep deprivation selectively impaired performance on several memory tasks whilst also impairing non-memory function on these tasks. Performance on other tasks was spared. Despite partially reversing the decline in subjective alertness associated with sleep deprivation, treatment with donepezil failed to significantly reverse the decline in cognitive performance on any of the tasks. CONCLUSIONS: the results demonstrate the sensitivity of certain tests, particularly those that measure memory function, to cognitive impairment after sleep deprivation. The inability of donepezil to reverse this performance decline suggests that the sleep deprivation model of cognitive impairment may not be suitable for detecting pro-cognitive effects of cholinergic augmentation.

Introduction Theory of visual attention (TVA; Bundesen 1990) whole report tasks allow the independent measurement of visual perceptual processing speed and visual short-term memory (vSTM) storage capacity, unconfounded by motor speed. This study investigates how cognitive enhancing effects of psychostimulants depend on baseline performance and individual plasma levels. Materials and methods Eighteen healthy volunteers (aged 20-35 years) received single oral doses of either 40 mg methylphenidate, 400 mg modafinil or placebo in a counterbalanced, double-blind crossover design. A whole report of visually presented letter arrays was performed 2.5-3.5 h after drug administration, and blood samples for plasma level analysis were taken. Results Methylphenidate and modafinil both enhanced perceptual processing speed in participants with low baseline (placebo) performance. These improvements correlated with subjective alertness. Furthermore, we observed differential plasma level-dependent effects of methylphenidate in lower and higher performing participants: higher plasma levels led to a greater improvement in low-performing participants and to decreasing improvement in high-performing participants. Modafinil enhanced visual short-term memory storage capacity in low-performing participants. Conclusions This is the first pharmacological investigation demonstrating the usefulness of a TVA task for highresolution and repeated cognitive parameter estimation after cognitive-enhancing medication. Our results confirm previous findings of attentional capacity improvements in low performers and extend the baseline dependency model to methylphenidate. Plasma level-dependent effects of psychostimulants can be modelled on an inverted U-shaped dose-response relationship, which is highly relevant to predict cognitive enhancing and detrimental effects of psychostimulants in patients with cognitive deficits (e.g. attention deficit hyperactivity disorder) and healthy volunteers (e.g. self-medicating academics). © Springer-Verlag 2010.

Regret and relief are complex emotional states associated with the counterfactual processing of nonobtained outcomes in a decision-making situation. In the "actor effect," a sense of agency and personal responsibility is thought to heighten these emotions. Using fMRI, we scanned volunteers (n = 22) as they played a task involving choices between two wheel-of-fortune gambles. We examined how neural responses to counterfactual outcomes were modulated by giving subjects the opportunity to change their minds, as a manipulation of personal responsibility. Satisfaction ratings to the outcomes were highly sensitive to the difference between the obtained and nonobtained outcome, and ratings following losses were lower on trials with the opportunity to change one's mind. Outcome-related activity in the striatum and orbitofrontal cortex was positively related to the satisfaction ratings. The striatal response was modulated by the agency manipulation: Following losses, the striatal signal was significantly lower when the subject had the opportunity to change his/her mind. These results support the involvement of frontostriatal mechanisms in counterfactual thinking and highlight the sensitivity of the striatum to the effects of personal responsibility.

Unilateral spatial neglect, a debilitating condition affecting awareness of one side of space, is commonly assessed using cancellation tasks in which patients cross out targets distributed over a sheet. Standard scores emphasize the left-right distribution of omissions. Here, the additional value of extracting temporal as well as spatial aspects of performance from video recordings was examined. Videos from 18 patients with left neglect and 19 healthy age-matched control participants were obtained. Interrater reliability of the video analysis was high. In addition to overall differences in target detection and bias, patients significantly differed from the control group in terms of the location of first cancellation, overall slowness, greater variability in speed, systematic slowing with time on task and as a function of target location, less coherent search organization, and a sharply increased tendency to recancel targets. Considering a subset of patients whose scores, by standard criteria, were at or near the normal range indicated that these additional variables indeed increased the sensitivity of the task as well as allowed the simultaneous assessment of spatial and nonspatial aspects of the disorder.

RATIONALE: Dopamine (DA) plays an important role in working memory. However, the precise functions supported by different DA receptor subtypes in different neural regions remain unclear. OBJECTIVE: the present study used pharmacological, event-related fMRI to test the hypothesis that striatal dopamine is important for the manipulation of information in working memory. METHODS: Twenty healthy human subjects were scanned twice, once after placebo and once after sulpiride 400 mg, a selective DA D2 receptor antagonist, while performing a verbal working memory task requiring different levels of manipulation. RESULTS: Whilst there was no overall effect of sulpiride on task-dependent activation, individual variation in sulpiride plasma levels predicted the effect of working memory manipulation on activation in the putamen, suggesting a dose-dependent effect of DA antagonism on a striatally based manipulation process. These effects occurred in the context of a drug-induced improvement in performance on trials requiring the manipulation of information in working memory but not on simple retrieval trials. No significant drug effects were observed in the prefrontal cortex. CONCLUSIONS: These results support models of dopamine function that posit a 'gating' function for dopamine D2 receptors in the striatum, which enables the flexible updating and manipulation of information in working memory.

Complete understanding of the neural mechanisms by which stimulants such as methylphenidate ameliorate attention deficit hyperactivity disorder is lacking. Theories of catecholamine function predict that the neural effects of stimulant drugs will vary according to task requirements. We used event-related, pharmacological functional magnetic resonance imaging to investigate the effects of 60 mg of methylphenidate, alone and in combination with 400 mg of sulpiride, on blood oxygenation level-dependent (BOLD) signal in a group of 20 healthy participants during probabilistic reversal learning, in a placebo-controlled design. In a whole-brain analysis, methylphenidate attenuated BOLD signal in the ventral striatum during response switching after negative feedback but modulated activity in the prefrontal cortex when subjects maintained their current response set. The results show that the precise neural site of modulation by methylphenidate depends on the nature of the cognitive subprocess recruited.

Research suggests that the severity of left spatial neglect can be modulated by changes in general alertness. Analogous effects in healthy volunteers now suggest that this may reflect an amplified form of a normal pattern. Recent neuropsychological studies also suggest that concurrent cognitive load may exacerbate rightward bias. In this study, for the first time, the authors examined the effect of both factors on spatial bias in healthy volunteers. Participants performed a task in which as many letters as possible needed to be reported from a briefly presented visual array under three conditions (alone, with a syllable-discrimination secondary task and with a pitch-discrimination secondary task). The results confirmed a significant rightward shift associated with time-on-task across all conditions--the first demonstration of such an effect within a fixation controlled, brief presentation task. While the secondary tasks influenced overall visual performance, there was no discernable effect on bias.

We investigated the prevalence and specificity of category-selective regions in human visual cortex. In the broadest survey to date of category selectivity in visual cortex, 12 participants were scanned with functional magnetic resonance imaging while viewing scenes and 19 different object categories in a blocked-design experiment. As expected, we found selectivity for faces in the fusiform face area (FFA), for scenes in the parahippocampal place area (PPA), and for bodies in the extrastriate body area (EBA). In addition, we describe 3 main new findings. First, evidence for the selectivity of the FFA, PPA, and EBA was strengthened by the finding that each area responded significantly more strongly to its preferred category than to the next most effective of the remaining 19 stimulus categories tested. Second, a region in the middle temporal gyrus that has been reported to respond significantly more strongly to tools than to animals did not respond significantly more strongly to tools than to other nontool categories (such as fruits and vegetables), casting doubt on the characterization of this region as tool selective. Finally, we did not find any new regions in the occipitotemporal pathway that were strongly selective for other categories. Taken together, these results demonstrate both the strong selectivity of a small number of regions and the scarcity of such regions in visual cortex.

Although transient neglect of contralesional space occurs following damage to either hemisphere, persistent forms are overwhelmingly associated with right hemisphere lesions. This has led to the suggestion that impairments in other right hemisphere systems--in particular those that mediate alertness--may undermine recovery. Reductions in neglect severity with stimulation, exacerbation with sedatives and the poor performance of chronic neglect patients on sustained attention tasks are consistent with this view. However, the question of whether changes in alertness exert a specific influence over spatial attention--or simply improve performance across many domains--is difficult to address using only patient studies. Here, we examine this question with individuals from the healthy adult population. On certain spatial tasks, adults show a modest but reliable leftward attentional bias. On the basis of the neglect studies, we hypothesised that this bias would diminish--or even reverse--as alertness levels declined. In the first study, participants were asked to judge the relative lengths of the left and right sections of a line when sleep deprived and when well rested. A significant rightward shift in attention was associated with sleep deprivation. A rightward shift was also observed over the course of the session. The second study replicated this time-on-task effect. The results suggest that a diminution in alertness may be sufficient to induce a rightward shift in visual attention in the healthy brain. Implications for the persistence of neglect in patients, for spatial biases in children and for normal free viewing asymmetries are discussed.