Value-based decision-making of cigarette and nondrug rewards in dependent and occasional cigarette smokers: An FMRI study.

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.

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study.

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 ß-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.

Structural neuroimaging correlates of allelic variation of the BDNF val66met polymorphism.

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.

Hypoactivation in right inferior frontal cortex is specifically associated with motor response inhibition in adult ADHD.

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.

Late cortical plasticity in motor and auditory cortex: role of met-allele in BDNF Val66Met polymorphism.

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.

Distribution of tract deficits in schizophrenia.

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 <0.05) including the genu, body and splenium of the corpus callosum and the left anterior limb of the internal capsule (ALIC). Using fiber tractography, FA was significantly lower in schizophrenia in the corpus callosum genu (p = 0.003). CONCLUSIONS: In schizophrenia, white matter diffusion deficits are prominent in medial frontal regions. These changes are consistent with the results of previous studies which have detected white matter changes in these areas. The pathology of schizophrenia may preferentially affect the prefrontal-thalamic white matter circuits traversing these regions.

The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction.

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 effects of the dopamine D3 receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects.

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.

Dissociating inhibition, attention, and response control in the frontoparietal network using functional magnetic resonance imaging.

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 relationship between fat mass, eating behaviour and obesity-related psychological traits in overweight and obese individuals.

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.

Effect of the dopamine D3 receptor antagonist GSK598809 on brain responses to rewarding food images in overweight and obese binge eaters.

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.

Effects of donepezil on cognitive performance after sleep deprivation.

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.

Methylphenidate has differential effects on blood oxygenation level-dependent signal related to cognitive subprocesses of reversal learning.

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.

Effects of working memory on naturally occurring cravings.

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.

Removal of copper from cattle footbath wastewater with layered double hydroxide adsorbents as a route to antimicrobial resistance mitigation on dairy farms.

Copper and zinc are routinely used in livestock antimicrobial footbaths in commercial farming. The footbath mix is a cost to farmers, and the disposal of spent footbath into slurry tanks leads to soil contamination, as well as the potential for antimicrobial metal resistance and co-selection. This study assesses the potential to mitigate a source of antimicrobial metal resistance in slurry tanks while recovering copper and zinc from spent cattle footbaths. This is the first study in literature to investigate the potential of recovering copper from cattle footbath solutions via any method. The sorbent, Ca2Al-EDTA Layered Double Hydroxides (LDH), were used to remove Cu2+ from a Cu2SO4·5H20 solution at different temperatures. The maximum Cu2+ uptake from the Cu2SO4·5H20 solution was 568 ±â€¯88 mg g-1. Faster and higher equilibrium uptake was achieved by increasing the temperature of the solution. The sorbent was found to be effective in removing copper and zinc from a commercially available cattle footbath solution (filtered footbath solution Cu2+ uptake 283 ±â€¯11.05 mg g-1, Zn2+ uptake 60 ±â€¯0.05 mg g-1). Thus, this study demonstrates the opportunity for a completely novel and potentially economically beneficial method of mitigating antimicrobial resistance in agriculture and the environment, while also providing a new valuable copper and zinc waste stream for secondary metal production.

Opioid Antagonists and the A118G Polymorphism in the µ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype.

This corrects the article DOI: 10.1038/npp.2016.60.

Towards sustainable processing of columbite group minerals: elucidating the relation between dielectric properties and physico-chemical transformations in the mineral phase.

Current methodologies for the extraction of tantalum and niobium pose a serious threat to human beings and the environment due to the use of hydrofluoric acid (HF). Niobium and tantalum metal powders and pentoxides are widely used for energy efficient devices and components. However, the current processing methods for niobium and tantalum metals and oxides are energy inefficient. This dichotomy between materials use for energy applications and their inefficient processing is the main motivation for exploring a new methodology for the extraction of these two oxides, investigating the microwave absorption properties of the reaction products formed during the alkali roasting of niobium-tantalum bearing minerals with sodium bicarbonate. The experimental findings from dielectric measurement at elevated temperatures demonstrate an exponential increase in the values of the dielectric properties as a result of the formation of NaNbO3-NaTaO3 solid solutions at temperatures above 700 °C. The investigation of the evolution of the dielectric properties during the roasting reaction is a key feature in underpinning the mechanism for designing a new microwave assisted high-temperature process for the selective separation of niobium and tantalum oxides from the remainder mineral crystalline lattice.

Sub-Tenon's Anesthesia.

The sub-Tenon's anesthesia block was reintroduced into clinical practice in the early 1990s as a simple, effective, and safe alternative to needle blocks. The technique has remained simple and effective but has evolved. Although still very unusual, both sight- and life-threatening complications have occurred. To safely perform the block, detailed knowledge of anatomy and methods for administering anesthesia are essential.

Ophthalmic regional block.

Cataract surgery is the commonest ophthalmic surgical procedure and a local anaesthetic technique is usually preferred but the provision of anaesthesia in terms of skills and resources varies worldwide. Intraconal and extraconal blocks using needles are commonly used. The techniques are generally safe but although rare, serious sight- and life-threatening complications have occurred following the inappropriate placement of needles. Sub-Tenon's block was introduced as a safe alternative to needle techniques but complications have arisen following this block as well. Currently, there is no absolutely safe ophthalmic regional block. It is essential that those who are involved in the care of these patients have a thorough knowledge of the techniques used. This review article outlines the relevant anatomy, commonly used techniques and their safe performance and perioperative care.