Matthew B. Wall

Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.

The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ9-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid CB1 receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associated with adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans. We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precise mechanisms underlying the effects of cannabis may also give rise to new treatment targets.

Glutamatergic and GABAergic dysfunction are implicated in the pathophysiology of schizophrenia. Previous work has shown relationships between glutamate, GABA, and brain activity in healthy volunteers. We conducted a systematic review to evaluate whether these relationships are disrupted in psychosis. Primary outcomes were the relationship between metabolite levels and fMRI BOLD response in psychosis relative to healthy volunteers. 17 case-control studies met inclusion criteria (594 patients and 538 healthy volunteers). Replicated findings included that in psychosis, positive associations between ACC glutamate levels and brain activity are reduced during resting state conditions and increased during cognitive control tasks, and negative relationships between GABA and local activation in the ACC are reduced. There was evidence that antipsychotic medication may alter the relationship between glutamate levels and brain activity. Emerging literature is providing insights into disrupted relationships between neurometabolites and brain activity in psychosis. Future studies determining a link to clinical variables may develop this approach for biomarker applications, including development or targeting novel therapeutics.

The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior.To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021.Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo.Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level-dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal.Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire-most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02).Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire.isrctn.org Identifier: ISRCTN17271094.

Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following PT.Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of psilocybin dosing sessions.Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions.Open-label trial. Relatively small sample size.These data suggest an effect of PT on the brain's response to music, implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.

Firms that design mechanical and electromechanical products confront a variety of difficult issues in their prototyping activities. For a given part, how can a choice among fabrication technologies be made? Where should investments in new prototyping technology be focused? How can new and existing prototyping technologies be evaluated? Our primary goal has been to develop a systematic method of evaluating prototyping processes in order to determine the best process for a given situation. A secondary goal has been to map the "space" of prototyping processes in order to determine future process development needs. Using data from a field study at the Kodak Apparatus Division, we have developed a systematic method for evaluating and selecting prototyping processes. Our data are drawn from (1) a user survey of prototyping perceptions and needs, (2) a survey to determine the importance of various prototype part performance attributes, and (3) estimates of the fabrication time, cost, and part performance for 104 parts and four prototyping processes.

Abstract Chronic use of drugs may alter the brain’s reward system, though the extant literature concerning long-term cannabis use and neural correlates of reward processing has shown mixed results. Adolescents may be more vulnerable to the adverse effects of cannabis than adults; however, this has not been investigated for reward processing. As part of the ‘CannTeen’ study, in the largest functional magnetic resonance imaging study of reward processing and cannabis use to date, we investigated reward anticipation and feedback in 125 adult (26–29 years) and adolescent (16–17 years) cannabis users (1–7 days/week cannabis use) and gender- and age-matched controls, using the Monetary Incentive Delay task. Blood-oxygen-level-dependent responses were examined using region of interest (ROI) analyses in the bilateral ventral striatum for reward anticipation and right ventral striatum and left ventromedial prefrontal cortex for feedback, and exploratory whole-brain analyses. Results showed no User-Group or User-Group × Age-Group effects during reward anticipation or feedback in pre-defined ROIs. These null findings were supported by post hoc Bayesian analyses. However, in the whole-brain analysis, cannabis users had greater feedback activity in the prefrontal and inferior parietal cortex compared to controls. In conclusion, cannabis users and controls had similar neural responses during reward anticipation and in hypothesised reward-related regions during reward feedback. The whole-brain analysis revealed tentative evidence of greater fronto-parietal activity in cannabis users during feedback. Adolescents showed no increased vulnerability compared with adults. Overall, reward anticipation and feedback processing appear spared in adolescent and adult cannabis users, but future longitudinal studies are needed to corroborate this.

Long-term harms of cannabis may be exacerbated in adolescence, but little is known about the acute effects of cannabis in adolescents. We aimed to (i) compare the acute effects of cannabis in adolescent and adult cannabis users and (ii) determine if cannabidiol (CBD) acutely modulates the effects of delta-9-tetrahydocannabinol (THC).Randomised, double-blind, placebo-controlled, crossover experiment. The experiment was registered on ClinicalTrials.gov (NCT04851392).Laboratory in London, United Kingdom.Twenty-four adolescents (12 women, 16- to 17-year-olds) and 24 adults (12 women, 26- to 29-year-olds) who used cannabis 0.5-3 days/week and were matched on cannabis use frequency (mean = 1.5 days/week).We administered three weight-adjusted vaporised cannabis flower preparations: 'THC' (8 mg THC for 75 kg person); 'THC + CBD' (8 mg THC and 24 mg CBD for 75 kg person); and 'PLA' (matched placebo).Primary outcomes were (i) subjective 'feel drug effect'; (ii) verbal episodic memory (delayed prose recall); and (iii) psychotomimetic effect (Psychotomimetic States Inventory).Compared with 'PLA', 'THC' and 'THC + CBD' significantly (P < 0.001) increased 'feel drug effect' (mean difference [MD] = 6.3, 95% CI = 5.3-7.2; MD = 6.8, 95% CI = 6.0-7.7), impaired verbal episodic memory (MD = -2.7, 95% CI = -4.1 to -1.4; MD = -2.9, 95% CI = -4.1 to -1.7) and increased psychotomimetic effects (MD = 7.8, 95% CI = 2.8-12.7; MD = 10.8, 95% CI = 6.2-15.4). There was no evidence that adolescents differed from adults in their responses to cannabis (interaction P ≥ 0.4). Bayesian analyses supported equivalent effects of cannabis in adolescents and adults (Bayes factor [BF01 ] >3). There was no evidence that CBD significantly modulated the acute effects of THC.Adolescent cannabis users are neither more resilient nor more vulnerable than adult cannabis users to the acute psychotomimetic, verbal memory-impairing or subjective effects of cannabis. Furthermore, in adolescents and adults, vaporised cannabidiol does not mitigate the acute harms caused by delta-9-tetrahydocannabinol.

Background: Adolescence is characterised by psychological and neural development. Cannabis harms may be accentuated during adolescence. We hypothesised that adolescents would be more vulnerable to the associations between cannabis use and mental health and addiction problems than adults. Method: As part of the ‘CannTeen’ study, we conducted a cross-sectional analysis. There were 274 participants: split into groups of adolescent users ( n = 76; 16–17 years old) and controls ( n = 63), and adult users ( n = 71; 26–29 years old) and controls ( n = 64). Among users, cannabis use frequency ranged from 1 to 7 days/week, while controls had 0–10 lifetime exposures to cannabis. Adolescent and adult cannabis users were matched on cannabis use frequency (mean=4 days/week). We measured Diagnostic and Statistical Manual (DSM-5) Cannabis Use Disorder (CUD), Beck Depression Inventory, Beck Anxiety Inventory and Psychotomimetic States Inventory-adapted. Results: After adjustment for covariates, adolescent users were more likely to have severe CUD than adult users (odd ratio = 3.474, 95% confidence interval (CI) = 1.501–8.036). Users reported greater psychotic-like symptoms than controls ( b = 6.004, 95% CI = 1.211–10.796) and adolescents reported greater psychotic-like symptoms than adults ( b = 5.509, 95% CI = 1.070–9.947). User-group was not associated with depression or anxiety. No significant interactions between age-group and user-group were identified. Exploratory analyses suggested that cannabis users with severe CUD had greater depression and anxiety levels than cannabis users without severe CUD. Conclusion: Adolescent cannabis users are more likely than adult cannabis users to have severe CUD. Adolescent cannabis users have greater psychotic-like symptoms than adult cannabis users and adolescent controls, through an additive effect. There was no evidence of an amplified vulnerability to cannabis-related increases in subclinical depression, anxiety or psychotic-like symptoms in adolescence. However, poorer mental health was associated with the presence of severe CUD.

Resting brain connectivity is a crucial component of human behavior demonstrated by disruptions in psychosexual and emotional disorders. Kisspeptin, a recently identified critical reproductive hormone, can alter activity in certain brain structures but its effects on resting brain connectivity and networks in humans remain elusive.We determined the effects of kisspeptin on resting brain connectivity (using functional neuroimaging) and behavior (using psychometric analyses) in healthy men, in a randomized double-blinded 2-way placebo-controlled study.Kisspeptin's modulation of the default mode network (DMN) correlated with increased limbic activity in response to sexual stimuli (globus pallidus r = 0.500, P = 0.005; cingulate r = 0.475, P = 0.009). Furthermore, kisspeptin's DMN modulation was greater in men with less reward drive (r = -0.489, P = 0.008) and predicted reduced sexual aversion (r = -0.499, P = 0.006), providing key functional significance. Kisspeptin also enhanced key mood connections including between the amygdala-cingulate, hippocampus-cingulate, and hippocampus-globus pallidus (all P < 0.05). Consistent with this, kisspeptin's enhancement of hippocampus-globus pallidus connectivity predicted increased responses to negative stimuli in limbic structures (including the thalamus and cingulate [all P < 0.01]).Taken together, our data demonstrate a previously unknown role for kisspeptin in the modulation of functional brain connectivity and networks, integrating these with reproductive hormones and behaviors. Our findings that kisspeptin modulates resting brain connectivity to enhance sexual and emotional processing and decrease sexual aversion, provide foundation for kisspeptin-based therapies for associated disorders of body and mind.NIHR, MRC, and Wellcome Trust.

Abstract Background Preclinical and human studies suggest that adolescent cannabis use may be associated with worse cognitive outcomes than adult cannabis use. We investigated the associations between chronic cannabis use and cognitive function in adolescent and adult cannabis users and controls. We hypothesised user-status would be negatively associated with cognitive function and this relationship would be stronger in adolescents than adults. Methods As part of the ‘CannTeen’ project, this cross-sectional study assessed cognitive performance in adolescent cannabis users ( n = 76; 16–17-year-olds), adolescent controls ( n = 63), adult cannabis users ( n = 71; 26–29-year-olds) and adult controls ( n = 64). Users used cannabis 1–7 days/week. Adolescent and adult cannabis users were matched on cannabis use frequency (4 days/week) and time since last use (2.5 days). Verbal episodic memory (VEM) was assessed using the prose recall task, spatial working memory (SWM) was assessed using the spatial n-back task, and response inhibition was assessed with the stop-signal task. Primary outcome variables were: delayed recall, 3-back discriminability, and stop signal reaction time, respectively. Results Users had worse VEM than controls ( F (1,268) = 7.423, p = 0.007). There were no significant differences between user-groups on SWM or response inhibition. Null differences were supported by Bayesian analyses. No significant interactions between age-group and user-group were found for VEM, SWM, or response inhibition. Conclusions Consistent with previous research, there was an association between chronic cannabis use and poorer VEM, but chronic cannabis use was not associated with SWM or response inhibition. We did not find evidence for heightened adolescent vulnerability to cannabis-related cognitive impairment.

There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown.We sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety.We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during functional magnetic resonance imaging) and cognitive (emotional appraisal) measures as well as subjective response to experimentally induced anxiety.CBD did not produce effects on brain responses to emotional faces and cognitive measures of emotional processing, or modulate experimentally induced anxiety, relative to placebo.Given the rising popularity of CBD for its putative medical benefits, these findings question whether further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.

Abstract Background Mitochondrial function plays a key role in regulating neurotransmission and may contribute to general intelligence. Mitochondrial complex I (MC-I) is the largest enzyme of the respiratory chain. Recently, it has become possible to measure MC-I distribution in vivo, using a novel positron emission tomography tracer [ 18 F]BCPP-EF, thus, we set out to investigate the association between MC-I distribution and measures of cognitive function in the living healthy brain. Results Analyses were performed in a voxel-wise manner and identified significant associations between [ 18 F]BCPP-EF DVR CS−1 in the precentral gyrus and parietal lobes and WAIS-IV predicted IQ, WAIS-IV arithmetic and WAIS-IV symbol-digit substitution scores (voxel-wise Pearson’s correlation coefficients transformed to Z-scores, thresholded at Z = 2.3 family-wise cluster correction at p &lt; 0.05, n = 16). Arithmetic scores were associated with middle frontal and post-central gyri tracer uptake, symbol-digit substitution scores were associated with precentral gyrus tracer uptake. RAVLT recognition scores were associated with [ 18 F]BCPP-EF DVR CS−1 in the middle frontal gyrus, post-central gyrus, occipital and parietal regions ( n = 20). Conclusions Taken together, our findings support the theory that mitochondrial function may contribute to general intelligence and indicate that interindividual differences in MC-I should be a key consideration for research into mitochondrial dysfunction in conditions with cognitive impairment.

Working memory performance is thought to depend on both striatal dopamine 2/3 receptors (D2/3Rs) and task-induced functional organisation in key cortical brain networks. Here, we combine functional magnetic resonance imaging and D2/3R positron emission tomography in 51 healthy volunteers, to investigate the relationship between working memory performance, task-induced default mode network (DMN) functional connectivity changes, and striatal D2/3R availability. Increasing working memory load was associated with reduced DMN functional connectivity, which was itself associated with poorer task performance. Crucially, the magnitude of the DMN connectivity reduction correlated with striatal D2/3R availability, particularly in the caudate, and this relationship mediated the relationship between striatal D2/3R availability and task performance. These results inform our understanding of natural variation in working memory performance, and have implications for understanding age-related cognitive decline and cognitive impairments in neuropsychiatric disorders where dopamine signalling is altered.

Abstract 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.

Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown.To test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD.This randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021.A 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion.Blood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli.Of the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects.These findings lay the foundations for clinical applications for kisspeptin in women with HSDD.ISRCTN trial registry identifier: ISRCTN17271094.

Adolescents may respond differently to cannabis than adults, yet no previous functional magnetic resonance imaging study has examined acute cannabis effects in this age group. In this study, we investigated the neural correlates of reward anticipation after acute exposure to cannabis in adolescents and adults. This was a double-blind, placebo-controlled, randomized, crossover experiment. Forty-seven adolescents (n = 24, 12 females, ages 16–17 years) and adults (n = 23, 11 females, ages 26–29 years) matched on cannabis use frequency (0.5–3 days/week) completed the Monetary Incentive Delay task during functional magnetic resonance imaging after inhaling cannabis with 0.107 mg/kg Δ⁹-tetrahydrocannabinol ("THC") (8 mg THC for a 75-kg person) or with THC plus 0.320 mg/kg cannabidiol ("THC+CBD") (24 mg CBD for a 75-kg person), or placebo cannabis. We investigated reward anticipation activity with whole-brain analyses and region of interest analyses in the right and left ventral striatum, right and left anterior cingulate cortex, and right insula. THC reduced anticipation activity compared with placebo in the right (p = .005, d = 0.49) and left (p = .003, d = 0.50) ventral striatum and the right insula (p = .01, d = 0.42). THC+CBD reduced activity compared with placebo in the right ventral striatum (p = .01, d = 0.41) and right insula (p = .002, d = 0.49). There were no differences between "THC" and "THC+CBD" conditions and no significant drug by age group interaction effect, supported by Bayesian analyses. There were no significant effects in the whole-brain analyses. In weekly cannabis users, cannabis suppresses the brain’s anticipatory reward response to money, and CBD does not modulate this effect. Furthermore, the adolescent reward circuitry is not differentially sensitive to acute effects of cannabis on reward anticipation.

CyVerse, the largest publicly-funded open-source research cyberinfrastructure for life sciences, has played a crucial role in advancing data-driven research since the 2010s. As the technology landscape evolved with the emergence of cloud computing platforms, machine learning and artificial intelligence (AI) applications, CyVerse has enabled access by providing interfaces, Software as a Service (SaaS), and cloud-native Infrastructure as Code (IaC) to leverage new technologies. CyVerse services enable researchers to integrate institutional and private computational resources, custom software, perform analyses, and publish data in accordance with open science principles. Over the past 13 years, CyVerse has registered more than 124,000 verified accounts from 160 countries and was used for over 1,600 peer-reviewed publications. Since 2011, 45,000 students and researchers have been trained to use CyVerse. The platform has been replicated and deployed in three countries outside the US, with additional private deployments on commercial clouds for US government agencies and multinational corporations. In this manuscript, we present a strategic blueprint for creating and managing SaaS cyberinfrastructure and IaC as free and open-source software.

Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback.We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback.We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions.The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo.Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders.

With the use of probabilistic and risk-based methods by industry it is often necessary to estimate and input values for the reliability of inspection methods typically in terms of probability of detection (POD). In many cases this has been based on expert judgement. In recent years a more structured approach has developed using multi-parameter POD models. POD models have been around since the early 1990s. Inspection reliability has featured recently in a number of important legal cases, which has focused attention on the factors affecting reliability and approaches used to estimate reliability in practical circumstances. This paper will review the development of models for POD in Europe and the USA in the last decade and the current state-of-the-art in inspection reliability modelling by ESR Technology and others. Examples will include models for composite inspection developed for the European Space Agency and a specific model-based and simulator 'POD Generator' approach developed in the offshore industry through the HOIS joint industry project. This allows the POD for corrosion mapping and radiography inspections to be estimated and parametric studies undertaken to estimate the reliability of commercial inspection eguipment in real situations. Other model-based approaches will be assessed. These include model-assisted POD approaches developed in the US aerospace industry, use of transfer functions to extend hit/miss and â versus a POD trial data to new applications, simulated POD trials, the addition of POD modules to established 3D and CAD inspection models and the use of NDT simulators. There are analogies now for POD modelling for NDT methods to the use of finite element analysis for stress analysis. In the early 1990s, FE analysis was treated with some suspicion and normal practice was to carry out expensive large-scale component tests. Nowadays, FE analysis is widely accepted and large-scale testing is carried out as the exception to validate the FE models. The use of model-assisted and model-derived methods to derive POD data has gained significant acceptance and arguably is becoming the preferred method to generate POD values, with POD trials providing model validation. Empirical methods developed in NNDTC to correct POD data for human and environmental effects are also discussed.

Abstract Background Cannabis use may be linked with anhedonia and apathy. However, previous studies have shown mixed results, and few have examined the association between cannabis use and specific reward sub-processes. Adolescents may be more vulnerable than adults to harmful effects of cannabis. This study investigated (1) the association between non-acute cannabis use and apathy, anhedonia, pleasure, and effort-based decision-making for reward; and (2) whether these relationships were moderated by age group. Methods We used data from the “CannTeen” study. Participants were 274 adult (26–29 years) and adolescent (16–17 years) cannabis users (1–7 d/wk use in the past 3 months) and gender- and age-matched controls. Anhedonia was measured with the Snaith-Hamilton Pleasure Scale (n = 274), and apathy was measured with the Apathy Evaluation Scale (n = 215). Effort-based decision-making for reward was measured with the Physical Effort task (n = 139), and subjective wanting and liking of rewards was measured with the novel Real Reward Pleasure task (n = 137). Results Controls had higher levels of anhedonia than cannabis users (F1,258 = 5.35, P = .02, η p2 = .02). There were no other significant effects of user-group and no significant user-group*age-group interactions. Null findings were supported by post hoc Bayesian analyses. Conclusion Our results suggest that cannabis use at a frequency of 3 to 4 d/wk is not associated with apathy, effort-based decision-making for reward, reward wanting, or reward liking in adults or adolescents. Cannabis users had lower anhedonia than controls, albeit at a small effect size. These findings are not consistent with the hypothesis that non-acute cannabis use is associated with amotivation.

Abstract CyVerse, the largest publicly-funded open-source research cyberinfrastructure for life sciences, has played a crucial role in advancing data-driven research since the 2010s. As the technology landscape evolved with the emergence of cloud computing platforms, machine learning and artificial intelligence (AI) applications, CyVerse has enabled access by providing interfaces, Software as a Service (SaaS), and cloud-native Infrastructure as Code (IaC) to leverage new technologies. CyVerse services enable researchers to integrate institutional and private computational resources, custom software, perform analyses, and publish data in accordance with open science principles. Over the past 13 years, CyVerse has registered more than 110,000 verified accounts from 160 countries and was used for over 1,600 peer-reviewed publications. Since 2011, 45,000 students and researchers have been trained to use CyVerse. The platform has been replicated and deployed in two countries outside the US, with additional private deployments on commercial clouds for US government agencies and multinational corporations. In this manuscript, we present a strategic blueprint for creating and managing SaaS cyberinfrastructure and IaC as free and open-source software.

In recent years there has been increased use of POD modelling to complement, and as an alternative to, probability ofdetection (POD) trials. A number of such models have been developed in ESR Technology's National NDT Centre (NNDTC) in the UK, at Iowa State University in the USA and at other institutions. Such models allow better planning of POD trials, can generate POD estimates in their own right and enable the sensitivity to individual parameters to be assessed. They are also a valuable training and set-up aid. Different methods are discussed that have evolved to take account of human error and environmental factors (HF) in the use of POD data from trials or model estimates. These methods are discussed in the context of the multiparameter POD and human reliability model developed in the European-American reliability workshops. Progress on validation of these methods is discussed. These approaches are discussed and a number of specific examples are given. These include: (i) use of empirical human factor data such as from the PISC III or PANI III trials; (ii) use of models and simulators developed for ESA and HOIS to carry out simulated POD trials ( ‘spot the flaw’); (iii) comparison of POD data from automated and manual inspections; and (iv) an axle simulator model which allows real crack indications to be added to A-scans from axles. A number of examples will be given utilising probability of detection (POD) and NDT simulation models that ESR Technology originally developed for the European Space Agency. These have recently been developed and customised for the offshore oil and gas industry through the HOIS joint industry project and also for railway axle inspection. The models have covered ultrasonics, radiography and other methods using a modular approach that can take inputs for signal, background noise and detection criteria from models or experimental data, reproducing what is done in practice. A feature of the models is that they produce simulated data, so the theoretical estimates can be compared with POD estimates in simulated trials for decision and analysis using the 'spot the flaw' method, providing insight on human reliability issues related to interpretation of data. Input data can be included representative of commercially available NDT equipment. In some areas such as railway axle inspection or turbine blade inspection inspectors rarely see a defect, and defects can be missed because of the unfamiliarity with how these appear against background geometric echoes. Such models or simulations allow signals from real defects to be included, allow human factors to be considered and assist inspectors in understanding how real cracks may appear in inspection data compared with the reference reflectors that are often used in reference and calibration samples.

Functional magnetic resonance imaging (fMRI) is a popular method for examining pharmacological effects on the brain; however, the BOLD response is dependent on intact neurovascular coupling, and potentially modulated by a number of physiological factors. Pharmacological fMRI is therefore vulnerable to confounding effects of pharmacological probes on general physiology or neurovascular coupling. Controlling for such non-specific effects in pharmacological fMRI studies is therefore an important consideration, and there is an additional need for well-validated fMRI task paradigms that could be used to control for such effects, or for general testing purposes.We have developed two variants of a standardized control task that are short (5 minutes duration) simple (for both the subject and experimenter), widely applicable, and yield a number of readouts in a spatially diverse set of brain networks. The tasks consist of four functionally discrete three-second trial types (plus additional null trials) and contain visual, auditory, motor and cognitive (eye-movements, and working memory tasks in the two task variants) stimuli. Performance of the tasks was assessed in a group of 15 subjects scanned on two separate occasions, with test-retest reliability explicitly assessed using intra-class correlation coefficients.Both tasks produced robust patterns of brain activation in the expected brain regions, and region of interest-derived reliability coefficients for the tasks were generally high, with four out of eight task conditions rated as 'excellent' or 'good', and only one out of eight rated as 'poor'. Median values in the voxel-wise reliability measures were also >0.7 for all task conditions, and therefore classed as 'excellent' or 'good'. The spatial concordance between the most highly activated voxels and those with the highest reliability coefficients was greater for the sensory (auditory, visual) conditions than the other (motor, cognitive) conditions.Either of the two task variants would be suitable for use as a control task in future pharmacological fMRI studies or for any other investigation where a short, reliable, basic task paradigm is required. Stimulus code is available online for re-use by the scientific community.

BS 7910 contains guidance on the assessment of flaws in metallic materials. This paper outlines how and why the advice relating to non-destructive testing (NDT) has been expanded, and explains the scope and origin of the information, describing the key features of the new Annex T. Annex T gives tolerances which should be subtracted from the critical flaw size determined by engineering critical assessment (ECA) with the purpose of providing conservative, deterministic assessment of either the fitness for service of a known flaw or to provide a quantitative flaw sizing criteria for NDT. Advice is also provided for the size of flaw that can be expected to be detected with an acceptable probability of detection. The advice provided is generally suitable for butt welded ferrous plate with thickness of 10–25 mm, but in some cases has broader applicability. Advice is provided for the more commonly used methods of NDT.

The reliability of NDT inspection has traditionally been determined by experimental trials; for example PISC I-III, NORDTEST and RACH. Such trials provide practical measures of the capability of inspection equipment. However, they can be expensive, may have poor statistics and the results obtained are specific to the equipment used as well as the specimens and defects included in the trials. An alternative approach is the use of computer modelling which, if sufficiently realistic, can provide a cost-effective alternative to experimental trials, and can be applied to a broad range of inspection equipment, geometries and defect characteristics. This paper describes a computer model for the prediction of the probability of detection (POD) of the zero degree ultrasonic corrosion mapping technique, which is widely used in the oil and gas industry for the in-service detection and characterisation of corrosion in pipes and vessels. The model has a relatively simple physical/mathematical basis but is believed to be a sufficiently good approximation to take into account the main factors which affect the POD of this inspection technique. The results from the model are compared with those from available experimental POD trials. Results are also given from a sensitivity study to identify and quantify the main parameters which influence POD under different inspection conditions.

Prism adaptation (PA) has proven to be effective in alleviating many signs of unilateral spatial neglect (USN). Generally, the principal improvement after PA treatment was found to be in the high-level cognitive function. Nevertheless, some evidence has also been found for it in somatosensory function. We have aimed to test the influence of PA on neglect hemianesthesia, a condition in which the high-level neglect-related deficit mimics hemianesthesia. Twenty-one USN patients were enrolled in the study. Each patient performed two sessions of PA, one with neutral glasses and one with prism glasses using a cross-over design. Sensitivity on the upper limb was tested using two methods. The first task was the sensibility subtest which was derived from the standard clinical examination. The second was the perceptual and motor electro-cutaneous threshold on the forearms using an electro-cutaneous stimulator. Four neuropsychological tests were used to diagnose USN and to check improvement: Star cancellation, Line bisection, Sentence reading and the Comb & Razor test. Comparing prism with sham conditions, our results show significant improvements in double extinction and in the electro-cutaneous perceptual threshold only for the contralesional hand. No improvement was found for the ipsilesional hand, for the motor threshold, and for neutral glasses. Significant improvement was found in personal neglect. Replication of the task in a subgroup of patients confirmed the primary results. The improvements in somatosensory perception together with the amelioration of personal neglect suggest that PA also has a specific effect on the neglect hemianesthesia.

Human factors (HFs) are a frequently mentioned topic when talking about the reliability of non-destructive testing (NDT). However, probability of detection (POD), the commonly used measure of NDT reliability, only looks at the technical capability of an NDT system to detect a defect. After several decades of research on the influence of HFs on NDT reliability, there is still no commonly accepted approach to rendering HFs visible in reliability assessment. This paper provides an overview of possible quantitative and qualitative methods for integrating HFs into the reliability assessment. It is concluded that reliability assessment is best carried out using both quantifiable and non-quantifiable approaches to HFs.

We introduce Cloud Automation and Continuous Analysis Orchestration (CACAO), an open source web platform designed to facilitate access and availability of cloud resources for education and research. By leveraging open source Infrastructure-as-Code (IaC) technologies such as Terraform and Ansible, CACAO empowers users to create customized cloud resources and complex software stacks through an intuitive web interface. CACAO integrates with CyVerse, another prominent open source cyberinfrastructure, and is a featured interface for Jetstream2, a public education and research cloud. CACAO effectively manages multi-cloud deployments in OpenStack and commercial service providers. In 2022 bioinformatics and machine learning workshops worldwide used CACAO during its alpha release. CACAO adheres to open science standards and the FAIR data principles, broadening access to cloud platforms and reducing the complexity of deploying the resources necessary for teaching advanced data informatics skills required in today’s workforce.

This paper presents a study of using site-specific statistical meteorological data in the construction of curved flight procedures to explore its potential in reducing the environmental impact of air traffic near the airports. In the study, the statistical meteorological data which covers a 10-year period of time, from 2009 to 2018, have been collected for the air space centred two major Swedish airports, Arlanda at Stockholm (ESSA) and Landvetter at Göteborg (ESGG). Two procedure design practices, one is an area navigation (RNAV) standard instrument departure (SID) procedure from runway 08 of Arlanda airport and another is a required navigation performance authorization required (RNP AR) approach procedure heading to the runway 03 at Landvetter airport, have been performed and analysed. When applying the 95th percentile wind speed from the collected meteorological data instead of the International Civil Aviation Organization (ICAO) standardized tailwind component (TWC) in the turn calculation, for the RNAV SID procedure from ESSA, the part of the designed departure path which is outside of the regulated noise dispersion area is significantly reduced. Whilst for the RNP AR approach procedure to ESGG, the smaller turning radius resulted from the lower TWC which is calculated from the local meteorological data makes it possible to avoid flying over an inhabited area. Besides the notable potential of noise impact reduction, flight distance shortening of 3.7 NM (RNAV SID ESSA case) and 1 NM (RNP AR ESGG case) compared to the same procedures designed on ICAO standard TWC have been observed. In general, the presented results are positive in supporting the use of local meteorological data in planning curved flight procedures during departures and approaches. A validation performed using an A320 full flight simulator has confirmed the operability of the ESGG RNP AR procedure from the design practice. In the full flight simulator, even with the 100th percentile wind condition from the collected statistical meteorological data, the designed RNP AR approach procedure can be operable considering RNP 0.3 corridor while a 30° bank angle is required for approximately 20 seconds during the turn.

Abstract Firms that design mechanical and electro-mechanical products confront a variety of difficult issues in their prototyping activities. For a given part, how can a choice among fabrication technologies be made? Where should investments in new prototyping technology be focused? How can new and existing prototyping technologies be evaluated? Our primary goal has been to develop a systematic method of evaluating prototyping processes in order to determine the best process for a given situation. This paper reports on a field study conducted at the Kodak Apparatus Division. Our data is drawn from (1) a user survey of prototyping perceptions and needs, (2) a survey to determine the importance of various prototype part performance attributes, and (3) estimates of the fabrication time, cost, and part performance for 104 parts and four prototyping processes.

Introduction Functional brain imaging has shown alterations in the basal ganglia, cortex and cerebellum in Parkinson's disease patients. However, few functional imaging studies have tested how these changes evolve over time. Our study aimed to test the longitudinal progression of movement-related functional activity in Parkinson's disease patients. Methods At baseline, 48 Parkinson's disease patients and 16 healthy controls underwent structural and functional magnetic resonance imaging during a joystick motor task. Patients had repeated imaging after 18-months (n = 42) and 36-months (n = 32). T-tests compared functional responses between Parkinson's disease patients and controls, and linear mixed effects models examined longitudinal differences within Parkinson's disease. Correlations of motor-activity with bradykinesia, rigidity and tremor were undertaken. All contrasts used whole-brain analyses, thresholded at Z > 3.1 with a cluster-wise P < 0.05. Results Baseline activation was significantly greater in patients than controls across contralateral parietal and occipital regions, ipsilateral precentral gyrus and thalamus. Longitudinally, patients showed significant increases in cerebellar activity at successive visits following baseline. Task-related activity also increased in the contralateral motor, parietal and temporal areas at 36 months compared to baseline, however this was reduced when controlling for motor task performance. Conclusion We have shown that there are changes over time in the blood-activation level dependent response of patients with Parkinson's disease undertaking a simple motor task. These changes are observed primarily in the ipsilateral cerebellum and may be compensatory in nature.

In primates, many neurons in MSTd are sensitive to the global flow structure of a pattern of moving dots, some cells responding preferentially to expansion and others to rotation. Such cells are rare in MT. We have explored sensitivity to optic flow in human MT and MST using an event-related fMRI adaptation paradigm, at 3 Tesla. On each trial, two brief random-dot kinematograms were presented sequentially with a gap of 2s. The first stimulus (S1, presented for 3s) is expected to reduce the response to the second (S2, presented for 1s) if they activate overlapping neural populations. In different trials, S1 and S2 contained either the same or different types of global motion. MT and MST were defined in separate experiments using the criteria of Huk et al. (J Neurosci 2002). In human MST, the compound response was smaller (indicating adaptation) when the two stimuli had the same flow structure than when they were different, suggesting specificity to global flow. The effect was large when optic flow was compared to random motion, as previously shown with more conventional paradigms (Smith et al. Eur. J. Neurosci. in press). It was smaller but robust when expansion and rotation were compared. Surprisingly, MT also showed flow specificity, even in the latter case. In V1, which is expected to respond only to local dot motions, there was no flow specificity. Our results suggest that human MT and MST both contain neurons that are selectively responsive to specific optic flow structures.

A number of computer models are available for prediction of nondestructive testing (NDT) inspection reliability in terms of probability of detection (POD) and false calls (PFI). These cover an increasing range of inspection techniques and run in real time on a standard PC. The models are being increasingly used and validated. Methods are evolving to correct model predictions for human error. The model approach provides complimentary data to experimental assessments and allows existing experimental data to be more widely used. The models can provide specific data not available from experimental measurements such as parametric studies, assessment of historical data and optimisation at the design stage. The models are already being used in economic assessments, integrity assessments, to support safety cases and validation of inspection procedures and plans. It is anticipated that he use of POD models will increase significantly in future years. There is a need for development of customised models for specific applications and industries and increased validation as use increases. Support from industry to meet these objectives is sought. (20 pages)

Article Figures and data Abstract Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Working memory performance is thought to depend on both striatal dopamine 2/3 receptors (D2/3Rs) and task-induced functional organisation in key cortical brain networks. Here, we combine functional magnetic resonance imaging and D2/3R positron emission tomography in 51 healthy volunteers, to investigate the relationship between working memory performance, task-induced default mode network (DMN) functional connectivity changes, and striatal D2/3R availability. Increasing working memory load was associated with reduced DMN functional connectivity, which was itself associated with poorer task performance. Crucially, the magnitude of the DMN connectivity reduction correlated with striatal D2/3R availability, particularly in the caudate, and this relationship mediated the relationship between striatal D2/3R availability and task performance. These results inform our understanding of natural variation in working memory performance, and have implications for understanding age-related cognitive decline and cognitive impairments in neuropsychiatric disorders where dopamine signalling is altered. https://doi.org/10.7554/eLife.45045.001 Introduction Working memory is the short-term maintenance, evaluation and manipulation of information ‘online’, necessary for higher cognitive processing (D'Esposito and Postle, 2015; Millan et al., 2012). Working memory impairment is an important component of age-related cognitive decline, (Braskie et al., 2008; Dahlin et al., 2008) and is reliably present in multiple neuropsychiatric disorders, where it predicts poor functional outcomes (Millan et al., 2012). The neurobiology underlying working memory variability in health and disease remains unknown, however converging evidence implicates the neuromodulator dopamine (Cools and D'Esposito, 2011). Moreover, age-related decline in striatal dopamine signalling could contribute to the cognitive decline seen in normal ageing, (Braskie et al., 2008; Dahlin et al., 2008; Bäckman et al., 2000; Berry et al., 2018a; Berry et al., 2016; Matuskey et al., 2016) and altered striatal dopamine signalling in schizophrenia and Parkinson’s Disease could contribute to cognitive impairments in these disorders (Millan et al., 2012; Simpson et al., 2010; McCutcheon et al., 2018a; Meder et al., 2019). One influential theory postulates that striatal dopamine 2/3 receptors (D2/3R) gate the flow of new information into the cortex, setting the balance between working memory stabilisation and updating (Dahlin et al., 2008; Cools and D'Esposito, 2011; Bäckman et al., 2011; Frank et al., 2001; Frank and O'Reilly, 2006). Recent animal studies show that striatal D2Rs induce changes in cortical activity and task-related mesocortical synchrony. Specifically, postsynaptic striatal D2R overexpression in mice causes a deficit in inhibitory signalling in the prefrontal cortex (PFC), (Kellendonk et al., 2006; Li et al., 2011) reduced activity in ventral tegmental area (VTA) dopamine neurons, and reduced VTA-PFC synchrony during working memory (Krabbe et al., 2015; Duvarci et al., 2018). These changes are accompanied by impairments in cognitive tasks that recruit the prefrontal cortex, including those that involve working memory (Kellendonk et al., 2006; Duvarci et al., 2018; Simpson and Kellendonk, 2017). Human and non-human primate studies also implicate the (dorsal) caudate in working memory function (Dahlin et al., 2008; Rieckmann et al., 2011; Levy et al., 1997). In humans, working memory-induced changes to whole-brain functional organisation can be studied using functional magnetic resonance imaging (fMRI), which allows measurement of the functional connectivity between cortical brain regions (Shine and Poldrack, 2018; Shine et al., 2016). Functional connectivity in this context refers to the pairwise correlation between the time course of neural activity in each region, and is a marker of shared information processing (Rubinov and Sporns, 2010). Cortical brain regions can be clustered into ‘networks’ based on their pattern of functional connectivity during rest (Rubinov and Sporns, 2010). Recent human fMRI studies indicate that working memory performance is supported by changes in the functional connectivity and organisation of cortical networks. Specifically, working memory performance induces a decrease in functional connectivity within the default mode network (DMN) (Cole et al., 2014; Finc et al., 2017; Liang et al., 2016). The DMN is the prototypical ‘task negative network’ that typically shows reductions in activity during working memory tasks, and includes ventromedial prefrontal cortex and posterior cingulate cortex (Finc et al., 2017). Moreover, task-induced connectivity changes within the DMN predict performance on working memory tasks such as the n-back (Finc et al., 2017). Working memory performance is also accompanied by changes in functional connectivity within ‘task positive networks’ (TPN) such as the dorsal attention network (DAN) and the frontoparietal network (FPN), which typically show increases in activity during working memory tasks (Shine and Poldrack, 2018). Together, these findings suggest that striatal D2/3R levels, particularly within the caudate, might exert an influence on working memory performance by modulating task-induced functional connectivity within task-relevant cortical networks. However, this hypothesis has not been tested in humans. In this study we address this question directly in a sample of 51 healthy volunteer participants. We used fMRI to measure functional connectivity within the DMN and TPN during a letter n-back working memory task that required updating of working memory representations. In the same participants, we measured baseline striatal D2/3R availability using positron emission tomography (PET). Our primary hypothesis was that striatal D2/3R availability would directly correlate with the magnitude of task-induced connectivity changes within our studied cortical networks, and that this relationship would mediate the influence of striatal D2/3Rs on performance. Results Task design, behaviour and task-induced neural activation All participants completed 18 task blocks of a letter n-back working memory task (six blocks each of 0-, 1- and 2-back conditions, in pseudo-randomised order) during fMRI scanning (Figure 1a). During the task, participants indicated whether the ‘target’ letter was present or absent on each trial, as quickly as possible. In the 0-back condition the target letter was specified at the start of the task block and remained unchanged throughout the block. In the 1-back and 2-back conditions the target letter changed on every trial (i.e. target letter for trial t was the letter presented on trial t-1 for the 1-back condition, and trial t-2 for the 2-back condition). Figure 1 Download asset Open asset Task design and behavioural results. (A) Letter n-back task design. The task consisted of 18 task blocks (20s each, interspersed with 10s rest blocks) that were pseudo-randomised to 0-, 1-, or 2-back conditions (6 blocks of each condition per task session). Participants indicated, as quickly as possible, whether the target was present or absent at the appearance of each letter, using two buttons of an MR-compatible button box. Each letter appeared on the screen for 2 s before the next letter was shown. This figure shows the last 4 trials of a 1-back task block, followed by a rest block. (B) Task behaviour. Penalised reaction time (pRT, using penalization ratio of 2.5) increases (indicating poorer performance) with increasing working memory load. Plotted as mean ± S.E.M. https://doi.org/10.7554/eLife.45045.002 We used a performance metric that is sensitive to processing speed and response omissions, as well as false positive responses. One such metric is the penalized reaction time (pRT, where reaction time set to maximum response time (2s) for incorrect or omitted responses) (Finc et al., 2017). However, using a fixed penalization of 2s fails to take into account individual- and condition-specific differences in mean reaction time. Consequently, we used a modified pRT metric, in which the reaction time of an incorrect response was replaced by a pRT that was a fixed ratio of the subject- and condition-specific RT. For clarity, we report behavioural results using the pRT defined with a penalization ratio of 2.5 (hereafter, pRT(2.5)), however the statistical significance of all results is unchanged when using penalization ratios from 2.5 to 4 (hereafter pRT(2.5-4)). We used this proportional pRT measure to derive a single measure of working memory ‘robustness’ to increasing working memory load. This was defined as the negative regression coefficient relating pRT to memory load (-ΔpRT). A value of 0 indicates that performance is unaffected by the increase in task difficulty, and increasingly negative values indicate that performance degrades with increased cognitive demands. Performance (pRT(2.5)) was negatively related to working memory load, indicating that our performance metric is sensitive to increasing cognitive demands (repeated measures ANOVA indicates a mean effect of cognitive load: F2,100 = 68.7, P < 0.001. Post-hoc paired t-tests indicate a significant difference between all pairwise comparison: t-tests: all t50 >5.3 and P < 0.001) (Figure 1b). As expected, (Owen et al., 2005) in a standard fMRI activation analysis there was activation in a widespread frontoparietal network that was parametrically related to working memory load, and deactivation in a network involving the ventromedial prefrontal cortex and posterior cingulate cortex (at P < 0.05, following whole-brain family wise error correction). Within the striatum, the activation cluster extended primarily into the dorsal striatum, in line with the postulated role of this region in updating working memory (Dahlin et al., 2008) (see Figure 2a and Table 1 for activation/deactivation clusters). There was no significant linear or quadratic relationship between neural activation/deactivation and behavioural performance (-ΔpRT (2.5)) when this variable was used as a regressor in a second-level voxel-wise analysis. Table 1 Whole brain activation/deactivation results for parametric working memory load regressor. https://doi.org/10.7554/eLife.45045.003 PeakMNI coordinates (mm)P(FWE-corr)TXYZActivation clustersLeft middle/superior frontal gyrus<0.001−30−30456Right middle/superior frontal gyrus<0.0012626457Left middle frontal gyrus<0.001−39−39633Left precuneus/superior parietal lobule<0.001-8-8−6951Right precuneus/superior parietal lobule<0.00199−6354Right superior parietal lobule<0.0013333−4844Deactivation clustersLeft central operculum/posterior insula<0.00110.35−36−1618Right central operculum/posterior insula<0.00110.2440−1622Left central operculum/anterior insula<0.0019.30−36315Left posterior cingulate<0.0017.79-4−4827Right posterior cingulate0.0125.636−4821Right posterior cingulate0.4554.2615−446 Activation/deactivation peaks present in the significant clusters at whole-brain threshold of P < 0.05 (family wise error (FWE) – corrected), using a cluster defining threshold P < 0.001 (uncorrected) for both contrasts. Anatomical labelling corresponds to the peak MNI co-ordinate. MNI = Montreal neurological institute. Task-induced functional connectivity change To investigate task-induced functional connectivity changes within task-relevant cortical networks, we first used a data-driven community detection algorithm (Blondel et al., 2008; Lancichinetti and Fortunato, 2012) to partition the cortex into group-level task positive (TPN, 53 nodes) and default mode (DMN, 42 nodes) networks, using the fMRI signal time course during the baseline (0-back) task condition (Figure 2b). The ‘empirical’ TPN and DMN networks derived from this algorithm overlapped respectively with the spatial activation and deactivation maps from the standard fMRI activation analysis, serving to highlight the functional relevance of these networks. Specifically, the set of voxels defined by the DMN nodes overlapped primarily with the voxels of the cortical deactivation cluster map (Dice similarity coefficient (DSC) = 0.22), compared to the voxels comprising the cortical activation clusters (DSC = 0.08). Conversely, the set of voxels defined by the empirical TPN nodes overlapped with the cortical activation cluster map (DSC = 0.33), but not cortical deactivation cluster map (DSC <0.001). Moreover, the empirical DMN node assignments overlapped with the a priori network assignments from the Gordon cortical parcellation for the DMN (DSC = 0.92) but not with the a priori Gordon assignments for the task-positive networks (‘DAN and FPN’) (DSC = 0.08). Conversely, the TPN nodes showed the opposite pattern, overlapping with the Gordon ‘DAN and FPN’ (DSC = 0.94) but not DMN (DSC = 0.04). Figure 2 Download asset Open asset Task-related neural activation and task-related cortical networks. (A) Significant task-induced activations (red) and deactivations (blue) that correlate with increasing working memory load, showing increased activation within dorsolateral prefrontal cortex and parietal cortex, and decreased activation within ventromedial prefrontal cortex, posterior cingulate cortex and medial temporal lobe. Activation and deactivation maps thresholded at whole-brain cluster threshold (cluster-level family-wise error corrected P < 0.05), and displayed in coronal, sagittal and axial sections overlaid on a single-subject normalized T1 image in MNI space (see Table 1 for statistical results). (B) Lateral (top) and top-down (bottom) rendering illustrating nodes of the empirical task-positive (TPN, in red) and default mode (DMN, in blue) networks identified by the community detection algorithm. https://doi.org/10.7554/eLife.45045.004 For each participant we defined the task-induced functional connectivity change within the DMN, TPN and the edges connecting the DMN and TPN (DMN-TPN) as the mean regression coefficient (w1) of a linear model describing functional connectivity strength (Fisher z-transformed r-value) of each edge (dependent variable) as a function of cognitive load (independent variable). Task-induced functional connectivity significantly decreased with working memory load in the DMN (w1 significantly less than zero: t50 = -2.33, P = 0.02, one-sample t-test), and significantly increased with working memory load in the TPN (w1 significantly more than zero: t50 = 2.70, P = 0.01, one-sample t-test) (Figure 3a and b). Figure 3 Download asset Open asset Task-induced changes in DMN and TPN functional connectivity. Increasing working memory load is accompanied by decreasing functional connectivity within the DMN (negative w1 values) and increasing functional connectivity within the TPN (positive w1 values). (A) Mean task-induced functional connectivity change of each network edge (node-node connection) in the whole sample. Each edge (cell of the matrix) represents the regression coefficient (w1 value) of connectivity change as a function of working memory load, averaged over the whole group. Arrows and black lines indicate the boundary separating nodes allocated to the empirical DMN vs TPN. (B) Mean task-induced functional connectivity change within the DMN, TPN and DMN-TPN across the whole group. Left: Group mean (± S.E.M) functional connectivity strength (Fisher z-transformed r-value) within the DMN, TPN and DMN-TPN as a function of working memory load. Right: Group mean (± S.E.M) task-induced functional connectivity change (w1) within the DMN, TPN and DMN-TPN. w1 was significantly different to zero in both the DMN (t50 = -2.33, P = 0.02, one-sample t-test) and TPN (t50 = 2.70, P = 0.01, one-sample t-test), but not the DMN-TPN (t50 = 0.65, P = 0.52, one-sample t-test). Repeated measures ANOVA indicated that w1 was not equal within the DMN, TPN and DMN-TPN edges (F2,100 = 11.16 P < 0.001), and post-hoc paired t-tests confirmed that the w1 of the DMN was significantly lower than both the TPN and DMN-TPN (t50 = -4.56, P < 0.001 and t50 = -3.01, P = 0.004, respectively), but that there was no significant difference between the w1 of the TPN and DMN-TPN (t50 = 1.62, P = 0.11). https://doi.org/10.7554/eLife.45045.005 Relationship between functional connectivity change and striatal D2/3Rs availability [11C]-(+)-PHNO binds selectively to both D2 and D3 receptors, and the D3R fraction of this measure differs between the ventral and dorsal striatum. In the (dorsal) caudate, the D3R fraction of the [11C]-(+)-PHNO BPND signal is negligible, while in the ventral striatum (including accumbens) the D3R fraction has been estimated at 20–25% (Tziortzi et al., 2011). In addition to molecular differences between striatal sub-regions, functional differences also exist. Specifically, working memory has been proposed to be supported by the (dorsal) caudate, with the accumbens being more relevant for limbic and reward processing (Dahlin et al., 2008; Rieckmann et al., 2011; Levy et al., 1997; McCutcheon et al., 2019; Haber, 2003). Consequently, we extracted [11C]-(+)-PHNO BPND separately for the caudate and accumbens striatal sub-regions, in order to investigate the relationship between striatal D2/3R availability and task-induced cortical network connectivity in a more fine-grained manner. For completeness we also report results using D2/3R availability measured from the whole striatum (caudate, accumbens and putamen). There was a positive correlation between caudate D2/3R availability and task-induced connectivity change in the DMN (rho = 0.45 [.18,. 65], d.f. = 46, P = 0.002), and DMN-TPN (rho = 0.33, [0.04, 0.57], d.f. = 46, P = 0.02), but not within the TPN (rho = 0.21, [-0.08, 0.48], d.f. = 46, P = 0.15). However, the difference between the correlations in the DMN and TPN was not itself significant (z = 1.41 [95% confidence interval for difference between correlations: −0.10,. 65], P = 0.16). D2/3R availability in the accumbens was similarly related to task-induced connectivity change in the DMN (rho = 0.31 [.017,. 55], d.f. = 46, P = 0.03), but not the TPN (rho = 0.003, [−0.29,. 29], d.f. = 46, P = 0.98) or DMN-TPN (rho = 0.15, [−0.15,. 42], d.f. = 46, P = 0.32). Although the magnitude of the D2/3R-DMN connectivity relationship was greater in the caudate compared to the accumbens, the difference between these two correlations was not statistically significant (z = 1.51 [-0.05, 0.37], P = 0.13). Taking the striatum as a whole, there was a positive correlation between D2/3R availability in the whole striatum and the task-induced connectivity change within the DMN (rho = 0.38 [.10,. 60], d.f. = 46, P = 0.008), but not within the TPN (rho = 0.11 [−0.18,. 39], d.f. = 46, P = 0.44) or DMN-TPN (rho = 0.17 [−0.12,. 43], d.f. = 46, P = 0.29) (Figure 4a). This indicates that participants who exhibited greater task-induced reduction in DMN connectivity had lower striatal D2/3R availability, particularly in the caudate. Figure 4 Download asset Open asset The relationship between striatal D2/3R availability, task-induced change in DMN connectivity, and task performance. (A) The significant positive correlation between striatal D2/3R availability and task-induced change in connectivity within the default mode network (DMN), where negative values on the y-axis indicate a reduction in connectivity. Lower caudate D2/3R availability is related to a task-induced reduction in DMN connectivity. (B) The relationship between task-induced functional connectivity change within the DMN and working memory robustness, -ΔpRT2.5 (a value of 0 indicates that performance is unaffected by increasing working memory load, while negative values indicate that performance decreases with increasing cognitive demands). Negative values on the x-axis indicate a task-induced reduction in DMN connectivity. Task-induced decreases in DMN connectivity were associated with greater working-memory related behavioural impairment. (C) Mediation analysis. Greater caudate D2/3R availability has a significant but indirect association with improved task performance, mediated via task-induced connectivity change within the DMN. Pearson’s correlation coefficients in (C) are reported in the sample of 48 participants (d.f. = 46) who had both PET and fMRI. https://doi.org/10.7554/eLife.45045.006 We investigated the specificity of the relationship between task-induced DMN connectivity change and striatal D2/3Rs in two additional analyses. First, there was no correlation between striatal D2/3R availability and functional connectivity averaged over the whole task session (i.e. mean network functional connectivity over all task blocks) in the DMN (Caudate: rho = 0.07 [−0.23,. 36], d.f. = 46, P = 0.63; Accumbens: rho = 0.05 [−0.25,. 34], d.f. = 46, P = 0.75; Whole Striatum: rho = 0.16 [−0.14,. 43], d.f. = 46, P = 0.29). Similarly, there was also no significant relationship between regional D2/3R availability and whole-session connectivity in the TPN or DMN-TPN (all P > 0.15). Second, there was no relationship between D2/3R availability in the substantia nigra/ventral tegmental area (SN/VTA, where the D3R fraction of the PHNO signal approaches 100% [Tziortzi et al., 2011]) and cortical network connectivity change (DMN: rho = 0.01 [−0.28,. 30], d.f. = 46, P = 0.93); TPN: (rho = −0.10 [−0.38,. 20], d.f. = 46, P = 0.50); DMN-TPN: (rho = −0.12 [−0.40,. 18], d.f. = 46, P = 0.42). Of note, the correlation between DMN connectivity change and D2/3R availability in the SN/VTA was significantly weaker than the correlation with D2/3R availability in the caudate (z = 2.54 [0.11, 0.83], P = 0.01), and whole striatum (z = 2.29 [0.06, 0.72], P = 0.02), but not the ventral striatum (z = 1.7 [-0.05, 0.67], P = 0.09). The relationship between network connectivity changes and performance There was a significant positive correlation between the task-induced change in DMN connectivity and working memory performance (defined as the robustness of performance to increasing cognitive load, -ΔpRT(2.5)) (rho = .45 [.20,.64], d.f. = 49, P < 0.001), indicating that participants who showed the greatest task-induced reduction of functional connectivity within the DMN also showed the most marked load-dependent impairment in task performance (Figure 4b). This result was robust to a wide range of penalization ratios from 2.5 to 4 (all P < 0.001). There was no similar relationship for connectivity change within the TPN or DMN-TPN (-ΔpRT2.5-4, all P > 0.50), and also no relationship between performance and mean functional connectivity averaged over the whole task session in the DMN or TPN (-ΔpRT2.5-4, all P > 0.50). The relationship between striatal D2/3Rs and performance There was a positive relationship between D2/3R availability in the caudate and -ΔpRT(2.5) (rho = 0.33 [.04,. 57], d.f. = 46, P = 0.02), which remained significant for penalization ratios from 2.5 to 4 (all P < 0.02). This relationship was not present for D2/3R availability in the accumbens (-ΔpRT(2.5): rho = 0.10 [−0.20,. 38], d.f. = 46,, P = 0.50. P > 0.4 for -ΔpRT(2.5-4)), and the difference between these correlation coefficients was itself significant (z = 2.44 [0.05, 0.44], P = 0.01). The correlation between performance and D2/3R availability in the whole striatum was present at trend level (-ΔpRT(2.5): rho = 0.27 [−0.02,. 52], d.f. = 46, p=0.06. P < 0.06 for -ΔpRT(2.5-4)). There was no relationship between D2/3R availability in the SN/VTA and performance (-ΔpRT(2.5) rho = 0.13 [−0.17,. 41], d.f. = 46, P = 0.37. P > 0.3 for -ΔpRT(2.5-4)). Striatal D2Rs are thought to exert an influence on cognitive function through a more direct effect on the excitability and function of cortical circuits (Cools and D'Esposito, 2011; Frank and O'Reilly, 2006; Salami et al., 2019). Having found a significant relationship between striatal D2/3R availability and both task-induced DMN connectivity, and a relationship between both measures and task performance, we tested whether the influence of striatal D2/3R availability on performance is mediated by the effect of the former on task-induced connectivity change within the DMN. A mediation analysis indicated that the effect of caudate D2/3R availability on working memory performance is mediated through the direct effect of D2/3R availability on task-induced DMN connectivity change (−ΔpRT(2.5): average causal mediation effect (ACME) = 0.03 [0.01, 0.12], P = 0.015. The mediation effect remains significant at P < 0.015 for -ΔpRT(2.5-4)) (Figure 4c). This analysis was also significant using D2/3R availability from the whole striatum (-ΔpRT(2.5): ACME = 0.04 [0.01, 0.14], P = 0.026. P < 0.03 for -ΔpRT(2.5-4)), but was not significant using D2/3R availability from the accumbens (-ΔpRT(2.5): ACME = 0.002 [<0.001, 0.12], P = 0.09. P > 0.08 for -ΔpRT(2.5-4)). As expected, there was no significant mediation effect when the mediator variable was task-induced connectivity changes within the TPN (all P > 0.6) or DMN-TPN (all P > 0.3). These results suggest that striatal D2/3Rs, particularly in the caudate, might exert an influence on working memory performance through a more direct effect on task-induced functional connectivity changes within the DMN. Participants with higher striatal D2/3R availability exhibited the least pronounced DMN connectivity decreases with working memory load, which predicted more robust task performance in the face of increasing working memory load. Relationship between striatal D2/3R availability and task-related activation Our results support the conclusion that striatal D2/3R availability, particularly within caudate, is related to task-induced changes in DMN connectivity and working memory performance. For completeness, we conducted two analyses to test for a relationship between D2/3R availability within this region and inter-individual differences in task-evoked BOLD activation. First, using a standard mass-univariate analysis we tested whether there was a relationship between the parametric BOLD response to working memory load and caudate D2/3R availability. We found no evidence for a linear or quadratic relationship at P < 0.05, whole-brain level. In a second analysis we used partial least squares (PLS) regression for fMRI, to test for the presence of a multivariate pattern of brain activity that shows a relationship to inter-individual differences in caudate D2/3R availability. This analysis again did not detect significant latent variables (LVs) showing a relationship to caudate D2/3R availability (1st LV P-value = 0.20). However, consistent with the standard mass univariate fMRI analysis (Figure 2a), a standard PLS analysis found strong evidence for BOLD modulation by working memory load in a widespread cortical frontoparietal network (1st latent variable significant at P < 0.001). Within-subject relationship between DMN strength and performance The between-subjects analysis so far has considered the relationship between the average task-induced connectivity change within the DMN and working memory performance, finding that as cognitive load increases, the individuals who showed the greatest DMN connectivity decreases also showed the greatest working memory performance degradation. We employed a within-subject linear regression approach to investigate whether block-specific DMN connectivity is a significant predictor of working memory performance (see Materials and methods). A simple regression analysis confirmed that block-wise DMN connectivity strength is a significant within-subject predictor of working-memory performance (using pRT2.5, w1 = -.10 [-.17, -.02], P = 0.01). The results remain significant when using pRT2.5-4). When including block-specific working memory load as an additional predictor variable in the model, this effect was not statistically significant (using pRT2.5, w2 = -.04 [-.10,. 01], P = 0.14. P > 0.2 when using pRT2.5-4). As expected, this analysis confirmed a significant effect of working memory load (w1) on performance (all P < 0.001). As increased pRT is indicative of poorer performance, the negative regression coefficients in these analyses indicate that in a given task block, stronger DMN connectivity is a predictor of improved working memory performance within an individual. This is in line with the between-subject finding that poorer performing participants show the most exaggerated DMN connectivity reductions with increased working memory load. Analysis using d-Prime behavioural measure Finally, for completeness we repeated the analysis using the discriminability index (d’) (Haatveit et al., 2010) as the measure of working memory performance. As with the pRT metric, for each individual we regressed mean d’ for each task condition on working memory load, and defined overall performance as the regression coefficient on working memory load. Using this performance metric, there was no relationship between task-induced DMN connectivity change and performance (rho = 0.12 [-.17,. 39], d.f. = 49, P = 0.4), and no relationship between performance and D2/3R availability in any striatal sub-region (all P > 0.2). Importantly, compared to pRT, d’ is not sensitive to differences in processing speed (i.e. reaction time) between task conditions with similar performance accuracy, and also cannot differentiate between (incorrect) response omissions

To estimate the efficiency of glucocorticoid signaling in multiple sclerosis in vivo, we measured mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and four genes regulated by GR and implicated in immune function, in whole blood. GR expression and MR expression were significantly lower in 52 patients than in 18 controls. In contrast, expression of GR regulated genes was increased (significantly for glucocorticoid induced leucine zipper, GILZ), especially in mildly impaired patients. Reduced GR expression appears to be compensated, either by hyperactive hypothalamo–pituitary–adrenal axis or by intracellular adaptations.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Poster for the 2012 University Scholars Day at the University of North Texas discussing skeletal lymph muscles as effectors of the arterial baroreflex in the cane toad (Rhinella marina).

Inspection by nondestructive testing techniques is not perfect and it has become common practice to quantify the reliability of flaw detection in terms of the probability of detection (POD) and the probability of false indication. Experimental measurement of these quantities is expensive and attention has therefore recently turned to modelling them. This paper discusses the benefits of, approaches to and applications of POD modelling. Examples are given of the application of POD models developed by AEA Technology.

In macaques, cortical area MST receives vestibular as well as visual input. The vestibular tuning of MST neurons can be either (i) congruent with their tuning for optic flow, suggesting combination of cues to specify self-motion more accurately, or (ii) opposite, perhaps allowing head motion to be discounted in order to facilitate detection of object motion. In contrast, it is thought that macaque MT does not have vestibular afferents. We have examined whether human MT and MST have vestibular inputs by applying galvanic vestibular stimulation (GVS) in combination with fMRI. GVS involves passing a controlled current between two electrodes attached to the mastoid processes, to stimulate the cranial nerves that connect the vestibular organs to the brainstem. We applied a 1Hz sinusoidal alternating current of ±1 mA during conventional fMRI acquisition at 3Tesla. All participants reliably experienced vestibular sensations during stimulation intervals (roll and/or yaw that alternated in direction at 1Hz). Scanning was performed in total darkness and also while continuously observing a static visual scene. In separate scans, MT and MST were identified conventionally with unilateral visual motion stimulation, exploiting the fact that MST but not MT responds to ipsilateral visual stimuli. During GVS, significant time-locked activation was seen in the MT+ complex. It occurred in darkness as well as during vision so cannot be attributed to image motion caused by cyclotorsional eye movements. In every case, it occurred only in the anterior portion of MT+ and the active region corresponded well to MST as defined visually. Activity was also seen in parieto-insular vestibular cortex (PIVC). Suppression was often seen in occipital cortex and in somatosensory cortex, consistent with known inhibitory interactions. We conclude that human MST receives vestibular afferents but human MT does not. In addition, GVS provides an alternative localizer for MST.

Primate visual cortical area MST is responsive to optic flow and can encode direction of heading but it may not directly signal motion of the body through space (egomotion). We identify two areas of the human brain that represent visual cues to egomotion more directly than does MST. Sensitivity to whether a flow pattern could have been caused by egomotion was tested with fMRI. Responses to a standard random-dot flow pattern were compared with responses to a 3×3 array of nine identical flow patches. Optic flow generated by egomotion can only have one centre of motion (expansion for forward motion). Consequently, the nine flow patches may drive neurons tuned to flow components such as expansion, but the overall stimulus is inconsistent with egomotion. Visual areas were defined in separate retinotopic mapping experiments. Areas V1–V4 and MT all responded about equally to both types of flow stimulus. MST also responded well to multiple patches but showed a modest preference for a single, egomotion-compatible patch. Putative area VIP in the anterior portion of the intraparietal sulcus showed much stronger selectivity, the response to a single flow stimulus being about twice that to the array. More striking still was the result in a new visual area, which we refer to as CSv (cingulate sulcus visual area). Here, a strong response was obtained with a single flow patch but the region was almost completely unresponsive to multiple patches. This requirement for egomotion-compatible stimulation may explain why CSv has not commonly been identified as a visual area. Various control experiments for dot motion parameters, size of motion patch and presence of motion boundaries all yielded similar results. We suggest that MST is merely an intermediate processing stage for visual cues to egomotion and that such cues are more comprehensively encoded by VIP and CSv.

Objective: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures.Although previous studies of AW and relapse have highlighted the critical importance of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and the detrimental role of stress, little is known about genetic risk factors.We therefore conducted genetic and neurobiological studies to identify and characterize novel risk loci.Methods: We performed a genome-wide association study (GWAS) of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent subjects, and bioinformatic analyses.We used genetically modified mouse neuronal cultures to conduct electrophysiological and pharmacological studies of neurobiological systems implicated by the GWAS.Results: The top association signal for AW severity was in sortilin-related gene SORCS2 on chromosome 4 (European-American meta-analysis n = 1,478, P = 4.3 x 10 -9 ), and the same risk allele also predicted more severe clinical outcomes in seizure disorder patients participating in a randomized trial of anticonvulsant effectiveness (n = 654, P = 3.2 x 10 -3 ).In humans, SORCS2 is most highly expressed in the nervous system, and bioinformatic analyses showed that the SORCS2 risk haplotype disrupts transcription factor (TF) binding motifs within a stress hormoneregulated enhancer element active in human hippocampus.In mouse hippocampal preparations, we demonstrate that SorCS2 is a key regulator of GluN2B-mediated synaptic responses.Conclusion: These translational findings identify new synaptic regulatory processes, and provide novel targets for managing the aversive consequences of abrupt alcohol cessation. PM297High-dose zolpidem dependence and detoxification from withdrawal symptoms using diazepam

With the advance of IT infrastructure and computer-based engineering solutions in manufacturing enterprises, design engineers have at their disposal numerous computer-based tools and methods that facilitate product development activities. Although these tools and methods have improved the quality and speed of product development processes, there remain many inefficiencies due to ineffective use and/or sharing of design knowledge and errors in communication. This paper identifies the typical issues in communications and design knowledge sharing in collaborative design environments and introduces a computer-based solution to enhance the product development process in terms of collaboration and design knowledge sharing. The solution is focused on preventing communication errors and the timely use of design knowledge assets, including design documents, specifications, test results, reports, reviews, memos, meeting minutes, and the like.

ABSTRACT Introduction Hypoactive sexual desire disorder (HSDD) is characterized by a persistent lack of sexual desire and sexual fantasies, causing marked interpersonal distress1. It is the most common global female sexual health problem, affecting up to 1 in 10 women2,3. Despite its significant social and economic burden4,5, the exact pathophysiology of this condition remains unknown. Furthermore, existing treatment options are limited by their efficacy and side effects6. Melanocortin-4 receptor (MC4R) agonists are a promising therapeutic avenue, although their exact mechanism of action within the CNS remains unknown. Investigating the neural pathways through which MC4Ra's exert their effect will deepen our knowledge of normal and abnormal sexual behaviour, and hence provide information which could contribute to the development of novel treatment strategies. Objective To determine the mechanism by which MC4R agonists mediate their effects on sexual behaviour in women with HSDD. Methods We performed a randomized, double-blind, placebo-controlled crossover study in 31 premenopausal women with HSDD. A combination of psychometric, functional neuroimaging and hormonal analyses was used to investigate the effect of MC4R agonism versus placebo on sexual brain processing. A standard fMRI block design task with short (20 second) erotic videos was used to examine brain activation. Additionally, a ‘naturalistic’ fMRI paradigm was used with long (ten minute) erotic videos to examine functional brain connectivity. Results MC4R agonism increased self-reported sexual desire for up to 24-hours following administration, when compared with placebo (P=0.007). The mechanism of action behind this effect may be explained by the changes in brain activation and connectivity, in response to visual erotic stimuli. In the short video task, MC4R agonism led to increased activation of the supplementary motor area and cerebellum, alongside deactivation of the secondary somatosensory cortex, when compared with placebo (Z=2.3, P&amp;lt;0.05). In the long video task, a reduction of functional connectivity between the amygdala and insula in response to erotic stimuli was prevented by MC4R agonism (F (1,30) = 5.553, P=0.025). Regarding hormonal analyses, MC4R agonism led to a small mean increase in LH of 1.1iU/L (F [1,58] = 13.38, P=0.0005) and FSH of 0.35iU/L (F [1,60] = 10.97, P=0.0016) during the study, with no effect on estradiol or progesterone levels. Conclusions This is the first study investigating the effect of MC4R agonism on sexual brain processing in women with HSDD. These results shed light on the neural substrates through which MC4R agonism increases sexual desire. The observed changes in brain activation may serve to ease self-consciousness, enhance sexual imagery and disinhibit the sexual response in women with HSDD. This is in line with the “top-down” neurofunctional model of HSDD whereby inspecting and monitoring one's sexual response interferes with desire7. This information is important for the ongoing development of therapies for HSDD, as well as MC4R agonist development more widely, such as in obesity medicine where there their use is being rapidly developed. Disclosure Work supported by industry: yes, by AMAG Pharmaceuticals Inc.

The final version, presented by the NDE-3-1 project team as a group review and commentary on the blind trial reports from Transkor and Speir Hunter. this describes the development program on Large Standoff Magnetometry (LSM) techniques claimed to provide integrity assessments on buried pipelines. The projectis a continuation of the PRCI research program on above the pipe NDE methods and is designated as Project NDE 3-1. The scope was as follows: Project kick-off and initial data review, noting any gaps in data. Performing the initial reliability analysis of the Transkor MTM and Speir Hunter SCZ data from PRCI; provision of draft final report to PRCI on the analysis of trial data. If necessary, establish contact with technology suppliers,more...

A defect criticality framework and assessment procedure for composite material systems has been proposed, based on the multi-level assessment philosophy contained within API (American Petroleum Industry) 579 - Recommended Practice for Fitness-For-Service and Continued Operation of Equipment. The basis for the framework detailed in this guide is a 3 Level approach which involves increasing levels of sophistication in the assessment approach, from operator to expert. For each level, guidance and recommendations have been provided as to the degree of knowledge and complexity required for non-destructive evaluation (NDE), defect classification, defect criticality assessment and materials characterisation. Four industrial case studies have been undertaken in order to demonstrate various aspects of the framework and to validate the approach proposed.

Historically relegated the “underdog” ventricle, a status perhaps bolstered by seminal work in the 1940s and 1950s supporting cardiac output preservation even in the face of complete right ventricular cauterization, the right ventricle (RV), and right heart, has leapt in repute and respect as it has humbled us with its importance in functional capacity and prognosis in congenital heart disease, pulmonary arterial hypertension, myocardial infarction, and heart failure. In this article, we summarize salient features of RV anatomy and physiology, review important hemodynamic concepts of the right heart in health and apply these concepts in major disease states, and review right heart hemodynamic assessment by both invasive and noninvasive approaches.

&lt;b&gt;Objective: &lt;/b&gt;Weight loss achieved with very low-calorie diets (VLCD) can produce remission of Type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesised that in patients living with obesity and pre-diabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference. &lt;b&gt;Methods:&lt;/b&gt; 16 participants underwent gastric bypass surgery and 19 matched participants undertook a very low calorie (meal replacement) diet for 4 weeks. Brain responses to food cues and resting state functional connectivity was assessed with functional MRI pre- and post-intervention and compared across groups. &lt;b&gt;Results:&lt;/b&gt; We show that RYGB results in three divergent brain responses in comparison to VLCD-induced weight loss: (i) VLCD resulted in increased brain reward centre food cue responsiveness whereas in RYGB this was reduced; (ii) VLCD resulted in higher neural activation of cognitive control regions in response to food cues, associated with exercising increased cognitive restraint over eating, whereas RYGB did not; (iii) a homeostatic appetitive system (centred on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD. &lt;b&gt;Conclusion:&lt;/b&gt; Taken together these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast with the enduring weight loss after RYGB.

&lt;b&gt;Objective: &lt;/b&gt;Weight loss achieved with very low-calorie diets (VLCD) can produce remission of Type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesised that in patients living with obesity and pre-diabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference. &lt;b&gt;Methods:&lt;/b&gt; 16 participants underwent gastric bypass surgery and 19 matched participants undertook a very low calorie (meal replacement) diet for 4 weeks. Brain responses to food cues and resting state functional connectivity was assessed with functional MRI pre- and post-intervention and compared across groups. &lt;b&gt;Results:&lt;/b&gt; We show that RYGB results in three divergent brain responses in comparison to VLCD-induced weight loss: (i) VLCD resulted in increased brain reward centre food cue responsiveness whereas in RYGB this was reduced; (ii) VLCD resulted in higher neural activation of cognitive control regions in response to food cues, associated with exercising increased cognitive restraint over eating, whereas RYGB did not; (iii) a homeostatic appetitive system (centred on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD. &lt;b&gt;Conclusion:&lt;/b&gt; Taken together these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast with the enduring weight loss after RYGB.

This report provides an assessment of the designs of turret and swivel systems for floating production, storage and offloading (FPSO) vessels and floating storage Units (FSU) which are either purpose built or converted from tankers. Use of FPSO and FSO in the North Sea with the move to subsea and deepwater production is discussed, and the background to FPSO and FSU turret systems is traced. Details are given of general issues relating to ship structure, systems affecting the turret, swivel systems, mooring systems, turret loading, scaffolding and support structure, on-board personnel, and construction standards. Turret system components and types are described, and failure modes, operation and safety relevant components are examined. Inspection and maintenance, examples of good and poor practice, and applicable regulations are considered. Annexes list UK installations and present information on individual turret design, fluid transfer systems, system manufacturers, specific UK and North Sea installations, and worldwide installations.