Age-dependent changes in clock neuron structural plasticity and excitability are associated with a decrease in circadian output behaviour and sleep

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAgeing has significant effects on circadian behaviour across a wide variety of species, but the underlying mechanisms are poorly understood. Previous work has demonstrated the age-dependent decline in behavioural output in the model organism Drosophila. We demonstrate this age-dependent decline in circadian output is combined with changes in daily activity of Drosophila. Ageing also has a large impact on sleep behaviour, significantly increasing sleep duration whilst reducing latency. We used electrophysiology to record from large ventral lateral neurons (l-LNv) of the Drosophila circadian clock, finding a significant decrease in input resistance with age, but no significant changes in spontaneous electrical activity or membrane potential. We propose this change contributes to observed behavioural and sleep changes in light-dark conditions. We also demonstrate a reduction in the daily plasticity of the architecture of the small ventral lateral neurons (s-LNv), likely underlying the reduction in circadian rhythmicity during ageing. These results provide further insights into the effect of ageing on circadian biology, demonstrating age-related changes in electrical activity in conjunction with the decline in behavioural outputs.Wellcome TrustLeverhulme TrustEngineering and Physical Sciences Research Council (EPSRC

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

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordLittle 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.Biotechnology and Biological Sciences Research Council (BBSRC)Medical Research Council (MRC)Society for the Study of AddictionUniversity College London, National Institute of Health Research Biomedical Research Centr

Documentation of individualized preoperative risk assessment: a multi-center study

Background: Individual surgical risk assessment (ISRA) enhances patient care experience and outcomes by informing shared decision-making, strengthening the consent process, and supporting clinical management. Neither the use of individual pre-surgical risk assessment tools nor the rate of individual risk assessment documentation is known. The primary endpoint of this study was to determine the rate of physician documented ISRAs, with or without a named ISRA tool, within the records of patients with poor outcomes. Secondary endpoints of this work included the effects of age, sex, race, ASA class, and time and type of surgery on the rate of documented presurgical risk. / Methods: The records of non-obstetric surgical patients within 22 community-based private hospitals in Arizona, Colorado, Nebraska, Nevada, and Wyoming, between January 1 and December 31, 2017, were evaluated. A two-sample proportion test was used to identify the difference between surgical documentation and anesthesiology documentation of risk. Logistic regression was used to analyze both individual and group effects associated with secondary endpoints. / Results: Seven hundred fifty-six of 140,756 inpatient charts met inclusion criteria (0.54%, 95% CI 0.50 to 0.58%). ISRAs were documented by 16.08% of surgeons and 4.76% of anesthesiologists (p < 0.0001, 95% CI −0.002 to 0.228). Cardiac surgeons documented ISRAs more frequently than non-cardiac surgeons (25.87% vs 16.15%) [p = 0.0086, R-squared = 0.970%]. Elective surgical patients were more likely than emergency surgical patients (19.57 vs 12.03%) to have risk documented (p = 0.023, R-squared = 0.730%). Patients over the age of 65 were more likely than patients under the age of 65 to have ISRA documentation (20.31 vs 14.61%) [p = 0.043, R-squared = 0.580%]. Only 10 of 756 (1.3%) records included documentation of a named ISRA tool. / Conclusions: The observed rate of documented ISRA in our sample was extremely low. Surgeons were more likely than anesthesiologists to document ISRA. As these individualized risk assessment discussions form the bedrock of perioperative informed consent, the rate and quality of risk documentation must be improved

Does variation in trait schizotypy and frequency of cannabis use influence the acute subjective, cognitive and psychotomimetic effects of delta-9-tetrahydrocannabinol?:A mega-analysis

Background: While the acute effects of cannabis are relatively benign for most users, some individuals experience significant adverse effects. This study aimed to identify whether variation in schizotypal personality traits and frequency of cannabis use influence the acute effects of delta-9-tetrahydrocannabinol (THC). Methods: Individual participant data from four double-blind, randomised, placebo-controlled, acute crossover studies involving 128 cannabis users were combined for a mega-analysis. Using multilevel linear models and moderation analyses, frequency of cannabis use and schizotypal personality traits were investigated as potential moderators of the subjective, cognitive and psychotomimetic effects of acute THC. Results: There was evidence of a moderating effect where increased frequency of cannabis use was associated with reduced intensity of subjective (changes in alertness and feeling stoned) and psychosis-like effects following THC when compared with placebo. Moderating effects of cannabis use frequency on acute memory impairment were weak. Trait schizotypy did not moderate the acute psychosis-like effects of THC compared with placebo. Conclusions: Our results suggest that a pattern of domain-specific tolerance develops to the acute effects of THC. Tolerance to the alertness-reducing effects occurred more readily than tolerance to psychotomimetic effects. Only partial tolerance to feeling stoned was found, and there was weak evidence for tolerance to memory impairment. Trait schizotypy did not moderate THC’s effects on psychotomimetic symptoms

The optimisation and production of stable homogeneous amine enriched surfaces with characterised nanotopographical properties for enhanced osteoinduction of mesenchymal stem cells

Silane modification has been proposed as a powerful biomaterial surface modification tool. This is the first comprehensive investigation into effect of silane chain length on the resultant properties of –NH2 silane monolayers (SAMS) and the associated osteoinductive properties of the surface. A range of –NH2 presenting silanes, chain length 3 to 11, were introduced to glass coverslips and characterised using water contact angles, atomic force microscopy, X-ray photoelectron spectroscopy and Ninhydrin assays. The ability of the variation in chain length to form a homogenous layer across the entirety of the surfaces was also assessed. The osteoinductive potential of the resultant surfaces was evaluated by real time polymerase chain reaction, immunocytochemistry and von Kossa staining. Control of surface chemistry and topography was directly associated with changes in chain length. This resulted in the identification of a specific, chain length 11 (CL11) which significantly increased the osteoinductive properties of the modified materials. Only CL11 surfaces had a highly regular nano-topography/roughness which resulted in the formation of an appetite-like layer on the surface that induced a significantly enhanced osteoinductive response (increased expression of osteocalcin, CBFA1, sclerostin and the production of a calcified matrix) across the entirety of the surface

Effect of four-week cannabidiol treatment on cognitive function: secondary outcomes from a randomised clinical trial for the treatment of cannabis use disorder

RATIONALE: Chronic cannabis use is associated with impaired cognitive function. Evidence indicates cannabidiol (CBD) might be beneficial for treating cannabis use disorder. CBD may also have pro-cognitive effects; however, its effect on cognition in people with cannabis use disorder is currently unclear. OBJECTIVES: We aimed to assess whether a 4-week CBD treatment impacted cognitive function. We hypothesised that CBD treatment would improve cognition from baseline to week 4, compared to placebo. METHODS: Cognition was assessed as a secondary outcome in a phase 2a randomised, double-blind, parallel-group and placebo-controlled clinical trial of 4-week daily 200 mg, 400 mg and 800 mg CBD for the treatment of cannabis use disorder. Participants had moderate or severe DSM-5 cannabis use disorder and intended to quit cannabis use. Our pre-registered primary cognitive outcome was delayed prose recall. Secondary cognitive outcomes were immediate prose recall, stop signal reaction time, trail-making task performance, verbal fluency and digit span. RESULTS: Seventy participants were randomly assigned to placebo (n = 23), 400 mg CBD (n = 24) and 800 mg CBD (n = 23). A 200 mg group was eliminated from the trial because it was an inefficacious dose at interim analysis (n = 12) and was not analysed here. For the primary cognitive outcome, there was no effect of CBD compared to placebo, evidenced by a lack of dose-by-time interaction at 400 mg (0.46, 95%CIs: - 1.41, 2.54) and 800 mg (0.89, 95%CIs: - 0.99, 2.81). There was no effect of CBD compared to placebo on secondary cognitive outcomes, except backwards digit span which increased following 800 mg CBD (0.30, 95%CIs: 0.02, 0.58). CONCLUSIONS: In this clinical trial for cannabis use disorder, CBD did not influence delayed verbal memory. CBD did not have broad cognitive effects but 800 mg daily treatment may improve working memory manipulation. CLINICAL TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov (NCT02044809) and the EU Clinical Trials Register (2013-000,361-36)

Cannabis dampens the effects of music in brain regions sensitive to reward and emotion

Background: Despite the current shift towards permissive cannabis policies, few studies have investigated the pleasurable effects users seek. Here we investigate the effects of cannabis on listening to music - a rewarding activity that frequently occurs in the context of recreational cannabis use. We additionally tested how these effects are influenced by cannabidiol (CBD), which may offset cannabis-related harms. Methods: Across three sessions, sixteen cannabis users inhaled cannabis with CBD, cannabis without CBD, and placebo. We compared their response to music relative to control excerpts of scrambled sound during functional Magnetic Resonance Imaging (fMRI) within regions identified in a meta-analysis of music-evoked reward and emotion. All results were False Discovery Rate corrected (p<0.05). Results: Compared to placebo, cannabis without CBD dampened response to music in bilateral auditory cortex (right: p=0.005, left: p=0.008), right hippocampus/parahippocampal gyrus (p=0.025), right amygdala (p=0.025) and right ventral striatum (p=0.033). Across all sessions, the effects of music in this ventral striatal region correlated with pleasure ratings (p=0.002) and increased functional connectivity with auditory cortex (right: p=0.000, left: p=0.000), supporting its involvement in music reward. Functional connectivity between right ventral striatum and auditory cortex was increased by CBD (right: p=0.003, left: p=0.030), and cannabis with CBD did not differ from placebo on any fMRI measures. Both types of cannabis increased ratings of wanting to listen to music (p<0.002) and enhanced sound perception (p<0.001). Conclusions: Cannabis dampens the effects of music in brain regions sensitive to reward and emotion. These effects were offset by a key cannabis constituent, cannabidol