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  • Pool size ratio of the substantia nigra in Parkinson's disease derived from two different quantitative magnetization transfer approaches.

    3 July 2018

    PURPOSE: We sought to measure quantitative magnetization transfer (qMT) properties of the substantia nigra pars compacta (SNc) in patients with Parkinson's disease (PD) and healthy controls (HCs) using a full qMT analysis and determine whether a rapid single-point measurement yields equivalent results for pool size ratio (PSR). METHODS: Sixteen different MT-prepared MRI scans were obtained at 3 T from 16 PD patients and eight HCs, along with B1, B0, and relaxation time maps. Maps of PSR, free and macromolecular pool transverse relaxation times ([Formula: see text], [Formula: see text]) and rate of MT exchange between pools (k mf ) were generated using a full qMT model. PSR maps were also generated using a single-point qMT model requiring just two MT-prepared images. qMT parameter values of the SNc, red nucleus, cerebral crus, and gray matter were compared between groups and methods. RESULTS: PSR of the SNc was the only qMT parameter to differ significantly between groups (p < 0.05). PSR measured via single-point analysis was less variable than with the full MT model, provided slightly better differentiation of PD patients from HCs (area under curve 0.77 vs. 0.75) with sensitivity of 0.75 and specificity of 0.87, and was better than transverse relaxation time in distinguishing PD patients from HCs (area under curve 0.71, sensitivity 0.87, and specificity 0.50). CONCLUSION: The increased PSR observed in the SNc of PD patients may provide a novel biomarker of PD, possibly associated with an increased macromolecular content. Single-point PSR mapping with reduced variability and shorter scan times relative to the full qMT model appears clinically feasible.

  • SlowMo, a digital therapy targeting reasoning in paranoia, versus treatment as usual in the treatment of people who fear harm from others: study protocol for a randomised controlled trial.

    2 July 2018

    BACKGROUND: Paranoia is one of the most common symptoms of schizophrenia-spectrum disorders, and is associated with significant distress and disruption to the person's life. Developing more effective and accessible psychological interventions for paranoia is a clinical priority. Our research team has approached this challenge in two main ways: firstly, by adopting an interventionist causal approach to increase effectiveness and secondly, by incorporating user-centred inclusive design methods to enhance accessibility and usability. Our resultant new digital intervention, SlowMo, intensively targets a reasoning style associated with paranoia, fast thinking, characterised by jumping to conclusions and belief inflexibility. It consists of an easy-to-use, enjoyable and memorable digital interface. An interactive web-based app facilitates delivery of face-to-face meetings which is then synchronised with an innovative mobile app for use in daily life. METHODS/DESIGN: We aim to test the clinical efficacy of SlowMo over 24 weeks to determine the mechanisms through which it reduces paranoia, and to identify participant characteristics that moderate its effectiveness. In a parallel-group randomised controlled trial, with 1:1 allocation, 360 participants with distressing persecutory beliefs will be independently randomised to receive either the SlowMo intervention added to treatment as usual (TAU) or TAU, using randomly varying permuted blocks, stratified by paranoia severity and site. Research workers will be blind to therapy allocation. The primary outcome is paranoia severity over 24 weeks; our hypothesised mechanism of change is reasoning; moderators include negative symptoms and working memory; and secondary outcomes include wellbeing, quality of life, and service use. The accessibility, usability and acceptability of the digital platform will be assessed. DISCUSSION: SlowMo has been developed as the first blended digital therapy to target fears of harm from others through an inclusive design approach. In addition to testing its efficacy, this trial will add to our understanding of psychological mechanisms in paranoia. The study will examine the usability and adherence of a novel digital therapy, including an app for self-management, in a large sample of people affected by severe mental health difficulties. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN32448671 . Registered prospectively on 30 January 2017. Date assigned 2 February 2017.

  • The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group.

    2 July 2018

    BACKGROUND: Previous studies have suggested that cannabidiol has anxiolytic and antipsychotic properties, raising hopes that cannabidiol will translate to the psychiatric clinic. Cannabidiol may be particularly useful for anxiety and paranoia in those at-risk of major mental illness. METHODS: Immersion in a controlled 3D virtual-reality scenario was used to assay persecutory ideation and anxiety in a sample of non-clinical volunteers ( n=32) pre-selected for high paranoid traits. Participants were randomised to receive oral cannabidiol (600 mg) or placebo 130 min prior to entering virtual-reality. Well-validated rating scales were used to assay persecutory thinking and anxiety. Salivary cortisol concentration, heart rate and blood pressure were measured over the course of the experimental session. RESULTS: Immersion in the virtual-reality session elicited anxiety as indexed by the Beck's anxiety inventory ( p<0.005), and increased cortisol concentration ( p=0.05), heart rate ( p<0.05) and systolic blood pressure ( p<0.05). However, cannabidiol had no impact upon any of these effects, except for a strong trend to increase anxiety ( p=0.09). Cannabidiol had no effect on persecutory ideation as assayed by the Community Assessment of Psychic Experiences questionnaire or the State Social Paranoia Scale. CONCLUSIONS: In contrast to previous studies, there was no evidence of any benefits of cannabidiol on anxiety or persecutory ideation in healthy volunteers with high trait paranoia. However, a larger sample will be required for a definitive study.

  • MAPT Genetic Variation and Neuronal Maturity Alter Isoform Expression Affecting Axonal Transport in iPSC-Derived Dopamine Neurons.

    3 July 2018

    The H1 haplotype of the microtubule-associated protein tau (MAPT) locus is genetically associated with neurodegenerative diseases, including Parkinson's disease (PD), and affects gene expression and splicing. However, the functional impact on neurons of such expression differences has yet to be fully elucidated. Here, we employ extended maturation phases during differentiation of induced pluripotent stem cells (iPSCs) into mature dopaminergic neuronal cultures to obtain cultures expressing all six adult tau protein isoforms. After 6 months of maturation, levels of exon 3+ and exon 10+ transcripts approach those of adult brain. Mature dopaminergic neuronal cultures display haplotype differences in expression, with H1 expressing 22% higher levels of MAPT transcripts than H2 and H2 expressing 2-fold greater exon 3+ transcripts than H1. Furthermore, knocking down adult tau protein variants alters axonal transport velocities in mature iPSC-derived dopaminergic neuronal cultures. This work links haplotype-specific MAPT expression with a biologically functional outcome relevant for PD.

  • Advances in noninvasive myelin imaging.

    3 July 2018

    Myelin is important for the normal development and healthy function of the nervous system. Recent developments in MRI acquisition and tissue modeling aim to provide a better characterization and more specific markers for myelin. This allows for specific monitoring of myelination longitudinally and noninvasively in the healthy brain as well as assessment of treatment and intervention efficacy. Here, we offer a nontechnical review of MRI techniques developed to specifically monitor myelin such as magnetization transfer (MT) and myelin water imaging (MWI). We further summarize recent studies that employ these methods to measure myelin in relation to development and aging, learning and experience, and neuropathology and psychiatric disorders. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 136-151, 2018.

  • Myelin plasticity and behaviour-connecting the dots.

    3 July 2018

    Myelin sheaths in the vertebrate nervous system enable faster impulse propagation, while myelinating glia provide vital support to axons. Once considered a static insulator, converging evidence now suggests that myelin in the central nervous system can be dynamically regulated by neuronal activity and continues to participate in nervous system plasticity beyond development. While the link between experience and myelination gains increased recognition, it is still unclear what role such adaptive myelination plays in facilitating and shaping behaviour. Additionally, fundamental mechanisms and principles underlying myelin remodelling remain poorly understood. In this review, we will discuss new insights into the link between myelin plasticity and behaviour, as well as mechanistic aspects of myelin remodelling that may help to elucidate this intriguing process.

  • Routine screening in the general hospital: What happens after discharge to those identified as at risk of dementia?

    3 July 2018

    © Royal College of Physicians 2017. All rights reserved. Cognitive screening is recommended for older patients with unplanned hospital admission. We determined rates of reassessment/specialist memory referral after routine inclusion of at risk of dementia status in discharge documentation to primary care. Questionnaires were sent to relevant GP practices on consecutive patients aged ≥75 years identified as at risk and discharged 6 months earlier. Among 53 patients (mean age ±SD = 87.3±6.0 years, mean±SD Abbreviated Mental Test Score = 4.4±2.7), 49 (92%) patients had been reviewed since discharge, and 12/43 (28%) without previously known cognitive problem had had a cognitive reassessment. The most common reasons for non-assessment/referral included clinical factors (eg terminal illness/comorbidities) (n=15) and patient/ family wishes (n=5) and that confusion was expected in unwell older patients (n=5). Routine cognitive reassessment/specialist referral appears unjustified in patients identified as at risk of dementia during unplanned hospital admission. However, the prognostic value of delirium/confusion in acute illness is under-recognised and could be used to highlight those at risk.

  • Increased rostral anterior cingulate activity following positive mental imagery training in healthy older adults.

    3 July 2018

    The ability to form positive mental images may be an important aspect of mental health and well-being. We have previously demonstrated that the vividness of positive prospective imagery is increased in healthy older adults following positive imagery cognitive training. The rostral anterior cingulate cortex (rACC) is involved in the simulation of future affective episodes. Here, we investigate the effect of positive imagery training on rACC activity during the imagination of novel, ambiguous scenarios vs closely matched control training. Seventy-five participants received 4 weeks of positive imagery or control training. Participants underwent a functional magnetic resonance imaging scan, during which they completed an Ambiguous Sentences Task, which required them to form mental images in response to cues describing ambiguous social events. rACC activity was positively correlated with the pleasantness ratings of images formed. Positive imagery training increased rACC and bilateral hippocampal activity compared with the control training. Here, we demonstrate that rACC activity during positive imagery can be changed by the cognitive training. This is consistent with other evidence that this training enhances the vividness of positive imagery, and suggests the training may be acting to increase the intensity and affective quality of imagery simulating the future.