Recent QBI publications

  • Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System

    Introduction: Therapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders. Methods: To promote standardized use of neuroimaging biomarkers for clinical trials, we aimed to develop a conceptual framework to characterize in more detail the kind of neuroimaging biomarkers needed in atypical parkinsonian disorders, identify the current challenges in ascribing utility of these biomarkers, and propose criteria for a system that may guide future studies. Results: As a consensus outcome, we describe the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and we propose a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. We included separate categories for the ability to accurately identify an intention-to-treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression). Discussion: We suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well-defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials.
  • Enhanced dopamine in prodromal schizophrenia (EDiPS): a new animal model of relevance to schizophrenia

    One of the most robust neurochemical abnormalities reported in patients living with schizophrenia is an increase in dopamine (DA) synthesis and release in the dorsal striatum (DS). Importantly, it appears that this increase progresses as a patient transitions from a prodromal stage to the clinical diagnosis of schizophrenia. Here we have recreated this pathophysiology in an animal model by increasing the capacity for DA synthesis preferentially within the DS. To achieve this we administer a genetic construct containing the rate-limiting enzymes in DA synthesis—tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH1) (packaged within an adeno-associated virus)—into the substantia nigra pars compacta (SNpc) of adolescent animals. We refer to this model as “Enhanced Dopamine in Prodromal Schizophrenia” (EDiPS). We first confirmed that the TH enzyme is preferentially increased in the DS. As adults, EDiPS animals release significantly more DA in the DS following a low dose of amphetamine (AMPH), have increased AMPH-induced hyperlocomotion and show deficits in pre-pulse inhibition (PPI). The glutamatergic response to AMPH is also altered, again in the DS. EDiPS represents an ideal experimental platform to (a) understand how a preferential increase in DA synthesis capacity in the DS relates to “positive” symptoms in schizophrenia; (b) understand how manipulation of DS DA may influence other neurotransmitter systems shown to be altered in patients with schizophrenia; (c) allow researchers to follow an “at risk”-like disease course from adolescence to adulthood; and (d) ultimately allow trials of putative prophylactic agents to prevent disease onset in vulnerable populations.
  • Ultrafast fMRI of the rodent brain using simultaneous multi-slice EPI

    Increasing spatial and temporal resolutions of functional MRI (fMRI) measurement has been shown to benefit the study of neural dynamics and functional interaction. However, acceleration of rodent brain fMRI using parallel and simultaneous multi-slice imaging techniques is hampered by the lack of high-density phased-array coils for the small brain. To overcome this limitation, we adapted phase-offset multiplanar and blipped-controlled aliasing echo planar imaging (EPI) to enable simultaneous multi-slice fMRI of the mouse brain using a single loop coil on a 9.4T scanner. Four slice bands of 0.3 × 0.3 × 0.5 mm resolution can be simultaneously acquired to cover the whole brain at a temporal resolution of 300 ms or the whole cerebrum in 150 ms. Instead of losing signal-to-noise ratio (SNR), both spatial and temporal SNR can be increased due to the increased k-space sampling compared to a standard single-band EPI. Task fMRI using a visual stimulation shows close to 80% increase of z-score and 4 times increase of activated area in the visual cortex using the multiband EPI due to the highly increased temporal samples. Resting-state fMRI shows reliable detection of bilateral connectivity by both single-band and multiband EPI, but no significant difference was found. Without the need of a dedicated hardware, we have demonstrated a practical method that can enable unparallelly fast whole-brain fMRI for preclinical studies. This technique can be used to increase sensitivity, distinguish transient response or acquire high spatiotemporal resolution fMRI.
  • Auditory white matter pathways are associated with effective connectivity of auditory prediction errors within a fronto-temporal network

    Auditory prediction errors, i.e. the mismatch between predicted, forthcoming auditory sensations and actual sensory input, trigger the detection of surprising auditory events in the environment. Auditory mismatches engage a hierarchical functional network of cortical sources, which are also interconnected by auditory white matter pathways. Hence it is plausible that these structural and functional networks are quantitatively related. The present study set out to investigate whether structural connectivity of auditory white matter pathways enables the effective connectivity underpinning auditory mismatch responses. Participants (N = 89) underwent diffusion weighted magnetic resonance imaging (MRI) and electroencephalographic (EEG) recordings. Anatomically-constrained tractography was used to extract auditory white matter pathways, namely the bilateral arcuate fasciculi, inferior fronto-occipital fasciculi (IFOF), and the auditory interhemispheric pathway, from which Apparent Fibre Density (AFD) was calculated. EEG data were recorded in the same participants during a stochastic oddball paradigm, which was used to elicit auditory prediction error responses. Dynamic causal modelling was used to investigate the effective connectivity underlying auditory mismatch responses generated in brain regions interconnected by the above mentioned auditory white matter pathways. Our results showed that brain areas interconnected by all auditory white matter pathways best explained the dynamics of auditory mismatch responses. Furthermore, AFD in the right arcuate fasciculus was significantly associated with the effective connectivity between the cortical regions that lie within it. Taken together, these findings indicate that auditory prediction errors recruit a fronto-temporal network of brain regions that are effectively and structurally connected by auditory white matter pathways.
  • Revisiting the role of the innate immune complement system in ALS

    Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the clinical and experimental evidence for the role of the complement system in driving neuroinflammation and contributing to ALS disease progression. Specifically, it will explore findings regarding the different complement activation pathways involved in ALS, with a focus on the terminal pathway. It will also examine potential future research directions for complement in ALS, highlighting the targeting of specific molecular components of the system.
  • Regional differences in the inflammatory and heat shock response in glia: implications for ALS

    Preferential neuronal vulnerability is characteristic of several neurodegenerative diseases including the motor neuron disease amyotrophic lateral sclerosis (ALS). It is well established that glia play a critical role in ALS, but it is unknown whether regional differences in the ability of glia to support motor neurons contribute to the specific pattern of neuronal degeneration. In this study, using primary mixed glial cultures from different mouse CNS regions (spinal cord and cortex), we examined whether regional differences exist in key glial pathways that contribute to, or protect against, motor neuron degeneration. Specifically, we examined the NF-κB-mediated inflammatory pathway and the cytoprotective heat shock response (HSR). Glial cultures were treated with pro-inflammatory stimuli, tumour necrosis factor-ɑ/lipopolysaccharide or heat stressed to stimulate the inflammatory and HSR respectively. We found that spinal cord glia expressed more iNOS and produced more NO compared to cortical glia in response to inflammatory stimuli. Intriguingly, we found that expression of ALS-causing SOD1 did not elevate the levels of NO in spinal cord glia. However, activation of the stress-responsive HSR was attenuated in SOD1 cultures, with a reduced Hsp70 induction in response to stressful stimuli. Exposure of spinal cord glia to heat shock in combination with inflammatory stimuli reduced the activation of the inflammatory response. The results of this study suggest that impaired heat shock response in SOD1 glia may contribute to the exacerbated inflammatory reactions observed in ALS mice. Graphical abstract Mixed primary glial cultures were established from cortical and spinal cord regions of wild-type mice and mice expressing ALS-causing mutant human SOD1 and the inflammatory and heat shock responses were investigated in these cultures. In the absence of stress, all cultures appeared to have similar cellular composition, levels of inflammatory mediators and similar expression level of heat shock proteins. When stimulated, spinal cord glia were more reactive and activated the inflammatory pathway more readily than cortical glia; this response was similar in wild-type and SOD1 glial cultures. Although the heat shock response was similar in spinal cord and cortical glial, in SOD1 expressing glia from both the spinal cord and cortex, the induction of heat shock response was diminished. This impaired heat shock response in SOD1 glia may therefore contribute to the exacerbated inflammatory reactions observed in ALS mice.
  • Bone-marrow mononuclear cell therapy in a mouse model of amyotrophic lateral sclerosis: Functional outcomes from different administration routes

    Amyotrophic lateral sclerosis (ALS) is a chronic degenerative disease that mainly affects motor neurons, leading to progressive paralysis and death. Recently, cell therapy has emerged as a therapeutic alternative for several neurological diseases, including ALS, and bone-marrow cells are one of the major cell sources. Considering the importance of pre-clinical trials to determine the best therapeutic protocol and the hope of translating this protocol to the clinical setting, we tested bone-marrow mononuclear cell (BMMC) therapy administered by different routes in the SOD1 model of ALS. BMMCs were isolated from non-transgenic, age matched animals and administered intravenously (IV), intramuscularly (IM), and intravenously and intramuscular concomitantly (IV+IM). BMMC therapy had no significant beneficial effects when injected IV or IM, but delayed disease progression when these two routes were used concomitantly. BMMC IV+IM treatment reduced the number of microglia cells in the spinal cord and partially protected of neuromuscular-junction innervation, but had no effect in preventing motor-neuron loss. This study showed that injection of BMMC IV+IM had better results when compared to each route in isolation, highlighting the importance of targeting multiple anatomical regions in the treatment of ALS.
  • Accounting for individual differences in the response to tDCS with baseline levels of neurochemical excitability

    There is now considerable evidence that applying a small electrical current to the cerebral cortex can have wide ranging effects on cognition and performance, and may provide substantial benefit as a treatment for conditions such as depression. However, there is variability across subjects in the extent to which stimulation modulates behaviour, providing a challenge for the development of applications. Here, we employed an individual differences approach to test if baseline concentrations of the neurochemicals GABA and glutamate are associated with an individual's response to transcranial direct current stimulation (tDCS). Using a previously replicated response selection training paradigm, we applied tDCS to the left prefrontal cortex part-way through the learning of a six-alternative-forced-choice task. Across three sessions, subjects received anodal, cathodal, or sham stimulation. Pre-tDCS baseline measures of GABA and glutamate, acquired using magnetic resonance spectroscopy (MRS), correlated with the extent to which stimulation modulated behaviour. Specifically, relative concentrations of GABA and glutamate (used as an index of neurochemical excitability) in the prefrontal cortex were associated with the degree to which active stimulation disrupted response selection training. This work represents an important step forward in developing models to predict stimulation efficacy, and provides a unique insight into how trait-based properties of the targeted cortex interact with stimulation.
  • Gut microbiota in ALS: possible role in pathogenesis?

    : The gut microbiota has important roles in maintaining human health. The microbiota and its metabolic byproducts could play a role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). : The authors evaluate the methods of assessing the gut microbiota, and also review how the gut microbiota affects the various physiological functions of the gut. The authors then consider how gut dysbiosis could theoretically affect the pathogenesis of ALS. They present the current evidence regarding the composition of the gut microbiota in ALS and in rodent models of ALS. Finally, the authors review therapies that could improve gut dysbiosis in the context of ALS. : Currently reported studies suggest some instances of gut dysbiosis in ALS patients and mouse models; however, these studies are limited, and more information with well-controlled larger datasets is required to make a definitive judgment about the role of the gut microbiota in ALS pathogenesis. Overall this is an emerging field that is worthy of further investigation. The authors advocate for larger studies using modern metagenomic techniques to address the current knowledge gaps.
  • OSCA: a tool for omic-data-based complex trait analysis

    The rapid increase of omic data has greatly facilitated the investigation of associations between omic profiles such as DNA methylation (DNAm) and complex traits in large cohorts. Here, we propose a mixed-linear-model-based method called MOMENT that tests for association between a DNAm probe and trait with all other distal probes fitted in multiple random-effect components to account for unobserved confounders. We demonstrate by simulations that MOMENT shows a lower false positive rate and more robustness than existing methods. MOMENT has been implemented in a versatile software package called OSCA together with a number of other implementations for omic-data-based analyses.
  • Differential BDNF methylation in combat exposed veterans and the association with exercise

    Brain-derived neurotrophic factor (BDNF) gene is associated with increased risk of posttraumatic stress disorder (PTSD) and plays a role in neuroplasticity, cognition and memory. BDNF has strong potential as a therapeutic target as studies have shown that antidepressants, electroconvulsive treatment and exercise modulate BDNF expression and methylation. In this study we examined the role of BDNF methylation and expression in PTSD and the implications of exercise in mediating these effects.BDNF DNA methylation and gene expression analysis was performed in a sample of 96 male Vietnam veterans. Cases were combat-exposed veterans with current PTSD (n = 48) and controls were combat exposed veterans with no past or current PTSD diagnosis (n = 48).No association between BDNF mRNA and PTSD was identified. PTSD was associated with decreased methylation at three BDNF CpG sites (cg01546433 P = 0.004835; cg24650785 P = 0.000259 and cg002298481 P = 0.000672). Differential BDNF methylation was associated with exercise, with active exercise associated with lower methylation levels at three CpG sites (cg04481212 P = 0.005; cg01546433 P = 0.025 and cg00298481 P = 0.035). Given that exercise mediates BDNF action on cognitive plasticity, exercise may be a non-invasive, drug free option in the treatment of PTSD.
  • The antidepressant effect of testosterone: an effect of neuroplasticity

    Background: Rodent and human studies indicate that testosterone has an antidepressant effect. The mechanisms via which testosterone exerts its antidepressant effect, however, remain to be elucidated. Some studies assume downstream effects of testosterone on sexual function and vitality followed by improvement of mood. Emerging evidence suggests that testosterone may be acting in the brain within depression-relevant areas, whereby eliciting direct antidepressant effects, potentially via neuroplasticity. Methods: Literature was searched focusing on testosterone treatment and depression and depression-like behavior. Due to the unilateral clinical use of testosterone in men and the different modes of action of sex hormones in the central nervous system in men and women, predominantly studies on male populations were identified. Results: The two proposed mechanisms via which testosterone might act as antidepressant in the central nervous system are the support of neuroplasticity as well as the activation of the serotonin system. Additionally, testosterone downregulates glucocorticoid output and reduces levels of pro-inflammatory markers, thereby acting as important counter regulatory agent reducing levels of neurotoxic factors in the central nervous system. Conclusion: Although it is possible that testosterone acts via the serotonin system or the downregulation of the immune or hyperactive stress physiological systems, recent evidence supports the hypothesis that testosterone also elicits anti-depressant effects via directly promoting neuroplasticity. Potential implementations of testosterone treatment in mood disorders are discussed.
  • Genotype–covariate correlation and interaction disentangled by a whole-genome multivariate reaction norm model

    The genomics era has brought useful tools to dissect the genetic architecture of complex traits. Here we propose a multivariate reaction norm model (MRNM) to tackle genotype-covariate (G-C) correlation and interaction problems. We apply MRNM to the UK Biobank data in analysis of body mass index using smoking quantity as a covariate, finding a highly significant G-C correlation, but only weak evidence for G-C interaction. In contrast, G-C interaction estimates are inflated in existing methods. It is also notable that there is significant heterogeneity in the estimated residual variances (i.e., variances not attributable to factors in the model) across different covariate levels, i.e., residual-covariate (R-C) interaction. We also show that the residual variances estimated by standard additive models can be inflated in the presence of G-C and/or R-C interactions. We conclude that it is essential to correctly account for both interaction and correlation in complex trait analyses.
  • Gaming the system: Using transactional analysis to explore dysfunctional processes in clinical supervision

    This paper discusses the ongoing relevance of concepts derived from transactional analysis to understanding the challenges that can emerge in clinical supervision under the Competency Based Fellowship Program.

    Defensive game playing has face validity as a framework for understanding dysfunctional processes in clinical supervision. Being aware of these concepts may aid trainees and supervisors in promoting effective clinical supervision practice.
  • Supervision contracts for mental health professionals: a systematic review and exploration of the potential relevance to psychiatry training in Australia and New Zealand

    The use of formal supervision contracts has been strongly advocated across non-medical mental health professions. However, the use of such agreements is not a feature of the RANZCP Competency-Based Fellowship Program. This paper critically examines the evidence to support the use of formal supervision contracts.

    A systematic review of empirical studies relating to the outcomes of supervision contracts was completed. Included records were subject to quality appraisal.

    Two studies met the inclusion criteria; both were assessed to be of poor quality. One study found improved supervision effectiveness associated with the use of supervision contracts, and the other found no significant differences associated with formal contracting.

    Despite strong advocacy, limited empirical evidence was found to support the value of formal supervision contracts across mental health professions. PROSPERO registration - PROSPERO 2018 CRD42018104142.
  • Vision using multiple distinct rod opsins in deep-sea fishes

    Vertebrate vision is accomplished through light-sensitive photopigments consisting of an opsin protein bound to a chromophore. In dim light, vertebrates generally rely on a single rod opsin [rhodopsin 1 (RH1)] for obtaining visual information. By inspecting 101 fish genomes, we found that three deep-sea teleost lineages have independently expanded their RH1 gene repertoires. Among these, the silver spinyfin (Diretmus argenteus) stands out as having the highest number of visual opsins in vertebrates (two cone opsins and 38 rod opsins). Spinyfins express up to 14 RH1s (including the most blueshifted rod photopigments known), which cover the range of the residual daylight as well as the bioluminescence spectrum present in the deep sea. Our findings present molecular and functional evidence for the recurrent evolution of multiple rod opsin-based vision in vertebrates.
  • Cost‐effectiveness of deep brain stimulation with movement disorders: A systematic review

    Background Movement disorders (MDs) are increasingly being managed with deep brain stimulation (DBS). High‐quality economic evaluations (EEs) are necessary to evaluate the cost‐effectiveness of DBS. We conducted a systematic review of published EEs of the treatment of MDs with DBS. The review compares and contrasts the reported incremental cost‐effectiveness ratios (ICERs) and methodology employed by trial‐based evaluations (TBEs) and model‐based evaluations (MBEs). Methods MeSH and search terms relevant to “MDs,” “DBS,” and “EEs” were used to search biomedical and economics databases. Studies that used a comparative design to evaluate DBS, including before‐after studies, were included. Quality and reporting assessments were conducted independently by 2 authors. Seventeen studies that targeted Parkinson's disease (PD), dystonia, and essential tremor (ET), met our selection criteria. Results Mean scores for methodological and reporting quality were 73% and 76%, respectively. The ICERs for DBS compared with best medical therapy to treat PD patients obtained from MBEs had a lower mean and range compared with those obtained from TBEs ($55,461–$735,192 per quality‐adjusted life‐year [QALY] vs. $9,301–$65,111 per QALY). Pre‐post ICER for DBS to treat dystonia was $64,742 per QALY. DBS was not cost‐effective in treating ET compared with focused‐ultrasound surgery. Cost‐effectiveness outcomes were sensitive to assumptions in health utilities, surgical costs, battery life‐span, model time horizons, and the discount rate. Conclusions The infrequent use of randomized, controlled trials to evaluate DBS efficacy, the paucity of data reporting the long‐term effectiveness and/or utility of DBS, and the uncertainty surrounding cost data limit our ability to report cost‐effectiveness summaries that are robust.
  • The adapted self-report delinquency scale for adolescents: validity and reliability among Portuguese youths

    Self-report delinquency scales have contributed greatly to the contemporary basis of our understanding of juvenile delinquency. Nevertheless, they have not been immune to criticism and further improvement and extensive measurement research is still necessary. The present study examined the psychometric properties of one such measure of self-reported delinquency, the Adapted Self-Report Delinquency Scale (ASRDS). The ASRDS was administered to a Portuguese sample of male youths (N = 470, 12-20 years of age), subdivided into a forensic sample (n = 217) and a school sample (n = 253). The Portuguese version of the ASRDS demonstrated satisfactory psychometric properties, in terms of its factor structure, internal consistency, convergent validity, discriminant validity, criterion-related validity, and known-groups validity, thereby justifying its use among this population.
  • Downregulation of SNX27 expression does not exacerbate amyloidogenesis in the APP/PS1 Alzheimer's disease mouse model

    There is in vitro evidence that sorting nexin family member 27 (SNX27), a member of the retromer complex, changes the distribution of the amyloid-beta (Aβ) precursor protein (APP) to promote its recycling and thereby prevent the production of Aβ, the toxic protein associated with Alzheimer's disease (AD). In this study, we analyzed the phenotype of the familial AD APP/PS mouse strain lacking one copy of the SNX27 gene. The reduction in SNX27 expression had no significant effect on the in vivo accumulation of soluble, total, or plaque-deposited Aβ, which is overproduced by the familial APP/PS transgenes. Hippocampal structure and cholinergic basal forebrain neuronal health were also unaffected. Nonetheless, mild positive and negative effects of age and/or genotype on spatial navigation performance were observed in SNX27 and SNX27APP/PS mice, respectively. These data suggest that downregulation of SNX27 alone does not have long-term negative consequences on spatial memory, but that cognitive dysfunction in the context of high Aβ deposition is exacerbated by the cellular or molecular changes induced by reduced SNX27 function.
  • Differentiation of functional networks during long-term memory retrieval in children and adolescents

    The processes that characterize the neural development of long-term memory (LTM) are largely unknown. In young adults, the degree of activation of a single large-scale memory network corresponds to the level of contextual detail involved; thus, differentiating between autobiographical, episodic, and semantic retrieval. In contrast to young adults, children and adolescents retrieve fewer contextual details, suggesting that they might not yet engage the entire memory circuitry and that this brain recruitment might lack the characteristic contextual differentiation found in adults. Twenty-one children (10–12 years of age), 20 adolescents (14–16 years of age), and 22 young adults (20–35 years of age) were assessed on a previously validated LTM retrieval task, while their brain activity was measured with functional magnetic resonance imaging. The results demonstrate that children, adolescents, and adults recruit a left-lateralized subset of the large-scale memory network, comprising semantic and language processing regions, with neither developmental group showing evidence of contextual differentiation within this network. Additionally, children and adolescents recruited occipital and parietal regions during all memory recall conditions, in contrast to adults who engaged the entire large-scale memory network, as described previously. Finally, a significant covariance between age and brain activation indicates that the reliance on occipital and parietal regions during memory retrieval decreases with age. These results suggest that both children and adolescents rely on semantic processing to retrieve long-term memories, which, we argue, may restrict the integration of contextual detail required for complex episodic and autobiographical memory retrieval.
  • Astaxanthin ameliorates scopolamine-induced spatial memory deficit via reduced cortical-striato-hippocampal oxidative stress

  • Toward in vivo determination of peripheral nervous system immune activity in amyotrophic lateral sclerosis

    We sought to identify patients with amyotrophic lateral sclerosis (ALS) who displayed suspected peripheral nervous system (PNS) inflammation to compare them to those with suspected PNS degeneration.

    We measured sonographic median and ulnar nerve cross-sectional area (CSA) and cerebrospinal fluid albumin/serum albumin ratio (Q ) in patients with ALS to classify them as having suspected PNS degeneration (small CSA/low Q ) or inflammation (larger CSA/high Q ).

    Fifty-seven percent of patients had suspected PNS degeneration, 21% had suspected PNS inflammation, and 21% displayed suspected "normal PNS state." Suspected PNS degeneration was related to classic ALS, shorter disease duration, and a smaller hypoechoic nerve area. Suspected PNS inflammation was associated with men, longer disease duration, and a larger hypoechoic nerve area and was the dominant finding in superoxide dismutase 1 mutation carriers.

    Our simple approach might aid in the in vivo differentiation of supposed ALS subtypes, those with suspected PNS degeneration vs. inflammation, for stratification in clinical trials. Muscle Nerve, 2019.
  • Non-linear acoustic emissions from therapeutically driven contrast agent microbubbles

    Non-linear emissions from microbubbles introduced to the vasculature for exposure to focused ultrasound are routinely monitored for assessment of therapy and avoidance of irreversible tissue damage. Yet the bubble-based mechanistic source for these emissions, under subresonant driving at typical therapeutic pressure amplitudes, may not be well understood. In the study described here, dual-perspective high-speed imaging at 210,000 frames per second (fps), and shadowgraphically at 10 Mfps, was used to observe cavitation from microbubbles flowing through a 500-µm polycarbonate capillary exposed to focused ultrasound of 692 kHz at therapeutically relevant pressure amplitudes. The acoustic emissions were simultaneously collected via a broadband calibrated needle hydrophone system. The observations indicate that periodic bubble-collapse shock waves can dominate the non-linear acoustic emissions, including subharmonics at higher driving amplitudes. Contributions to broadband emissions through variance in shock wave amplitude and emission timings are also identified. Possible implications for in vivo microbubble cavitation detection, mechanisms of therapy and the conventional classification of cavitation activity as stable or inertial are discussed.
  • Author correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

    Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.
  • Evidence of causal effect of major depression on alcohol dependence: Findings from the psychiatric genomics consortium

    BackgroundDespite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC.MethodsLinkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals).ResultsPositive genetic correlation was observed between MD and AD (rg = + 0.47, P = 6.6 × 10 ). AC-quantity showed positive genetic correlation with both AD (rg = + 0.75, P = 1.8 × 10 ) and MD (rg = + 0.14, P = 2.9 × 10 ), while there was negative correlation of AC-frequency with MD (rg = -0.17, P = 1.5 × 10 ) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10 ). There was no evidence for reverse causation.ConclusionThis study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
  • Associations between brain structure and perceived intensity of sweet and bitter tastes

    Functional neuroimaging studies have identified brain regions associated with human taste perception, but only a few have investigated the associations with brain structure. Here, in this exploratory study, we examined the association between the volumes of 82 regions of interest (ROI) and the perceived intensities of sweet (a weighted mean rating of glucose, fructose, aspartame, neohesperidin dihydrochalcone) and bitter (propylthiouracil, quinine, caffeine) substances in a large Australian healthy cohort from the Queensland Twin IMaging (QTIM, n = 559) study and the perceived intensity of quinine in a large U.S. healthy cohort from the Human Connectome Project (HCP, n = 1101). In QTIM, the volumes of 3 cortical (right cuneus gyrus, left transverse temporal gyrus, right inferior temporal gyrus) and one subcortical structure (both left and right caudate) were associated with more than one taste stimulus (P < 0.05) and tended to be associated with both sweet and bitter tastes in the same direction, suggesting these ROIs were more broadly tuned for taste sensation. A further 11 ROIs were associated with a specific taste (sweetness: 4; propylthiouracil: 3; caffeine: 2; quinine: 2). In HCP, volumes of 5 ROIs were associated with quinine bitterness. The quinine-left entorhinal cortex association was found in both QTIM (r = -0.12, P = 3.7 × 10) and HCP (r = -0.06, P = 2.0 × 10). This study provides the first evidence that, even in healthy people, variation in brain structure is associated with taste intensity ratings, and provides new insights into the brain gustatory circuit.
  • Label-free fluorescent poly(amidoamine) dendrimer for traceable and controlled drug delivery

    Poly(amidoamine) dendrimer (PAMAM) is well-known for its high efficiency as a drug delivery vehicle. However, the intrinsic cytotoxicity and lack of a detectable signal to facilitate tracking have impeded its practical applications. Herein, we have developed a novel label-free fluorescent and biocompatible PAMAM derivative by simple surface modification of PAMAM using acetaldehyde. The modified PAMAM possessed a strong green fluorescence, which was generated by the C=N bonds of the resulting Schiff Bases via n-?∗ transition, while the intrinsic cytotoxicity of PAMAM was simultaneously ameliorated. Through further PEGylation, the fluorescent PAMAM demonstrated excellent intracellular tracking in human melanoma SKMEL28 cells. In addition, our PEGylated fluorescent PAMAM derivative achieved enhanced loading and delivery efficiency of the anticancer drug doxorubicin (DOX) compared to the original PAMAM. Importantly, the accelerated kinetics of DOX-encapsulated fluorescent PAMAM nanocomposites in an acidic environment facilitated intracellular drug release, which demonstrated comparable cytotoxicity to that of the free-form doxorubicin hydrochloride (DOX·HCl) against melanoma cells. Overall, our label free fluorescent PAMAM derivative offers a new opportunity of traceable and controlled delivery for DOX and other drugs of potential clinical importance.
  • ‘Woe betides anybody who tries to turn me down.’ A qualitative analysis of neuropsychiatric symptoms following subthalamic deep brain stimulation for Parkinson’s disease

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of Parkinson’s disease (PD) can lead to the development of neuropsychiatric symptoms. These can include harmful changes in mood and behaviour that alienate family members and raise ethical questions about personal responsibility for actions committed under stimulation-dependent mental states. Qualitative interviews were conducted with twenty participants (ten PD patient-caregiver dyads) following subthalamic DBS at a movement disorders centre, in order to explore the meaning and significance of stimulation-related neuropsychiatric symptoms amongst a purposive sample of persons with PD and their spousal caregivers. Interview transcripts underwent inductive thematic analysis. Clinical and experiential aspects of post-DBS neuropsychiatric symptoms were identified. Caregivers were highly burdened by these symptoms and both patients and caregivers felt unprepared for their consequences, despite having received information prior to DBS, desiring greater family and peer engagement prior to neurosurgery. Participants held conflicting opinions as to whether emergent symptoms were attributable to neurostimulation. Many felt that they reflected aspects of the person’s “real” or “younger” personality. Those participants who perceived a close relationship between stimulation changes and changes in mental state were more likely to view these symptoms as inauthentic and uncontrollable. Unexpected and troublesome neuropsychiatric symptoms occurred despite a pre-operative education programme that was delivered to all participants. This suggests that such symptoms are difficult to predict and manage even if best practice guidelines are followed by experienced centres. Further research aimed at predicting these complications may improve the capacity of clinicians to tailor the consent process.
  • Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016

    Background Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders.Methods We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach.Findings Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247-308]) and second leading cause of deaths (9.0 million [8.8-9.4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34-44] and DALYs by 15% [9-21]) whereas their age-standardised rates decreased (deaths by 28% [26-30] and DALYs by 27% [24-31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42.2% [38.6-46.1]), migraine (16.3% [11.7-20.8]), Alzheimer's and other dementias (10.4% [9.0-124]), and meningitis (7.9% [6.6-10.4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1.12 [1.05-1.20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0.7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88.8% (86.5-90.9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22.3% [11.8-35.1] of DALYs are risk attributable) and idiopathic epilepsy (14.1% [10.8-17.5] of DALYs are risk attributable).Interpretation Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies. Copyright (C) The Author(s). Published by Elsevier Ltd.
  • Genome-wide association study identifies 30 loci associated with bipolar disorder

    Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
  • Disrupting the hippocampal Piwi pathway enhances contextual fear memory in mice

    The Piwi pathway is a conserved gene regulatory mechanism comprised of Piwi-like proteins and Piwi-interacting RNAs, which modulates gene expression via RNA interference and through interaction with epigenetic mechanisms. The mammalian Piwi pathway has been defined by its role in transposon control during spermatogenesis; however, despite an increasing number of studies demonstrating its expression in the nervous system, relatively little is known about its function in neurons or potential contribution to behavioural regulation. We have discovered that all three Piwi-like genes are expressed in the adult mouse brain, and that viral-mediated knockdown of the Piwi-like genes Piwil1 and Piwil2 in the dorsal hippocampus leads to enhanced contextual fear memory without affecting generalised anxiety. These results implicate the Piwi pathway in behavioural regulation in the adult mammalian brain, likely through modulation of plasticity-related gene expression.
  • Vitamin D Levels Are Not Associated with Hippocampal-Dependent Learning in Young Adult Male C57BL/6J Mice: A Negative Report

    It is well established that vitamin D is essential in calcium homeostasis and bone metabolism. Recent evidence has exposed further roles of vitamin D in adult brain function, specifically indicating that low vitamin D levels during adulthood may be related to cognitive impairment. We have recently shown that adult vitamin D (AVD) deficiency disrupts hippocampal-dependent learning and structural brain connectivity in BALB/c mice. The BALB/c mouse strain is more vulnerable to social stress compared with other resilient mouse strains, such as C57BL/6J mice. Therefore, the primary aim of this research was to examine C57BL/6J mice exposed to varying levels of vitamin D (0, 1500 and 15,000 IU/vitamin D3/kg referred to as deficient, control and elevated, respectively) for 10 weeks. The mice were assessed for hippocampaldependent learning using the active place avoidance (APA) task. Mice were tested for behaviours that could alter performance on the APA task, and hippocampal tissue was analysed for catecholamine and protein expression. Vitamin D status did not affect spatial learning and memory, general behavioural domains, or catecholamine or protein expression in C57BL/6J mice. Overall, these results indicate that, in contrast to BALB/c mice, vitamin D status does not impact on hippocampal-dependent behaviour in young and healthy, adult male C57BL/6J mice.
  • Pterin-pigmented nanospheres create the colours of the polymorphic damselfly Ischnura elegans

    Animal colours commonly act as signals for mates or predators. In many damselfly species, both sexes go through a developmental colour change as adults, and females often show colour polymorphism, which may have a function in mate choice, avoidance of mating harassment and camouflage. In the blue-tailed damselfly, Ischnura elegans, young males are bright green and turn blue as they reach maturity. Females are red ( rufescens) or violet ( violacea) as immatures and, when mature, either mimic the blue colour of the males ( androchrome), or acquire an inconspicuous olive-green ( infuscans) or olive-brown ( obsoleta). The genetic basis of these differences is still unknown. Here, we quantify the colour development of all morphs of I. elegans and investigate colour formation by combining anatomical data and reflectance spectra with optical finite-difference time-domain simulations. While the coloration primarily arises from a disordered assembly of nanospheres in the epidermis, morph-dependent changes result from adjustments in the composition of pterin pigments within the nanospheres, and from associated shifts in optical density. Other pigments fine-tune hue and brilliance by absorbing stray light. These mechanisms produce an impressive palette of colours and offer guidance for genetic studies on the evolution of colour polymorphism and visual communication.
  • Differentiating beyond name agreement for picture naming: insight from age-related selection deficits

    Purpose Pictures consistently referred to by the same name (high agreement) are named faster than pictures that elicit inconsistent responses across individuals (low agreement). Although this effect is more pronounced in older adults apparently due to slower lexical selection, it is unclear whether this is consistent for different types of low agreement pictures. We investigated whether pictures with different sources of disagreement have differing selection requirements, as indexed by naming latencies. Method Picture naming latencies were compared for 20 young (ages 18-35 years) and 20 older adults (ages 60-80 years) across 3 object naming conditions: high name agreement, low name agreement due to multiple correct names, and low agreement due to abbreviations and elaborations. Results Compared to high agreement items, responses were slower specifically for low agreement items with multiple names, and to a lesser extent, items with abbreviations and elaborations ( p < .001). Older adults were slower than younger adults, especially for low agreement items with abbreviations and elaborations ( p = .031). Conclusions Our findings indicate differential lexical selection requirements for low agreement pictures, depending on the reason for agreement being low. This demonstrates the importance of differentiating the source of disagreement in any experimental or clinical assessment of picture naming.
  • Genome-wide association study of medication-use and associated disease in the UK Biobank

    Genome-wide association studies (GWASs) of medication use may contribute to understanding of disease etiology, could generate new leads relevant for drug discovery and can be used to quantify future risk of medication taking. Here, we conduct GWASs of self-reported medication use from 23 medication categories in approximately 320,000 individuals from the UK Biobank. A total of 505 independent genetic loci that meet stringent criteria (P < 10 /23) for statistical significance are identified. We investigate the implications of these GWAS findings in relation to biological mechanism, potential drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes are 16 known therapeutic-effect target genes for medications from 9 categories. Two of the medication classes studied are for disorders that have not previously been subject to large GWAS (hypothyroidism and gastro-oesophageal reflux disease).
  • Metal toxicity links to Alzheimer's disease and neuroinflammation

    As the median age of the population increases, the number of individuals with Alzheimer's disease (AD) and the associated socio-economic burden are predicted to worsen. While aging and inherent genetic predisposition play major roles in the onset of AD, lifestyle, physical fitness, medical condition, and social environment have emerged as relevant disease modifiers. These environmental risk factors can play a key role in accelerating or decelerating disease onset and progression. Among known environmental risk factors, chronic exposure to various metals has become more common among the public as the aggressive pace of anthropogenic activities releases excess amount of metals into the environment. As a result, we are exposed not only to essential metals, such as iron, copper, zinc and manganese, but also to toxic metals including lead, aluminum, and cadmium, which perturb metal homeostasis at the cellular and organismal levels. Herein, we review how these metals affect brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species (i.e., β-amyloid and tau). We also discuss studies that validate the disruption of immune-related pathways as an important mechanism of toxicity by which metals can contribute to AD. Our goal is to increase the awareness of metals as players in the onset and progression of AD.
  • The (in)visibility of groomed ski runs

    I analyse the visibility of "groomed" ski runs under different lighting conditions. A model of human contrast sensitivity predicts that the spatial period of groomed snow may render it invisible in the shade or on overcast days. I confirm this prediction with visual demonstrations and make a suggestion to improve visibility.
  • Differential effects of novel dopamine reuptake inhibitors on interference with long-term social memory in mice

    In the laboratory, long-term social recognition memory (SRM) in mice is highly susceptible to proactive and retroactive interference. Here, we investigate the ability of novel designed dopamine (DA) re-uptake inhibitors (rac-CE-123 and S-CE-123) to block retroactive and proactive interference, respectively. Our data show that administration of rac-CE-123 30 min before learning blocks retroactive interference that has been experimentally induced at 3 h, but not at 6 h, post-learning. In contrast, S-CE-123 treatment 30 min before learning blocked the induction of retroactive interference at 6 h, but not 3 h, post-learning. Administration of S-CE-123 failed to interfere with proactive interference at both 3 h and 6 h. Analysis of additional behavioral parameters collected during the memory task implies that the effects of the new DA re-uptake inhibitors on retroactive and proactive interference cannot easily be explained by non-specific effects on the animals’ general social behavior. Furthermore, we assessed the mechanisms of action of drugs using intracerebral in vivo-microdialysis technique. The results revealed that administration of rac-CE-123 and S-CE-123 dose-dependently increased DA release within the nucleus accumbens of freely behaving mice. Thus, the data from the present study suggests that the DA re-uptake inhibitors tested protect the consolidation of long-term social memory against interference for defined durations after learning. In addition, the data implies that DA signaling in distinct brain areas including the nucleus accumbens is involved in the consolidation of SRM in laboratory mice.
  • Disruption of RAB-5 increases EFF-1 fusogen availability at the cell surface and promotes the regenerative axonal fusion capacity of the neuron

    Following a transection injury to the axon, neurons from a number of species have the ability to undergo spontaneous repair via fusion of the two separated axonal fragments. In the nematode , this highly efficient regenerative axonal fusion is mediated by epithelial fusion failure-1 (EFF-1), a fusogenic protein that functions at the membrane to merge the two axonal fragments. Identifying modulators of axonal fusion and EFF-1 is an important step toward a better understanding of this repair process. Here, we present evidence that the small GTPase RAB-5 acts to inhibit axonal fusion, a function achieved via endocytosis of EFF-1 within the injured neuron. Therefore, we find that perturbing RAB-5 activity is sufficient to restore axonal fusion in mutant animals with decreased axonal fusion capacity. This is accompanied by enhanced membranous localization of EFF-1 and the production of extracellular EFF-1-containing vesicles. These findings identify RAB-5 as a novel regulator of axonal fusion in hermaphrodites and the first regulator of EFF-1 in neurons. Peripheral and central nerve injuries cause life-long disabilities due to the fact that repair rarely leads to reinnervation of the target tissue. In the nematode , axonal regeneration can proceed through axonal fusion, whereby a regrowing axon reconnects and fuses with its own separated distal fragment, restoring the original axonal tract. We have characterized axonal fusion and established that the fusogen epithelial fusion failure-1 (EFF-1) is a key element for fusing the two separated axonal fragments back together. Here, we show that the small GTPase RAB-5 is a key cell-intrinsic regulator of the fusogen EFF-1 and can in turn regulate axonal fusion. Our findings expand the possibility for this process to be controlled and exploited to facilitate axonal repair in medical applications.
  • Exercise-induced activated platelets increase adult hippocampal precursor proliferation and promote neuronal differentiation

    Physical activity is a strong positive physiological modulator of adult neurogenesis in the hippocampal dentate gyrus. Although the underlying regulatory mechanisms are still unknown, systemic processes must be involved. Here we show that platelets are activated after acute periods of running, and that activated platelets promote neurogenesis, an effect that is likely mediated by platelet factor 4. Ex vivo, the beneficial effects of activated platelets and platelet factor 4 on neural precursor cells were dentate gyrus specific and not observed in the subventricular zone. Moreover, the depletion of circulating platelets in mice abolished the running-induced increase in precursor cell proliferation in the dentate gyrus following exercise. These findings demonstrate that platelets and their released factors can modulate adult neural precursor cells under physiological conditions and provide an intriguing link between running-induced platelet activation and the modulation of neurogenesis after exercise.Using the neurogenesis-promoting stimulus of physical activity, Walker and colleagues show that platelets are activated after acute running periods and that activated platelets and their released protein PF4 following exercise, increase neurogenesis. They show that the pro-neurogenic effects of platelets are dentate gyrus specific and that platelet depletion in mice abolishes the running-induced increase in precursor proliferation in the dentate gyrus.
  • Protocol update and statistical analysis plan for CADENCE-BZ: a randomized clinical trial to assess the efficacy of sodium benzoate as an adjunctive treatment in early psychosis

    Background CADENCE-BZ is a multi-centre, parallel-group, double-blind randomized controlled trial designed to examine the clinical efficacy and safety of an accessible food preservative, sodium benzoate, as an add-on treatment for patients with early psychosis. The original study protocol was published in 2017. Here, we describe the updated protocol along with the Statistical Analysis Plan (SAP) for the CADENCE-BZ trial prior to study completion. Methods and materials Two important changes were made to the original protocol: (1) improvements to our statistical analysis plan permitted a reduction in sample size; and (2) a revision in the secondary outcomes with the intent of reducing redundancy and excluding those measures that were not appropriate as outcomes. Conclusions We provide the updated SAP prior to the completion of the study with the intent of increasing the transparency of the data analyses for CADENCE-BZ. The final participants are currently completing the study and the results will be published in the near future.
  • Probiotics mixture increases butyrate, and subsequently rescues the nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity

  • rSK1 in rat neurons: a controller of membrane rSK2?

    In mammalian neurons, small conductance calcium-activated potassium channels (SK channels) are activated by calcium influx and contribute to the afterhyperpolarization (AHP) that follows action potentials. Three types of SK channel, SK1, SK2 and SK3 are recognized and encoded by separate genes that are widely expressed in overlapping distributions in the mammalian brain. Expression of the rat genes, rSK2 and rSK3 generates functional ion channels that traffic to the membrane as homomeric and heteromeric complexes. However, rSK1 is not trafficked to the plasma membrane, appears not to form functional channels, and the role of rSK1 in neurons is not clear. Here, we show that rSK1 co-assembles with rSK2. rSK1 is not trafficked to the membrane but is retained in a cytoplasmic compartment. When rSK2 is present, heteromeric rSK1-rSK2 channels are also retained in the cytosolic compartment, reducing the total SK channel content on the plasma membrane. Thus, rSK1 appears to act as chaperone for rSK2 channels and expression of rSK1 may control the level of functional SK current in rat neurons.
  • Mid-air conflict avoidance and recovery: an acceleration-based approach for unmanned aircraft

    We describe a novel technique for increasing the minimum separation between two aircraft by using a constant acceleration based speed change. The technique predicts the required acceleration each aircraft should execute in order to obtain a safe separation-while accounting for each aircraft's acceleration and velocity limits. In addition, we present a method for each aircraft to recover to its original trajectory, once the conflict has been mitigated, without reducing the obtained minimum separation. The theory presented in this letter demonstrates that it is indeed possible to accomplish the task of avoidance and recovery independently (without any aircraft-to-aircraft communication) in an elegant, feasible, and mutually beneficial manner. Both techniques are validated in a virtual environment, which incorporates a real quadcopter's dynamics, as well as in an indoor test arena with two quadcopter platforms.
  • Trunk exercises improve balance in Parkinson disease: A Phase II randomized controlled trial

    BACKGROUND AND PURPOSE: Trunk control is important for maintaining balance; hence, deficient trunk control may contribute to balance problems in people with Parkinson disease (PD). Unfortunately, this deficit is poorly managed with pharmacological therapies, emphasizing the need for alternative therapies for these patients. This randomized controlled trial sought to examine the effects of a 12-week trunk-specific exercise-based intervention on balance in people with PD. METHODS: Twenty-four people with PD and with a history of falls completed assessments of motor symptom severity, balance confidence, mobility, quality of life, and quiet-standing balance. Participants were then randomized to receive either 12 weeks of exercise or education and reassessed after 12 and 24 weeks. RESULTS: Linear mixed-models analyses showed no significant changes in clinical outcomes following the intervention. However, during quiet standing, sway area on a foam surface without vision was reduced for the exercise group at 12 (-6.9 ± 3.1 cm; 95% confidence interval [CI] = -13.1 to -0.7; P = 0.029; d = 0.66) and 24 weeks (-7.9 ± 3.1 cm; 95% CI = -14.1 to -1.7; P = 0.013; d = 0.76). Furthermore, the exercise group demonstrated reduced sway variability at 12 (-0.2 ± 0.1 cm; 95% CI = -0.4 to 0.0; P = 0.042; d = 0.62) and 24 weeks in the medial-lateral direction (-0.2 ± 0.1 cm; 95% CI = -0.4 to 0.0; P = 0.043; d = 0.62). No changes in quiet standing balance were recorded for the education group. DISCUSSION AND CONCLUSIONS: The results of this study suggest that exercise-based interventions targeting trunk strength, endurance, and mobility may be effective for improving quiet-standing balance in people with PD. However, additional research is needed to determine whether these improvements are sufficient to reduce falls risk.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at:
  • A comparison of hallucinatory experiences and their appraisals in those with and without mental illness

    Few studies have compared the content and appraisal of hallucinatory experiences (HE) by people with psychosis and those without. This study compared the characteristics of HE, and their appraisals, in individuals with psychotic disorder, non-psychotic mental disorder and no disorder in the general population. Participants (n = 253) aged between 30-33 years who reported HE were recruited from a birth cohort and assessed for lifetime diagnoses of mental disorders. They were allocated to groups based on their diagnosis and their HE were rated to assess their form, content and associated appraisals. Compared to those with no mental disorder, participants with a psychotic disorder had almost twelve times the odds of appraising their HE as distressing and dangerous and nine times the odds of experiencing recurrent HE. Those with a non-psychotic disorder had more than twice the odds of recurrent HE compared to those with no disorder. Overall, HE showed more similarities than differences across the diagnostic groups. Negative appraisals of HE and their recurrence differentiated clinical from non-clinical populations. Screening for HE and assessment of their associated appraisals is essential in those seeking care for mental health difficulties. Interventions aimed at modifying maladaptive appraisals can assist in reducing hallucination related distress.
  • CRISPR/Cas9-mediated PINK1 deletion leads to neurodegeneration in rhesus monkeys

  • From R.A. Fisher’s 1918 paper to GWAS a century later

    The genetics and evolution of complex traits, including quantitative traits and disease, have been hotly debated ever since Darwin. A century ago, a paper from R.A. Fisher reconciled Mendelian and biometrical genetics in a landmark contribution that is now accepted as the main foundation stone of the field of quantitative genetics. Here, we give our perspective on Fisher's 1918 paper in the context of how and why it is relevant in today's genome era. We mostly focus on human trait variation, in part because Fisher did so too, but the conclusions are general and extend to other natural populations, and to populations undergoing artificial selection.
  • Silencing PD-1 and PD-L1 with nanoparticle-delivered small interfering RNA increases cytotoxicity of tumor-infiltrating lymphocytes

    Aim: To determine if silencing PD-1 on tumor-infiltrating lymphocytes (TILs) and its ligand-1 (PD-L1) on cancer cells will enhance the cytotoxicity of TILs. Materials & methods: Lipid-coated calcium phosphate nanoparticles were synthesized to deliver siRNAs against PD-1 and PD-L1 to TILs and breast cancer MCF-7 cells. The downregulation of PD-1/PD-L1 expressions was determined by real-time PCR and western blotting assays. The killing efficacy of TILs to MCF-7 cells was determined by cytotoxic T lymphocyte assay. Results: Lipid-coated calcium phosphate nanoparticles effectively delivered siRNAs and silenced PD-1 and PD-L1sh expression. The knockdown of either gene or both greatly improved the cytotoxicity of TILs. Conclusion: Silencing PD-1 and PD-L1 is an effective approach to increase TIL cytotoxicity to cancer cells.
  • Stepping forward: challenges and pathways to building a vibrant research culture through the Scholarly Project

    Objectives: The Scholarly Project is a relevant task to support building a culture of research in psychiatry across Australia and New Zealand. However, there are several impediments to trainees’ confident completion of this project. The authors review recent literature on the challenges voiced by trainees, as well as solutions posed by clinician-researchers and medical educators. Relevant strategies are highlighted, and several practical solutions to support the completion of the Scholarly Project are proposed. Conclusions: There are several pathways available to alleviate barriers to trainees’ timely commencement and completion of the Scholarly Project, including enhancing research capacity within services, familiarity with the requirements, access to supervisors and additional support for trainees.