Recent QBI publications

  • Modulating brain activity and behaviour with tDCS: Rumours of its death have been greatly exaggerated

    Transcranial electrical brain stimulation (tES) techniques have shown substantial promise in research and applied settings. However, over the last few years the technique has courted significant controversy, resulting in scepticism regarding its reported beneficial effects and future potential. In this opinion article, we examine the key points of criticism raised to date, including whether tES has any meaningful effect on the cortex, issues of replicability, and the variability in its efficacy across individuals. For each point, we assess the strength of the evidence for and against the argument and, where relevant, suggest how the field can improve. We conclude that while some of the highlighted shortcomings of research using electrical brain stimulation are justified, on balance the arguments against using such techniques in cognitive neuroscience are often overstated and elevate the risk of the field “throwing the baby out with the bath water”.
  • White matter microstructural differences across major depressive disorder, bipolar disorder and schizophrenia: a tract-based spatial statistics study

    Background: White matter abnormalities have been implicated in mental disorders including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ); however, the shared and distinct white matter integrity across mental disorders is still unclear. Methods: A total of 290 participants (MDD = 85, BD = 42, SZ = 68, and healthy controls = 95) were included in the present study. Tract-based spatial statistics were performed to measure fractional anisotropy (FA) and characterize shared and distinguishing white matter changes across mental disorders. Results: We found that decreased FA converged across MDD, BD and SZ in the body and genu of the corpus callosum, bilateral anterior and posterior corona radiata, and right superior corona radiata. By contrast, diagnosis-specific effect was only found in MDD in the anterior portion of anterior corona radiata. Limitations: The small and imbalanced sample size, and possible confounding effects of medication. Conclusions: Our findings suggest that abnormally reduced white matter integrity in the interhemispheric and thalamocortical circuit could be consistently involved in the pathogenesis of MDD, BD and SZ.
  • Parallel processing of two mechanosensory modalities by a single neuron in C.elegans

    Sensory neurons process multiple sensory modalities to generate diverse behaviors. Tao et al. show that the C. elegans PVD neuron detects both proprioceptive and nociceptive stimuli but with distinct sensors. In response, PVD generates two types of depolarization patterns via either dendrite or axon, ultimately leading to distinct behaviors.Neurons convert synaptic or sensory inputs into cellular outputs. It is not well understood how a single neuron senses, processes multiple stimuli, and generates distinct neuronal outcomes. Here, we describe the mechanism by which the C. elegans PVD neurons sense two mechanical stimuli: external touch and proprioceptive body movement. These two stimuli are detected by distinct mechanosensitive DEG/ENaC/ASIC channels, which trigger distinct cellular outputs linked to mechanonociception and proprioception. Mechanonociception depends on DEGT-1 and activates PVD's downstream command interneurons through its axon, while proprioception depends on DEL-1, UNC-8, and MEC-10 to induce local dendritic Ca increase and dendritic release of a neuropeptide NLP-12. NLP-12 directly modulates neuromuscular junction activity through the cholecystokinin receptor homolog on motor axons, setting muscle tone and movement vigor. Thus, the same neuron simultaneously uses both its axon and dendrites as output apparatus to drive distinct sensorimotor outcomes.
  • Quantitative Colour Pattern Analysis (QCPA): A comprehensive framework for the analysis of colour patterns in nature

    1. To understand the function of colour signals in nature, we require robust quantitative analytical frameworks to enable us to estimate how animal and plant colour patterns appear against their natural background as viewed by ecologically relevant species. Due to the quantitative limitations of existing methods, colour and pattern are rarely analysed in conjunction with one another, despite a large body of literature and decades of research on the importance of spatio‐chromatic colour pattern analyses. Furthermore, key physiological limitations of animal visual systems such as spatial acuity, spectral sensitivities, photoreceptor abundances and receptor noise levels are rarely considered together in colour pattern analyses. 2. Here, we present a novel analytical framework, called the Quantitative Colour Pattern Analysis (QCPA). We have overcome many quantitative and qualitative limitations of existing colour pattern analyses by combining calibrated digital photography and visual modelling. We have integrated and updated existing spatio‐chromatic colour pattern analyses, including adjacency, visual contrast and boundary strength analysis, to be implemented using calibrated digital photography through the Multispectral Image Analysis and Calibration (MICA) Toolbox. 3. This combination of calibrated photography and spatio‐chromatic colour pattern analyses is enabled by the inclusion of psychophysical colour and luminance discrimination thresholds for image segmentation, which we call ‘Receptor Noise Limited Clustering’, used here for the first time. Furthermore, QCPA provides a novel psycho‐physiological approach to the modelling of spatial acuity using convolution in the spatial or frequency domains, followed by ‘Receptor Noise Limited Ranked Filtering’ to eliminate intermediate edge artefacts and recover sharp boundaries following smoothing. We also present a new type of colour pattern analysis, the ‘local edge intensity analysis’ as well as a range of novel psycho‐physiological approaches to the visualization of spatio‐chromatic data. 4. QCPA combines novel and existing pattern analysis frameworks into what we hope is a unified, free and open source toolbox and introduces a range of novel analytical and data‐visualization approaches. These analyses and tools have been seamlessly integrated into the MICA toolbox providing a dynamic and user‐friendly workflow.
  • Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

    Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
  • 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.
  • 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.
  • Intra- and extracellular β-amyloid overexpression via adeno-associated virus-mediated gene transfer impairs memory and synaptic plasticity in the hippocampus

    Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is currently conceptualized as a disease of synaptic failure. Synaptic impairments are robust within the AD brain and better correlate with dementia severity when compared with other pathological features of the disease. Nevertheless, the series of events that promote synaptic failure still remain under debate, as potential triggers such as β-amyloid (Aβ) can vary in size, configuration and cellular location, challenging data interpretation in causation studies. Here we present data obtained using adeno-associated viral (AAV) constructs that drive the expression of oligomeric Aβ either intra or extracellularly. We observed that expression of Aβ in both cellular compartments affect learning and memory, reduce the number of synapses and the expression of synaptic-related proteins, and disrupt chemical long-term potentiation (cLTP). Together, these findings indicate that during the progression AD the early accumulation of Aβ inside neurons is sufficient to promote morphological and functional cellular toxicity, a phenomenon that can be exacerbated by the buildup of Aβ in the brain parenchyma. Moreover, our AAV constructs represent a valuable tool in the investigation of the pathological properties of Aβ oligomers both in vivo and in vitro.
  • Longitudinal trajectories of amyloid deposition, cortical thickness, and tau in Down syndrome: A deep-phenotyping case report

    Introduction: Comorbid Alzheimer disease pathologies are frequently found in people with Down syndrome (DS). We report a deep phenotyping study undertaken over 7 years in a participant with DS who was nondemented at baseline but developed dementia after 5 years. Methods: Throughout the course of the study, the participant was seen 4 times (2010, 2013, 2015, and 2017). Multimodal neuroimaging, including three serial scans of [C]-PiB-PET, four structural magnetic resonance imagings, as well as a [F]-AV1451 scan, was interpreted alongside detailed neuropsychological assessments over the study period. Results: Amyloid beta accumulation preceded the onset of dementia and cognitive decline, which in turn corresponded to the predominant deposition of tau in temporoparietal cortices. Discussion: Until now, data on the longitudinal trajectories of amyloid accumulation, tau pathology, and brain atrophy over multiple time points remain scarce in DS. This case report highlights the potential for deep phenotyping imaging to elucidate the substrates of cognitive decline in DS, although further longitudinal studies are necessary to clarify the relative contributions of both amyloid and tau.
  • Non-linear realignment improves hippocampus subfield segmentation reliability

    Participant movement can deleteriously affect MR image quality. Further, for the visualization and segmentation of small anatomical structures, there is a need to improve image quality, specifically signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), by acquiring multiple anatomical scans consecutively. We aimed to ameliorate movement artefacts and increase SNR in a high-resolution turbo spin-echo (TSE) sequence acquired thrice using non-linear realignment in order to improve segmentation consistency of the hippocampus subfields. We assessed the method in 29 young healthy participants, 11 Motor Neuron Disease patients, and 11 age matched controls at 7T, and 24 healthy adolescents at 3T. Results show improved image segmentation of the hippocampus subfields when comparing template-based segmentations with individual segmentations with Dice overlaps N = 75; ps < 0.001 (Friedman's test) and higher sharpness ps < 0.001 in non-linearly realigned scans as compared to linearly, and arithmetically averaged scans.
  • The α1-adrenoceptor inhibitor ρ-TIA facilitates net hunting in piscivorous Conus tulipa

    Cone snails use separately evolved venoms for prey capture and defence. While most use a harpoon for prey capture, the Gastridium clade that includes the well-studied Conus geographus and Conus tulipa, have developed a net hunting strategy to catch fish. This unique feeding behaviour requires secretion of "nirvana cabal" peptides to dampen the escape response of targeted fish allowing for their capture directly by mouth. However, the active components of the nirvana cabal remain poorly defined. In this study, we evaluated the behavioural effects of likely nirvana cabal peptides on the teleost model, Danio rerio (zebrafish). Surprisingly, the conantokins (NMDA receptor antagonists) and/or conopressins (vasopressin receptor agonists and antagonists) found in C. geographus and C. tulipa venom failed to produce a nirvana cabal-like effect in zebrafish. In contrast, low concentrations of the non-competitive adrenoceptor antagonist ρ-TIA found in C. tulipa venom (EC = 190 nM) dramatically reduced the escape response of zebrafish larvae when added directly to aquarium water. ρ-TIA inhibited the zebrafish α-adrenoceptor, confirming ρ-TIA has the potential to reverse the known stimulating effects of norepinephrine on fish behaviour. ρ-TIA may act alone and not as part of a cabal, since it did not synergise with conopressins and/or conantokins. This study highlights the importance of using ecologically relevant animal behaviour models to decipher the complex neurobiology underlying the prey capture and defensive strategies of cone snails.
  • Functional connectivity of brain associated with passive range of motion exercise: proprioceptive input promoting motor activation?

    Soft robotics have come to the forefront of devices available for rehabilitation following stroke; however, objective evaluation of the specific brain changes following rehabilitation with these devices is lacking. In this study, we utilized functional Magnetic Resonance Imaging (fMRI) and dynamic causal modeling (DCM) to characterize the activation of brain areas with a MRI compatible glove actuator compared to the conventional manual therapy. Thirteen healthy volunteers engaged in a motor-visual fMRI task under four different conditions namely active movement, manual passive movement, passive movement using a glove actuator, and crude tactile stimulation. Brain activity following each task clearly identified the somatosensory motor area (SMA) as a major hub orchestrating activity between the primary motor (M1) and sensory (S1) cortex. During the glove-induced passive movement, activity in the motor-somatosensory areas was reduced, but there were significant increases in motor cortical activity compared to manual passive movement. We estimated the modulatory signaling from within a defined sensorimotor network (SMA, M1, and S1), through DCM and highlighted a dual-gating of sensorimotor inputs to the SMA. Proprioceptive signaling from S1 to the SMA reflected positive coupling for the manually assisted condition, while M1 activity was positively coupled to the SMA during the glove condition. Importantly, both the S1 and M1 were shown to influence each other's connections with the SMA, with inhibitory nonlinear modulation by the M1 on the S1-SMA connection, and similarly S1 gated the M1-SMA connection. The work is one of the first to have applied effective connectivity to examine sensorimotor activity ensued by manual or robotic passive range of motion exercise, crude tactile stimulation, and voluntary movements to provide a basis for the mechanism by which soft actuators can alter brain activity.
  • Variants in nuclear factor I genes influence growth and development

    The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in individuals with intellectual disability and brain overgrowth, with individual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.
  • Idea formulation for spoken language production: the interface of cognition and language

    Language and communication are fundamental to the human experience, and, traditionally, spoken language is studied as an isolated skill. However, before propositional language (i.e., spontaneous, voluntary, novel speech) can be produced, propositional content or 'ideas' must be formulated.

    This review highlights the role of broader cognitive processes, particularly 'executive attention', in the formulation of propositional content (i.e., 'ideas') for propositional language production.

    Several key lines of evidence converge to suggest that the formulation of ideas for propositional language production draws on executive attentional processes. Larger-scale clinical research has demonstrated a link between attentional processes and language, while detailed case studies of neurological patients have elucidated specific idea formulation mechanisms relating to the generation, selection and sequencing of ideas for expression. Furthermore, executive attentional processes have been implicated in the generation of ideas for propositional language production. Finally, neuroimaging studies suggest that a widely distributed network of brain regions, including parts of the prefrontal and parietal cortices, supports propositional language production.

    Theoretically driven experimental research studies investigating mechanisms involved in the formulation of ideas are lacking. We suggest that novel experimental approaches are needed to define the contribution of executive attentional processes to idea formulation, from which comprehensive models of spoken language production can be developed. Clinically, propositional language impairments should be considered in the context of broader executive attentional deficits.
  • A detailed investigation of the visual system and visual ecology of the Barrier Reef anemonefish, Amphiprion akindynos

    Vision plays a major role in the life of most teleosts, and is assumingly well adapted to each species ecology and behaviour. Using a multidisciplinary approach, we scrutinised several aspects of the visual system and ecology of the Great Barrier Reef anemonefish, Amphiprion akindynos, including its orange with white patterning, retinal anatomy and molecular biology, its symbiosis with anemones and sequential hermaphroditism. Amphiprion akindynos possesses spectrally distinct visual pigments and opsins: one rod opsin, RH1 (498 nm), and five cone opsins, SWS1 (370 nm), SWS2B (408 nm), RH2B (498 nm), RH2A (520 nm), and LWS (554 nm). Cones were arranged in a regular mosaic with each single cone surrounded by four double cones. Double cones mainly expressed RH2B (53%) in one member and RH2A (46%) in the other, matching the prevailing light. Single cones expressed SWS1 (89%), which may serve to detect zooplankton, conspecifics and the host anemone. Moreover, a segregated small fraction of single cones coexpressed SWS1 with SWS2B (11%). This novel visual specialisation falls within the region of highest acuity and is suggested to increase the chromatic contrast of Amphiprion akindynos colour patterns, which might improve detection of conspecifics.
  • Genetic risk scores for major psychiatric disorders and the risk of postpartum psychiatric disorders

    Postpartum psychiatric disorders are heritable, but how genetic liability varies by other significant risk factors is unknown. We aimed to (1) estimate associations of genetic risk scores (GRS) for major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ) with postpartum psychiatric disorders, (2) examine differences by prior psychiatric history, and (3) compare genetic and familial risk of postpartum psychiatric disorders. We conducted a nested case-control study based on Danish population-based registers of all women in the iPSYCH2012 cohort who had given birth before December 31, 2015 (n = 8850). Cases were women with a diagnosed psychiatric disorder or a filled psychotropic prescription within one year after delivery (n = 5829 cases, 3021 controls). Association analyses were conducted between GRS calculated from Psychiatric Genomics Consortium discovery meta-analyses for MD, BD, and SCZ and case-control status of a postpartum psychiatric disorder. Parental psychiatric history was associated with postpartum psychiatric disorders among women with previous psychiatric history (OR, 1.14; 95% CI 1.02-1.28) but not without psychiatric history (OR, 1.08; 95% CI: 0.81-1.43). GRS for MD was associated with an increased risk of postpartum psychiatric disorders in both women with (OR, 1.44; 95% CI: 1.19-1.74) and without (OR, 1.88; 95% CI: 1.26-2.81) personal psychiatric history. SCZ GRS was only minimally associated with postpartum disorders and BD GRS was not. Results suggest GRS of lifetime psychiatric illness can be applied to the postpartum period, which may provide clues about distinct environmental or genetic elements of postpartum psychiatric disorders and ultimately help identify vulnerable groups.
  • Improved polygenic prediction by Bayesian multiple regression on summary statistics

    Accurate prediction of an individual's phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. We extend a powerful individual-level data Bayesian multiple regression model (BayesR) to one that utilises summary statistics from genome-wide association studies (GWAS), SBayesR. In simulation and cross-validation using 12 real traits and 1.1 million variants on 350,000 individuals from the UK Biobank, SBayesR improves prediction accuracy relative to commonly used state-of-the-art summary statistics methods at a fraction of the computational resources. Furthermore, using summary statistics for variants from the largest GWAS meta-analysis (n ≈ 700, 000) on height and BMI, we show that on average across traits and two independent data sets that SBayesR improves prediction R by 5.2% relative to LDpred and by 26.5% relative to clumping and p value thresholding.
  • Interneurons in the prefrontal cortex: a role in the genesis of anxiety in adolescence?

  • Scanning ultrasound in the absence of blood-brain barrier opening is not sufficient to clear β-amyloid plaques in the APP23 mouse model of Alzheimer's disease

    A major challenge in treating brain diseases is presented by the blood-brain barrier (BBB) that constitutes an efficient barrier not only for toxins but also a wide range of therapeutic agents. In overcoming this impediment, ultrasound in combination with intravenously injected microbubbles has emerged as a powerful technology that allows for the selective brain uptake of blood-borne factors and therapeutic agents by transient opening of the blood-brain barrier. We have previously shown that ultrasound in combination with microbubbles, but in the absence of a therapeutic agent, can effectively clear protein aggregates such as the hallmark lesions of Alzheimer's disease, amyloid-β (Aβ) plaques and Tau-containing neurofibrillary tangles. We have also demonstrated that the associated memory and motor impairments can be ameliorated or even restored. These studies included a negative sham control that received microbubbles in the absence of ultrasound. However, considering that ultrasound on its own is a pressure wave which has bioeffects, the possibility remained that ultrasound, without microbubbles, would also clear amyloid. We addressed this by performing repeated ultrasound only treatments of one brain hemisphere of Aβ-depositing APP23 mice, using the contralateral hemisphere as the unsonicated control. This was followed by an extensive histological analysis of fibrillar and non-fibrillar amyloid. We found that ultrasound on its own was not sufficient to clear amyloid. This implies that although ultrasound on its own has neuromodulatory effects, exogenously supplied microbubbles are required for the clearance of Aβ deposits.
  • Co-expression of synaptic genes in the sponge Amphimedon queenslandica uncovers ancient neural submodules

    The synapse is a complex cellular module crucial to the functioning of neurons. It evolved largely through the exaptation of pre-existing smaller submodules, each of which are comprised of ancient sets of proteins that are conserved in modern animals and other eukaryotes. Although these ancient submodules themselves have non-neural roles, it has been hypothesized that they may mediate environmental sensing behaviors in aneural animals, such as sponges. Here we identify orthologues in the sponge Amphimedon queenslandica of genes encoding synaptic submodules in neural animals, and analyse their cell-type specific and developmental expression to determine their potential to be co-regulated. We find that genes comprising certain synaptic submodules, including those involved in vesicle trafficking, calcium-regulation and scaffolding of postsynaptic receptor clusters, are co-expressed in adult choanocytes and during metamorphosis. Although these submodules may contribute to sensory roles in this cell type and this life cycle stage, total synaptic gene co-expression profiles do not support the existence of a functional synapse in A. queenslandica. The lack of evidence for the co-regulation of genes necessary for pre- and post-synaptic functioning in A. queenslandica suggests that sponges, and perhaps the last common ancestor of sponges and other extant animals, had the ability to promulgate sensory inputs without complete synapse-like functionalities. The differential co-expression of multiple synaptic submodule genes in sponge choanocytes, which have sensory and feeding roles, however, is consistent with the metazoan ancestor minimally being able to undergo exo- and endocytosis in a controlled and localized manner.
  • Auditory prediction errors and auditory white matter microstructure associated with psychotic-like experiences in healthy individuals

    Our sensory systems actively predict sensory information based on previously learnt patterns, which are continuously updated with information from the actual sensory input via prediction errors. Individuals with schizophrenia consistently show reduced auditory prediction errors as well as altered fractional anisotropy (indicative of white matter changes) in the arcuate fasciculus and the auditory interhemispheric pathway, both of which are auditory white matter pathways associated with prediction errors. However, it is not clear if healthy individuals with psychotic-like experiences exhibit similar deficits. Participants underwent electroencephalography (EEG) recordings while listening to a classical two-tone duration deviant oddball paradigm (n = 103) and a stochastic oddball paradigm (n = 89). A subset of participants (n = 89) also underwent diffusion-weighted magnetic resonance imaging (MRI). Fractional anisotropy (FA), was extracted from the arcuate fasciculi and the auditory interhemispheric pathway. While prediction errors evoked by the classical oddball paradigm failed to reveal significant effects, the stochastic oddball paradigm elicited significant clusters at the typical mismatch negativity time window. Furthermore, we observed that FA of the arcuate fasciculi and auditory interhemispheric pathway significantly improved predictive models of psychotic-like experiences in healthy individuals over and above predictions made by auditory prediction error responses alone. Specifically, we observed that decreasing FA in the auditory interhemispheric pathway and reducing ability to learn stochastic irregularities are associated with increasing CAPE + scores. To the extent that these associations have previously been reported in patients with schizophrenia, the findings from this study suggest that both, auditory prediction errors and white matter changes in the auditory interhemispheric pathway, may have the potential to be translated into early screening markers for psychosis.
  • Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue

    The formation of Aβ amyloid fibrils is a neuropathological hallmark of Alzheimer's disease and cerebral amyloid angiopathy. However, the structure of Aβ amyloid fibrils from brain tissue is poorly understood. Here we report the purification of Aβ amyloid fibrils from meningeal Alzheimer's brain tissue and their structural analysis with cryo-electron microscopy. We show that these fibrils are polymorphic but consist of similarly structured protofilaments. Brain derived Aβ amyloid fibrils are right-hand twisted and their peptide fold differs sharply from previously analyzed Aβ fibrils that were formed in vitro. These data underscore the importance to use patient-derived amyloid fibrils when investigating the structural basis of the disease.
  • The Parkinson's disease Mendelian randomization research portal

    Background Mendelian randomization is a method for exploring observational associations to find evidence of causality. Objective To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. Methods We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. Results We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. Conclusions We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
  • A comparison study of three physical activity measurement tools examining acceptability in people with psychosis

    Objective: To compare the acceptability of three distinct physical activity measurement tools in people with psychosis: an objective measurement tool, a self-report measure, and an exercise capacity test.

    Methods: We measured the completion rate for each measurement tool. Participants rated the ease/difficulty of each measure using a 7-point Likert scale. Participants were also asked to rank the three tools in order of the ease of use.

    Results: Sixty-six per cent (46/69) of participants completed all three assessment tools, and 60.9% (42/69) completed the acceptability questionnaire. The majority of the participants found it easy to complete all three measurement tools. The majority (52.8%) of the participants ranked the objective measurement tool as the easiest to use.

    Conclusion: All three measures were acceptable to people with psychosis, but objective measurement tools may be easier to use.
  • Prevalence and determinants of frailty in the absence of disability among older population: a cross sectional study from rural communities in Nepal

    Background: Longevity and frailty have significant implications for healthcare delivery. They increase demands for healthcare service and surge risk of hospitalization. Despite gaining global attention, determinants of frailty have remained unmeasured in the rural community settings in Nepal. This study aimed to address this gap by accessing the prevalence and determinants of frailty in the absence of disability among older population living in rural communities in eastern Nepal. Methods: We conducted a cross-sectional analytical study of 794 older adults aged ≥60 living in the rural part of Sunsari and Morang district of eastern Nepal between January and April in 2018. Multi-stage cluster sampling was applied to recruit the study participants. Study measures included socio-demographics; Frail Non-disabled scale (FiND) measuring frailty, Barthel's Index measuring basic activities of daily living and Geriatric depression scale. Determinants of frailty in the absence of disability were identified using generalized estimating equation (GEE). Results: About 65% of the participants self-reported the presence of frailty in the absence of disability. In the adjusted models, those from underprivileged ethnic groups, lack of daily physical exercise, presence of depressive symptoms and those not getting enough social support from family were found to be significantly associated with frailty among older participants. Conclusions: The prevalence of frailty in the absence of disability was high among rural community old population living in eastern Nepal. Our findings suggest that need of frailty awareness (both for clinicians and general public), so as to avoid negative consequences. To reduce the healthcare burden early screening frailty in primary care has potentials to prevent implications of frailty in Nepal.
  • Genetic architecture of subcortical brain structures in 38,851 individuals

    Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
  • Current challenges: the ups and downs of tACS

    The non-invasive delivery of electric currents through the scalp (transcranial electrical stimulation) is a popular tool for neuromodulation, mostly due to its highly adaptable nature (waveform, montage) and tolerability at low intensities (< 2 mA). Applied rhythmically, transcranial alternating current stimulation (tACS) may entrain neural oscillations in a frequency- and phase-specific manner, providing a causal perspective on brain-behaviour relationships. While the past decade has seen many behavioural and electrophysiological effects of tACS that suggest entrainment-mediated effects in the brain, it has been difficult to reconcile such reports with the weak intracranial field strengths (< 1 V/m) achievable at conventional intensities. In this review, we first describe the ongoing challenges faced by users of tACS. We outline the biophysics of electrical brain stimulation and the factors that contribute to the weak field intensities achievable in the brain. Since the applied current predominantly shunts through the scalp-stimulating the nerves that innervate it-the plausibility of transcutaneous (rather than transcranial) effects of tACS is also discussed. In examining the effects of tACS on brain activity, the complex problem of salvaging electrophysiological recordings from artefacts of tACS is described. Nevertheless, these challenges by no means mark the rise and fall of tACS: the second part of this review outlines the recent advancements in the field. We describe some ways in which artefacts of tACS may be better managed using high-frequency protocols, and describe innovative methods for current interactions within the brain that offer either dynamic or more focal current distributions while also minimising transcutaneous effects.
  • The reniform body: an integrative lateral protocerebral neuropil complex of Eumalacostraca identified in Stomatopoda and Brachyura

    Mantis shrimps (Stomatopoda) possess in common with other crustaceans, and with Hexapoda, specific neuroanatomical attributes of the protocerebrum, the most anterior part of the arthropod brain. These attributes include assemblages of interconnected centers called the central body complex and in the lateral protocerebra, situated in the eyestalks, paired mushroom bodies. The phenotypic homologues of these centers across Panarthropoda support the view that ancestral integrative circuits crucial to action selection and memory have persisted since the early Cambrian or late Ediacaran. However, the discovery of another prominent integrative neuropil in the stomatopod lateral protocerebrum raises the question whether it is unique to Stomatopoda or at least most developed in this lineage, which likely originated quite late in the upper Ordovician or early Devonian. Here we describe the neuroanatomical structure of this center, called the reniform body. Using confocal microscopy and classical silver staining, we demonstrate that the reniform body receives inputs from multiple sources, including the optic lobe's lobula. Although the mushroom body also receives projections from the lobula, it is entirely distinct from the reniform body, albeit connected to it by discrete tracts. We discuss the implications of their co-existence in Stomatopoda, the occurrence of the reniform body in another eumalacostracan lineage and what this may mean for our understanding of brain functionality in Pancrustacea.
  • Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity

    Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross-sectional study, we employed C-Pittsburgh Compound-B (PiB) positron emission tomography in order to group participants with Down's syndrome based on the presence of fibrillar beta-amyloid neuropathology. We also acquired resting state functional magnetic resonance imaging data to interrogate the connectivity of the default mode network; a large-scale system with demonstrated links to Alzheimer's disease. The results revealed widespread positive connectivity of the default mode network in people with Down's syndrome (n = 34, ages 30–55, median age = 43.5) and a stark lack of anti-correlation. However, in contrast to typically developing controls (n = 20, ages 30–55, median age = 43.5), the Down's syndrome group also showed significantly weaker connections in localised frontal and posterior brain regions. Notably, while a comparison of the PiB-negative Down's syndrome group (n = 19, ages 30–48, median age = 41.0) to controls suggested that alterations in default mode connectivity to frontal brain regions are related to atypical development, a comparison of the PiB-positive (n = 15, ages 39–55, median age = 48.0) and PiB-negative Down's syndrome groups indicated that aberrant connectivity in posterior cortices is associated with the presence of Alzheimer's disease neuropathology. Such distinct profiles of altered connectivity not only further our understanding of the brain physiology that underlies these two inherently linked conditions but may also potentially provide a biomarker for future studies of neurodegeneration in people with Down's syndrome.
  • Subjective estimates of uncertainty during gambling and impulsivity after subthalamic deep brain stimulation for Parkinson’s disease

    Subthalamic deep brain stimulation (DBS) for Parkinson's disease (PD) may modulate chronometric and instrumental aspects of choice behaviour, including motor inhibition, decisional slowing, and value sensitivity. However, it is not well known whether subthalamic DBS affects more complex aspects of decision-making, such as the influence of subjective estimates of uncertainty on choices. In this study, 38 participants with PD played a virtual casino prior to subthalamic DBS (whilst 'on' medication) and again, 3-months postoperatively (whilst 'on' stimulation). At the group level, there was a small but statistically significant decrease in impulsivity postoperatively, as quantified by the Barratt Impulsiveness Scale (BIS). The gambling behaviour of participants (bet increases, slot machine switches and double or nothing gambles) was associated with this self-reported measure of impulsivity. However, there was a large variance in outcome amongst participants, and we were interested in whether individual differences in subjective estimates of uncertainty (specifically, volatility) were related to differences in pre- and postoperative impulsivity. To examine these individual differences, we fit a computational model (the Hierarchical Gaussian Filter, HGF), to choices made during slot machine game play as well as a simpler reinforcement learning model based on the Rescorla-Wagner formalism. The HGF was superior in accounting for the behaviour of our participants, suggesting that participants incorporated beliefs about environmental uncertainty when updating their beliefs about gambling outcome and translating these beliefs into action. A specific aspect of subjective uncertainty, the participant's estimate of the tendency of the slot machine's winning probability to change (volatility), increased subsequent to DBS. Additionally, the decision temperature of the response model decreased post-operatively, implying greater stochasticity in the belief-to-choice mapping of participants. Model parameter estimates were significantly associated with impulsivity; specifically, increased uncertainty was related to increased postoperative impulsivity. Moreover, changes in these parameter estimates were significantly associated with the maximum post-operative change in impulsivity over a six month follow up period. Our findings suggest that impulsivity in PD patients may be influenced by subjective estimates of uncertainty (environmental volatility) and implicate a role for the subthalamic nucleus in the modulation of outcome certainty. Furthermore, our work outlines a possible approach to characterising those persons who become more impulsive after subthalamic DBS, an intervention in which non-motor outcomes can be highly variable.
  • Amyloid-beta impairs TOM1-mediated IL-1R1 signaling

    Defects in interleukin-1β (IL-1β)-mediated cellular responses contribute to Alzheimer's disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1β inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1β receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.
  • Diffusion tensor MRI to distinguish progressive supranuclear palsy from α-synucleinopathies

    Background: The differential diagnosis of progressive supranuclear palsy (PSP) and Lewy body disorders, which include Parkinson disease and dementia with Lewy bodies, is often challenging due to the overlapping symptoms. Purpose To develop a diagnostic tool based on diffusion tensor imaging (DTI) to distinguish between PSP and Lewy body disorders at the individual-subject level. Materials and Methods: In this retrospective study, skeletonized DTI metrics were extracted from two independent data sets: the discovery cohort from the Swedish BioFINDER study and the validation cohort from the Penn Frontotemporal Degeneration Center (data collected between 2010 and 2018). Based on previous neuroimaging studies and neuropathologic evidence, a combination of regions hypothesized to be sensitive to pathologic features of PSP were identified (ie, the superior cerebellar peduncle and frontal white matter) and fractional anisotropy (FA) was used to compute an FA score for each individual. Classification performances were assessed by using logistic regression and receiver operating characteristic analysis. Results: In the discovery cohort, 16 patients with PSP (mean age ± standard deviation, 73 years ± 5; eight women, eight men), 34 patients with Lewy body disorders (mean age, 71 years ± 6; 14 women, 20 men), and 44 healthy control participants (mean age, 66 years ± 8; 26 women, 18 men) were evaluated. The FA score distinguished between clinical PSP and Lewy body disorders with an area under the curve of 0.97 ± 0.04, a specificity of 91% (31 of 34), and a sensitivity of 94% (15 of 16). In the validation cohort 34 patients with PSP (69 years ± 7; 22 women, 12 men), 25 patients with Lewy body disorders (70 years ± 7; nine women, 16 men), and 32 healthy control participants (64 years ± 7; 22 women, 10 men) were evaluated. The accuracy of the FA score was confirmed (area under the curve, 0.96 ± 0.04; specificity, 96% [24 of 25]; and sensitivity, 85% [29 of 34]). Conclusion: These cross-validated findings lay the foundation for a clinical test to distinguish progressive supranuclear palsy from Lewy body disorders. © RSNA, 2019 See also the editorial by Shah in this issue.
  • Shisa7 is a GABAA receptor auxiliary subunit controlling benzodiazepine actions

    The function and pharmacology of γ-aminobutyric acid type A receptors (GABAARs) are of great physiological and clinical importance and have long been thought to be determined by the channel pore-forming subunits. We discovered that Shisa7, a single-passing transmembrane protein, localizes at GABAergic inhibitory synapses and interacts with GABAARs. Shisa7 controls receptor abundance at synapses and speeds up the channel deactivation kinetics. Shisa7 also potently enhances the action of diazepam, a classic benzodiazepine, on GABAARs. Genetic deletion of Shisa7 selectively impairs GABAergic transmission and diminishes the effects of diazepam in mice. Our data indicate that Shisa7 regulates GABAAR trafficking, function, and pharmacology and reveal a previously unknown molecular interaction that modulates benzodiazepine action in the brain.
  • Targets of olivocochlear collaterals in cochlear nucleus of rat and guinea pig

    Descending auditory pathways can modify afferent auditory input en route to cortex. One component of these pathways is the olivocochlear system which originates in brainstem and terminates in cochlea. Medial olivocochlear (MOC) neurons also project collaterals to cochlear nucleus and make synaptic contacts with dendrites of multipolar neurons. Two broadly distinct populations of multipolar cells exist: T-stellate and D-stellate neurons, thought to project to inferior colliculus and contralateral cochlear nucleus, respectively. It is unclear which of these neurons receive direct MOC collateral input due to conflicting results between in vivo and in vitro studies. This study used anatomical techniques to identify which multipolar cell population receives synaptic innervation from MOC collaterals. The retrograde tracer Fluorogold was injected into inferior colliculus or cochlear nucleus to label T-stellate and D-stellate neurons, respectively. Axonal branches of MOC neurons were labelled by biocytin injections at the floor of the fourth ventricle. Fluorogold injections resulted in labelled cochlear nucleus multipolar neurons. Biocytin abundantly labelled MOC collaterals which entered cochlear nucleus. Microscopic analysis revealed that MOC collaterals made some putative synaptic contacts with the retrogradely labelled neurons but many more putative contacts were observed on unidentified neural targets. This suggest that both T- and D-stellate neurons receive synaptic innervation from the MOC collaterals on their somata and proximal dendrites. The prevalence of these contacts cannot be stated with certainty because of technical limitations, but the possibility exists that the collaterals may also make contacts with neurons not projecting to inferior colliculus or the contralateral cochlear nucleus.
  • Genome-wide association studies in ancestrally diverse populations: opportunities, methods, pitfalls, and recommendations

    Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
  • Long-term coastline monitoring on a coral reef island (Moorea, French Polynesia)

    While many monitoring programs on coral reefs (for lagoons and outer slopes) exist in the South Pacific, there are no observatories dedicated to monitoring the coastline, a small strip of land and sea upon which many environmental and economic issues coincide. The present study compares the extent of coastline modification at Moorea Island (French Polynesia) between 1977 and 2018. Our coastal monitoring highlighted a strong increase in artificial embankments, and a decrease in beach-dominated coast from 1977 to 2009. From 2009 to 2018, the percentage of embankments have been relatively stable. However, we observed 20% of beach-dominated coast without high vegetation in 2009 and only 10% in 2018. Furthermore, we found that 12% of beach-dominated coast with coarse mud and detrital substrate in 2009 and 22% in 2018. These findings highlighted that anthropogenic factors were principal drivers of coastline changes at Moorea Island. In order to inform conservation and management strategies for coastlines in the South Pacific Islands, it is imperative to conduct ongoing monitoring of coastlines through the creation of dedicated coastline observatories. This work will enhance our understanding of the impact of human-induced environmental changes on this ecologically, economically and culturally important ecosystem.
  • Genetic correlations of polygenic disease traits: from theory to practice

    The genetic correlation describes the genetic relationship between two traits and can contribute to a better understanding of the shared biological pathways and/or the causality relationships between them. The rarity of large family cohorts with recorded instances of two traits, particularly disease traits, has made it difficult to estimate genetic correlations using traditional epidemiological approaches. However, advances in genomic methodologies, such as genome-wide association studies, and widespread sharing of data now allow genetic correlations to be estimated for virtually any trait pair. Here, we review the definition, estimation, interpretation and uses of genetic correlations, with a focus on applications to human disease.
  • A comprehensive analysis of mortality-related health metrics associated with mental disorders: a nationwide, register-based cohort study

    Background Systematic reviews have consistently shown that individuals with mental disorders have an increased risk of premature mortality. Traditionally, this evidence has been based on relative risks or crude estimates of reduced life expectancy. The aim of this study was to compile a comprehensive analysis of mortality-related health metrics associated with mental disorders, including sex-specific and age-specific mortality rate ratios (MRRs) and life-years lost (LYLs), a measure that takes into account age of onset of the disorder. Methods In this population-based cohort study, we included all people younger than 95 years of age who lived in Denmark at some point between Jan 1, 1995, and Dec 31, 2015. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and the date and cause of death was obtained from the Danish Register of Causes of Death. We classified mental disorders into ten groups and causes of death into 11 groups, which were further categorised into natural causes (deaths from diseases and medical conditions) and external causes (suicide, homicide, and accidents). For each specific mental disorder, we estimated MRRs using Poisson regression models, adjusting for sex, age, and calendar time, and excess LYLs (ie, difference in LYLs between people with a mental disorder and the general population) for all-cause mortality and for each specific cause of death. Findings 7 369 926 people were included in our analysis. We found that mortality rates were higher for people with a diagnosis of a mental disorder than for the general Danish population (28·70 deaths [95% CI 28·57–28·82] vs 12·95 deaths [12·93–12·98] per 1000 person-years). Additionally, all types of disorders were associated with higher mortality rates, with MRRs ranging from 1·92 (95% CI 1·91–1·94) for mood disorders to 3·91 (3·87–3·94) for substance use disorders. All types of mental disorders were associated with shorter life expectancies, with excess LYLs ranging from 5·42 years (95% CI 5·36–5·48) for organic disorders in females to 14·84 years (14·70–14·99) for substance use disorders in males. When we examined specific causes of death, we found that males with any type of mental disorder lost fewer years due to neoplasm-related deaths compared with the general population, although their cancer mortality rates were higher. Interpretation Mental disorders are associated with premature mortality. We provide a comprehensive analysis of mortality by different types of disorders, presenting both MRRs and premature mortality based on LYLs, displayed by age, sex, and cause of death. By providing accurate estimates of premature mortality, we reveal previously underappreciated features related to competing risks and specific causes of death.
  • Physiological and anatomical investigation of the auditory brainstem in the fat-tailed dunnart (Sminthopsis crassicaudata)

    The fat-tailed dunnart () is a small (10-20 g) native marsupial endemic to the south west of Western Australia. Currently little is known about the auditory capabilities of the dunnart, and of marsupials in general. Consequently, this study sought to investigate several electrophysiological and anatomical properties of the dunnart auditory system. Auditory brainstem responses (ABR) were recorded to brief (5 ms) tone pips at a range of frequencies (4-47.5 kHz) and intensities to determine auditory brainstem thresholds. The dunnart ABR displayed multiple distinct peaks at all test frequencies, similar to other mammalian species. ABR showed the dunnart is most sensitive to higher frequencies increasing up to 47.5 kHz. Morphological observations (Nissl stain) revealed that the auditory structures thought to contribute to the first peaks of the ABR were all distinguishable in the dunnart. Structures identified include the dorsal and ventral subdivisions of the cochlear nucleus, including a cochlear nerve root nucleus as well as several distinct nuclei in the superior olivary complex, such as the medial nucleus of the trapezoid body, lateral superior olive and medial superior olive. This study is the first to show functional and anatomical aspects of the lower part of the auditory system in the Fat-tailed dunnart.
  • Platelets: the missing link between the blood and brain?

    It is becoming increasingly clear that interactions between the peripheral immune system and the central nervous system are important in maintaining healthy brain function. Platelets are small blood cells traditionally known for their role in wound healing. However, platelets have recently been shown to exhibit many alternative functions. In this perspective, we summarize the repertoire of platelet functions, focusing on how these cells contribute to the maintenance of brain homeostasis and propose the mechanisms via which they could communicate with brain cells, including exosome and microparticle release and receptor interactions at local sites. In particular, we highlight the potential role that platelets play in maintaining brain plasticity via the modulation of new neuron generation from neural precursor cells, an interaction which could have important implications in the development of therapeutic interventions to promote cognitive function in aging and disease.
  • Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

    Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up-regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β-amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD-related tauopathy (human neuroblastoma cells SH-SY5Y stably overexpressing the P301L-mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR-180,575 and Ro5-4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD-related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.
  • The p75 neurotrophin receptor is required for the survival of neuronal progenitors and normal formation of the basal forebrain, striatum, thalamus and neocortex

    During development, the p75 neurotrophin receptor (p75) is widely expressed in the nervous system where it regulates neuronal differentiation, migration and axonal outgrowth. p75 also mediates the survival and death of newly born neurons, with functional outcomes being dependent on both timing and cellular context. Here we show that knockout of p75 from embryonic day 10 (E10) in neural progenitors using a conditional Nestin-Cre; p75 floxed mouse causes increased apoptosis of progenitor cells. By E14.5, the number of Tbr2-positive progenitor cells was significantly reduced and the rate of neurogenesis was halved. Furthermore, in adult knockout mice, there were fewer cortical pyramidal neurons, interneurons, cholinergic basal forebrain neurons, and striatal neurons, corresponding to a relative reduction in volume of these structures. Thalamic midline fusion during early postnatal development was also impaired in Nestin-Cre p75 floxed mice, indicating a novel role of p75 in the formation of this structure. The phenotype of this strain demonstrates that p75 regulates multiple aspects of brain development, including cortical progenitor cell survival, and that expression during early neurogenesis is required for appropriate formation of telencephalic structures.
  • The relationship between social cognitive difficulties in the acute stages of stroke and later functional outcomes

    Although social cognitive difficulties are common following stroke, the extent to which such difficulties observed in the acute phase are related to long-term socioemotional outcomes remains poorly understood. To address this question empirically, fifty-three stroke patients completed a measure of Theory of Mind (The Reading the Mind in the Eyes Test) and a cognitive flexibility measure that has been related to social cognitive processes (a Reversal Learning Task) at hospital bedside. These participants then completed measures of socioemotional functioning at a six month follow-up. Baseline difficulties on the two measures were found to predict distinct types of socioemotional difficulties. The RMET uniquely predicted self-reported depression and loneliness whereas the Reversal Learning task uniquely predicted peer-reported social behaviour, specifically social inappropriateness and stereotyping and prejudice. Importantly, a measure of general cognitive function did not explain variance in these outcome measures, suggesting that social cognitive difficulties are linked to poor socioemotional outcomes. By showing for the first time that social cognitive deficits observed acutely post-stroke are related to longer term functional outcomes, these findings reinforce the importance of including brief social cognitive measures as part of routine post-stroke clinical assessment.
  • Mitochondrial genome (mtDNA) mutations that generate reactive oxygen species

    Mitochondria are critical for the energetic demands of virtually every cellular process within nucleated eukaryotic cells. They harbour multiple copies of their own genome (mtDNA), as well as the protein-synthesing systems required for the translation of vital subunits of the oxidative phosphorylation machinery used to generate adenosine triphosphate (ATP). Molecular lesions to the mtDNA cause severe metabolic diseases and have been proposed to contribute to the progressive nature of common age-related diseases such as cancer, cardiomyopathy, diabetes, and neurodegenerative disorders. As a consequence of playing a central role in cellular energy metabolism, mitochondria produce reactive oxygen species (ROS) as a by-product of respiration. Here we review the evidence that mutations in the mtDNA exacerbate ROS production, contributing to disease.
  • Size-dependent vulnerability of lumbar motor neuron dendritic degeneration in SOD1(G93A) mice

    The motor neuron (MN) soma surface area is correlated with motor unit type. Larger MNs innervate fast fatigue-intermediate (FInt) or fast-fatiguable (FF) muscle fibers in type FInt and FF motor units, respectively. Smaller MNs innervate slow-twitch fatigue-resistant (S) or fast fatigue-resistant (FR) muscle fibers in type S and FR motor units, respectively. In amyotrophic lateral sclerosis (ALS), FInt and FF motor units are more vulnerable, with denervation and MN death occurring for these units before the more resilient S and FR units. Abnormal MN dendritic arbors have been observed in ALS in humans and rodent models. We used a Golgi-Cox impregnation protocol to examine soma size-dependent changes in the dendritic morphology of lumbar MNs in SOD1(G93A) mice, a model of ALS, at pre-symptomatic, onset and mid-disease stages. In wildtype control mice, the relationship between MN soma surface area and dendritic length or dendritic spine number was highly linear (i.e., increased MN soma size correlated with increased dendritic length and spines). By contrast, in SOD1(G93A) mice, this linear relationship was lost and dendritic length reduction and spine loss were observed in larger MNs, from pre-symptomatic stages onward. These changes correlated with the neuromotor symptoms of ALS in rodent models. At presymptomatic ages, changes were restricted to the larger MNs, likely to comprise vulnerable FInt and FF motor units. Our results suggest morphological changes of MN dendrites and dendritic spines are likely to contribute ALS pathogenesis, not compensate for it.
  • A Cold-Sensing Receptor Encoded by a Glutamate Receptor Gene

    In search of the molecular identities of cold-sensing receptors, we carried out an unbiased genetic screen for cold-sensing mutants in C. elegans and isolated a mutant allele of glr-3 gene that encodes a kainate-type glutamate receptor. While glutamate receptors are best known to transmit chemical synaptic signals in the CNS, we show that GLR-3 senses cold in the peripheral sensory neuron ASER to trigger cold-avoidance behavior. GLR-3 transmits cold signals via G protein signaling independently of its glutamate-gated channel function, suggesting GLR-3 as a metabotropic cold receptor. The vertebrate GLR-3 homolog GluK2 from zebrafish, mouse, and human can all function as a cold receptor in heterologous systems. Mouse DRG sensory neurons ex- prc GluK2, and GluK2 knockdown in these neurons suppresses their sensitivity to cold but not cool temperatures. Our study identifies an evolutionarily conserved cold receptor, revealing that a central chemical receptor unexpectedly functions as a thermal receptor in the periphery.
  • Economic evaluation of deep-brain stimulation for Tourette’s syndrome: an initial exploration

    Deep-brain stimulation (DBS) can be effective in controlling medically intractable symptoms of Tourette's syndrome (TS). There is no evidence to date, though, of the potential cost-effectiveness of DBS for this indication.

    To provide the first estimates of the likely cost-effectiveness of DBS in the treatment of severe TS.

    We conducted a cost-utility analysis using clinical data from 17 Australian patients receiving DBS. Direct medical costs for DBS using non-rechargeable and rechargeable batteries and for the alternative best medical treatment (BMT), and health utilities for BMT were sourced from the literature. Incremental cost-effectiveness ratios (ICERs) were estimated using a Markov models with a 10-year time horizon and 5% discount rate.

    DBS increased quality-adjusted life year (QALY) gained from 2.76 to 4.60 over a 10-year time horizon. The ICER for DBS with non-rechargeable (rechargeable) batteries, compared to BMT, was A$33,838 (A$15,859) per QALY. The ICER estimates are sensitive to DBS costs and selected time horizon.

    Our study indicates that DBS may be a cost-effective treatment for severe TS, based on the very limited clinical data available and under particular assumptions. While the limited availability of data presents a challenge, we also conduct sensitivity analyses to test the robustness of the results to the assumptions used in the analysis. We nevertheless recommend the implementation of randomised controlled trials that collect a comprehensive range of costs and the use of a widely accepted health-related quality of life instrument to enable more definitive statements about the cost-effectiveness of DBS for TS.
  • The effects of insecticides on two splice variants of the glutamate-gated chloride channel receptor of the major malaria vector, Anopheles gambiae

    Between half to one million people die annually from malaria. Anopheles gambiae mosquitos are major malaria vectors. Unfortunately, resistance to currently used A. gambiae control agents has emerged, creating a demand for novel control measures. The pentameric glutamate-gated chloride channel receptors (GluClRs) expressed in the muscle and nerve cells of these organisms are a potentially important biological target for malaria control. The pharmacological properties of Anophiline GluClRs are, however, largely unknown. Accordingly, we compared the efficacy of four insecticides (lindane, fipronil, picrotoxin and ivermectin) on two A. gambiae GluClR splice variants with the aim of providing a molecular basis for designing novel anti-malaria treatments.

    The A. gambiae GluClR b1 and c splice variants were expressed homomerically in Xenopus laevis oocytes and studied using two-electrode voltage-clamp.

    The b1 and c GluClRs were activated with similar potencies by glutamate and ivermectin. Fipronil was more potent than picrotoxin and lindane at inhibiting glutamate and ivermectin-gated currents. Importantly, b1 GluClRs exhibited a reduced sensitivity to picrotoxin and lindane. They also recovered from these effects to a greater extent than c GluClRs.

    We show that the two splice variant subunits exhibit differential sensitivities to multiple, structurally divergent insecticides. This is achieved without accompanying changes in the sensitivity to the endogenous neurotransmitter, glutamate, implying that drug resistance may be caused by alterations in relative subunit expression levels without affecting physiological function. Finally, our results strongly suggest that it should be feasible to develop novel subunit-specific pharmacological agents.
  • Extreme inbreeding in a European ancestry sample from the contemporary UK population

    In most human societies, there are taboos and laws banning mating between first- and second-degree relatives, but actual prevalence and effects on health and fitness are poorly quantified. Here, we leverage a large observational study of ~450,000 participants of European ancestry from the UK Biobank (UKB) to quantify extreme inbreeding (EI) and its consequences. We use genotyped SNPs to detect large runs of homozygosity (ROH) and call EI when >10% of an individual's genome comprise ROHs. We estimate a prevalence of EI of ~0.03%, i.e., ~1/3652. EI cases have phenotypic means between 0.3 and 0.7 standard deviation below the population mean for 7 traits, including stature and cognitive ability, consistent with inbreeding depression estimated from individuals with low levels of inbreeding. Our study provides DNA-based quantification of the prevalence of EI in a European ancestry sample from the UK and measures its effects on health and fitness traits.
  • YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis

    YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.