Recent QBI publications

  • A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

    Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, p < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, p: 0.049 to 1.28 × 10) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.
  • Genome-wide microRNA profiling in brain and blood samples in a mouse model of epileptogenesis

    Objectives: This study profiled circulating and hippocampal microRNAs (miRNAs) to identify alterations associated with the risk of epileptogenesis in a mouse temporal lobe epilepsy model. Methods: Next-generation sequencing was performed to examine the changes in miRNA expression 24 h after pilocarpine-induced status epilepticus (SE) in C57BL/6NCrl mice using both blood and hippocampus samples. Differentially expressed miRNAs were identified from SE animals and matched controls that failed to develop SE after receiving equal doses of pilocarpine (NS animals). Blood and brain miRNA profiles were then compared to identify circulating miRNA alterations reflecting the changes in the brain. Results: We identified 3 miRNAs that were significantly up-regulated and 4 miRNAs that were significantly down-regulated in the blood of SE animals compared with NS animals. When hippocampal miRNAs of SE animals and NS animals were compared, 5 miRNAs were up-regulated and 4 were down-regulated. Of these, miR-434-3p and miR-133a-3p were observed to have greatest changes in both blood and brain of SE animals. Significance: This study extends current knowledge of changes in miRNAs associated with epileptogenesis by profiling miRNAs in SE and NS animals in an experimental temporal lobe epilepsy model. The study was designed to allow non-specific changes due to the activation of muscarinic cholinergic receptors in peripheral organs by pilocarpine to be ruled out. Significantly altered circulating miRNAs that reflect changes in the brain during epileptogenesis after SE have the potential to be developed as prognostic biomarkers for epileptogenesis.
  • Longitudinal Automatic Segmentation of Hippocampal Subfields (LASHiS) using multi-contrast MRI

    The volumetric and morphometric examination of hippocampus formation subfields in a longitudinal manner using in vivo MRI could lead to more sensitive biomarkers for neuropsychiatric disorders and diseases including Alzheimer's disease, as the anatomical subregions are functionally specialised. Longitudinal processing allows for increased sensitivity due to reduced confounds of inter-subject variability and higher effect-sensitivity than cross-sectional designs. We examined the performance of a new longitudinal pipeline (Longitudinal Automatic Segmentation of Hippocampus Subfields [LASHiS]) against three freely available, published approaches. LASHiS automatically segments hippocampus formation subfields by propagating labels from cross-sectionally labelled time point scans using joint-label fusion to a non-linearly realigned 'single subject template', where image segmentation occurs free of bias to any individual time point. Our pipeline measures tissue characteristics available in in vivo high-resolution MRI scans, at both clinical (3 Tesla) and ultra-high field strength (7 Tesla) and differs from previous longitudinal segmentation pipelines in that it leverages multi-contrast information in the segmentation process. LASHiS produces robust and reliable automatic multi-contrast segmentations of hippocampus formation subfields, as measured by higher volume similarity coefficients and Dice coefficients for test-retest reliability and robust longitudinal Bayesian Linear Mixed Effects results at 7 T, while showing sound results at 3 T. All code for this project including the automatic pipeline is available at https://github.com/CAIsr/LASHiS.
  • Altered structural connectivity networks in a mouse model of complete and partial dysgenesis of the corpus callosum

    Corpus callosum dysgenesis (CCD) describes a collection of brain malformations in which the main fiber tract connecting the two hemispheres is either absent (complete CCD, or 'agenesis of the corpus callosum') or reduced in size (partial CCD). Humans with these neurodevelopmental disorders have a wide range of cognitive outcomes, including seemingly preserved features of interhemispheric communication in some cases. However, the structural substrates that could underlie this variability in outcome remain to be fully elucidated. Here, for the first time, we characterize the global brain connectivity of a mouse model of complete and partial CCD. We demonstrate features of structural brain connectivity that model those predicted in humans with CCD, including Probst bundles in complete CCD and heterotopic sigmoidal connections in partial CCD. Crucially, we also histologically validate the recently predicted ectopic sigmoid bundle present in humans with partial CCD, validating the utility of this mouse model for fine anatomical studies of this disorder. Taken together, this work describes a mouse model of altered structural connectivity in variable severity CCD and forms a foundation for future studies investigating the function and mechanisms of development of plastic tracts in developmental disorders of brain connectivity.
  • Long-distance aberrant heterotopic connectivity in a mouse strain with a high incidence of callosal anomalies

    Corpus callosum dysgenesis (CCD) is a developmental brain condition in which some white matter fibers fail to find their natural course across the midplane, reorganizing instead to form new aberrant pathways. This type of white matter reorganization is known as long-distance plasticity (LDP). The present work aimed to characterize the Balb/c mouse strain as a model of CCD. We employed high-resolution anatomical MRI in 81 Balb/c and 27 C57bl6 mice to show that the Balb/c mouse strain presents a variance in the size of the CC that is 3.9 times higher than the variance of normotypical C57bl6. We also performed high-resolution diffusion-weighted imaging (DWI) in 8 Balb/c and found that the Balb/c strain shows aberrant white matter bundles, such as the Probst (5/8 animals) and the Sigmoid bundles (7/8 animals), which are similar to those found in humans with CCD. Using a histological tracer technique, we confirmed the existence of these aberrant bundles in the Balb/c strain. Interestingly, we also identified sigmoid-like fibers in the C57bl6 strain, thought to a lesser degree. Next, we used a connectome approach and found widespread brain connectivity differences between Balb/c and C57bl6 strains. The Balb/c strain also exhibited increased variability of global connectivity. These findings suggest that the Balb/c strain presents local and global changes in brain structural connectivity. This strain often presents with callosal abnormalities, along with the Probst and the Sigmoid bundles, making it is an attractive animal model for CCD and LDP in general. Our results also show that even the C57bl6 strain, which typically serves as a normotypical control animal in a myriad of studies, presents sigmoid-fashion pattern fibers laid out in the brain. These results suggest that these aberrant fiber pathways may not necessarily be a pathological hallmark, but instead an alternative roadmap for misguided axons. Such findings offer new insights for interpreting the significance of CCD-associated LDP in humans.
  • Randomized controlled trial of social cognition and interaction training compared to befriending group

    Background: Deficits in social cognition are common in people with schizophrenia and are associated with impaired functioning. Finding effective interventions to address these deficits is a priority. Social Cognition Interaction Training (SCIT) is a psychosocial intervention that has demonstrated acceptability and feasibility in various health care settings. Larger, well-designed randomized controlled trials are needed to examine the effectiveness of this intervention. Design: A randomized controlled trial. Methods: One hundred and twenty adults diagnosed with schizophrenia spectrum disorder were randomized to receive SCIT (n = 61) or Befriending Therapy (BT) (n = 59). Both intervention groups were delivered weekly for 2 hr over 12 weeks. Neurocognitive assessment was completed at baseline. Participants completed assessments of social cognition, social functioning, and meta-cognition at baseline, post-intervention, and 3-month follow-up. Results: There were no clinically significant differences between group outcomes on any measure of social cognition or social functioning. There was a trend for both groups to improve over time but not at a level of statistical significance. Conclusions: SCIT did not show any additional benefits on measures of social cognition compared to Befriending Therapy for people with schizophrenia spectrum disorder. The findings are discussed in terms of potential improvements to the programme. Practitioner points: Effective interventions for the social cognitive deficits of schizophrenia spectrum disorders are still being refined. Social Cognition Interaction Training is a promising therapy but requires further modifications to improve its effectiveness.
  • Behavioral and electrophysiological evidence for a dissociation between working memory capacity and feature-based attention

    When attending to visual objects with particular features, neural processing is typically biased toward those features. Previous work has suggested that maintaining such feature-based attentional sets may involve the same neural resources as visual working memory. If so, the extent to which feature-based attention influences stimulus processing should be related to individuals’ working memory capacity. Here we used electroencephalography (EEG) to record brain activity in 60 human observers while they monitored stimulus streams for targets of a specific color. Distractors presented at irrelevant locations evoked strong electrophysiological markers of attentional signal enhancement (the N2pc and PD components) despite producing little or no behavioral interference. Critically, there was no relationship between individual differences in the magnitude of these feature-based biases on distractor processing and individual differences in working memory capacity as measured using three separate working memory tasks. Bayes factor analyses indicated substantial evidence in support of the null hypothesis of no relationship between working memory capacity and the effects of feature-based attention on distractor processing. We consider three potential explanations for these findings. One is that working memory and feature-based attention draw upon distinct neural resources, contrary to previous claims. A second is that working memory is only related to feature-based attention when the attentional template has recently changed. A third is that feature-based attention tasks of the kind employed in the current study recruit just one of several subcomponents of working memory, and so are not invariably correlated with an individual’s overall working memory capacity.
  • Global effects of feature-based attention depend on surprise

    Recent studies have shown that prediction and attention can interact under various circumstances, suggesting that the two processes are based on interdependent neural mechanisms. In the visual modality, attention can be deployed to the location of a task-relevant stimulus (‘spatial attention’) or to a specific feature of the stimulus, such as colour or shape, irrespective of its location (‘feature-based attention’). Here we asked whether predictive processes are influenced by feature-based attention outside the current spatial focus of attention. Across two experiments, we recorded neural activity with electroencephalography (EEG) as human observers performed a feature-based attention task at fixation and ignored a stream of peripheral stimuli with predictable or surprising features. Central targets were defined by a single feature (colour or orientation) and differed in salience across the two experiments. Task-irrelevant peripheral patterns usually comprised one particular conjunction of features (standards), but occasionally deviated in one or both features (deviants). Consistent with previous studies, we found reliable effects of feature-based attention and prediction on neural responses to task-irrelevant patterns in both experiments. Crucially, we observed an interaction between prediction and feature-based attention in both experiments: the neural effect of feature-based attention was larger for surprising patterns than it was for predicted patterns. These findings suggest that global effects of feature-based attention depend on surprise, and are consistent with a recent theory that suggests attention optimises the precision of predictions by modulating the gain of prediction errors.
  • Region-specific sex differences in the hippocampus

    The hippocampus is a brain region critical for learning and memory, and is also implicated in several neuropsychiatric disorders that show sex differences in prevalence, symptom expression, and mean age of onset. On average, males have larger hippocampal volumes than females, but findings are inconclusive after adjusting for overall brain size. Although the hippocampus is a heterogenous structure, few studies have focused on sex differences in the hippocampal subfields – with little consensus on whether there are regionally specific sex differences in the hippocampus after adjusting for brain size, or whether it is important to adjust for total hippocampal volume (HPV). Here, using two young adult cohorts from the Queensland Twin IMaging study (QTIM; N ​= ​727) and the Human Connectome Project (HCP; N ​= ​960), we examined differences between males and females in the volumes of 12 hippocampal subfields, extracted using FreeSurfer 6.0. After adjusting the subfield volumes for either HPV or brain size (brain segmentation volume (BSV)) using four controlling methods (allometric, covariate, residual and matching), we estimated the percentage difference of the sex effect (males versus females) and Cohen's d using hierarchical general linear models. Males had larger volumes compared to females in the parasubiculum (up to 6.04%; Cohen's d ​= ​0.46) and fimbria (up to 8.75%; d ​= ​0.54) after adjusting for HPV. These sex differences were robust across the two cohorts and multiple controlling methods, though within cohort effect sizes were larger for the matched approach, due to the smaller sub-sample. Additional sex effects were identified in the HCP cohort and combined (QTIM and HCP) sample (hippocampal fissure (up to 6.79%), presubiculum (up to 3.08%), and hippocampal tail (up to −0.23%)). In contrast, no sex differences were detected for the volume of the cornu ammonis (CA)2/3, CA4, Hippocampus-Amygdala Transition Area (HATA), or the granule cell layer of the dentate gyrus (GCDG). These findings show that, independent of differences in HPV, there are regionally specific sex differences in the hippocampus, which may be most prominent in the fimbria and parasubiculum. Further, given sex differences were less consistent across cohorts after controlling for BSV, adjusting for HPV rather than BSV may benefit future studies. This work may help in disentangling sex effects, and provide a better understanding of the implications of sex differences for behaviour and neuropsychiatric disorders.
  • A validated quantitative method for the assessment of neuroprotective barrier impairment in neurodegenerative disease models

    The blood brain barrier (BBB) and blood spinal cord barrier (BSCB) are highly specialised structures that limit molecule entry from the blood and maintain homeostasis within the central nervous system (CNS). BBB and BSCB breakdown are associated with multiple neurodegenerative diseases. Given the key role of neuroprotective barrier impairment in neurodegeneration, it is important to identify an effective quantitative method to assess barrier integrity in animal models. In the present study, we developed and validated a quantitative method for assessing BBB and BSCB integrity using sodium fluorescein, a compound that outperformed other fluorescent dyes. We demonstrated using this method that multiple CNS regions progressively increase in permeability in models of Huntington's disease and amyotrophic lateral sclerosis, while biphasic disruption occurred in a mouse model of Alzheimer's disease with disease progression. Collectively, we report a quantitative fluorometric marker with validated reproducible experimental methods, that allows the effective assessment of BBB and BSCB integrity in animal models. This method could be useful to further the understanding of the contribution of these neuroprotective barriers to neurodegeneration processes.
  • The astonishing diversity of vision: introduction to an issue of vision research on animal vision

  • An analytical approach to designing optimal sparse 1-D phased arrays for handheld ultrasound imaging

    Sparse arrays have been studied mainly to reduce the large numbers of elements in 2-D arrays. However, they can also provide an effective means of miniaturizing ultrasound 1-D array systems for point-of-care applications. Although a variety of sparse array design strategies have been proposed, designing an optimum sparse array to simultaneously satisfy the system specification requirements and performance criteria remains a challenge. This article presents an analytical approach for the design of an optimum pair of periodic sparse arrays (PSAs), one for transmission and the other for reception. The approach is based on three newly derived theorems that describe the most important properties of the two PSAs forming the sparse array pair and their relationship pertaining to the overall beam pattern. The proposed approach can be used to design 1-D sparse array pairs with arbitrary sparseness factors while meeting given performance criteria. The computer simulation verified that the spatial resolution of a 64-element phased array can be obtained with a PSA pair consisting of transmit and receive sparse arrays, of which the number of elements is reduced to 32 and 22, respectively.
  • Pharmacological activation of IKr in models of long QT Type 2 risks overcorrection of repolarization

    Aims: Current treatment for congenital long QT syndrome Type 2 (cLQTS2), an electrical disorder that increases the risk of life-threatening cardiac arrhythmias, is aimed at reducing the incidence of arrhythmia triggers (beta-blockers) or terminating the arrhythmia after onset (implantable cardioverter-defibrillator). An alternative strategy is to target the underlying disease mechanism, which is reduced rapid delayed rectifier current (IKr) passed by Kv11.1 channels. Small molecule activators of Kv11.1 have been identified but the extent to which these can restore normal cardiac signalling in cLQTS2 backgrounds remains unclear. Here, we examined the ability of ICA-105574, an activator of Kv11.1 that impairs transition to the inactivated state, to restore function to heterozygous Kv11.1 channels containing either inactivation enhanced (T618S, N633S) or expression deficient (A422T) mutations. Methods and results: ICA-105574 effectively restored Kv11.1 current from heterozygous inactivation enhanced or expression defective mutant channels in heterologous expression systems. In a human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of cLQTS2 containing the expression defective Kv11.1 mutant A422T, cardiac repolarization, estimated from the duration of calcium transients in isolated cells and the rate corrected field potential duration (FPDc) in culture monolayers of cells, was significantly prolonged. The Kv11.1 activator ICA-105574 was able to reverse the prolonged repolarization in a concentration-dependent manner. However, at higher doses, ICA-105574 produced a shortening of the FPDc compared to controls. In vitro and in silico analysis suggests that this overcorrection occurs as a result of a temporal redistribution of the peak IKr to much earlier in the plateau phase of the action potential, which results in early repolarization. Conclusion: Kv11.1 activators, which target the primary disease mechanism, provide a possible treatment option for cLQTS2, with the caveat that there may be a risk of overcorrection that could itself be pro-arrhythmic.
  • Effects of GluN2A and GluN2B gain-of-function epilepsy mutations on synaptic currents mediated by diheteromeric and triheteromeric NMDA receptors

    Mutations in synaptic NMDA receptors (NMDARs) are associated with epilepsy and neurodevelopmental disorders. The effects of several such mutations have been investigated in recombinantly-expressed NMDARs under conditions of steady-state activation. Such experiments provide only limited insight into how mutations affect NMDAR-mediated excitatory synaptic currents (EPSCs). The present study aimed to characterize the effects of the GluN2A, GluN2B and GluN2B gain-of-function mutations on EPSCs mediated by diheteromeric GluN1/2A and GluN1/2B receptors and triheteromeric GluN1/2A/2B receptors, as these are the most abundant synaptic NMDARs in vivo. Subunit composition was controlled by studying ‘artificial’ synapses formed between cultured neurons (which provide presynaptic terminals) and HEK293 cells that express the NMDAR subunits of interest plus the synapse-promoting molecule, neuroligin-1B. When incorporated into diheteromeric receptors, all three mutations ablated voltage-dependent Mg block of EPSCs, as previously shown. In addition, we were surprised to find that increasing external Mg from 0 to 1 mM strongly enhanced the magnitude of EPSCs mediated by mutant diheteromers. In contrast, triheteromeric receptors exhibited normal voltage-dependent Mg block. The GluN2A mutation also slowed the decay of GluN1/2A/2B- but not GluN1/2A-mediated EPSCs. The GluN2B mutation enhanced the magnitude of both GluN1/2B- and GluN1/2A/2B-mediated EPSCs. The GluN2B mutation enhanced the magnitude of both GluN1/2B- and GluN1/2A/2B-mediated EPSCs, although these effects were partly compensated by a faster EPSC decay rate. The mutations also diminished the potency of the anti-epileptic pore-blocker, memantine, thus explaining the lack of memantine efficacy in patients with GluN2B or GluN2B mutations. Given these effects, the three mutations would be expected to enhance the cation influx rate and thereby contribute to epilepsy phenotypes.
  • "Grumpy" or "furious"? arousal of emotion labels influences judgments of facial expressions

    Whether language information influences recognition of emotion from facial expressions remains the subject of debate. The current studies investigate how variations in emotion labels that are paired with expressions influences participants' judgments of the emotion displayed. Static (Study 1) and dynamic (Study 2) facial expressions depicting eight emotion categories were paired with emotion labels that systematically varied in arousal (low and high). Participants rated the arousal, valence, and dominance of expressions paired with labels. Isolated faces and isolated labels were also rated. As predicted, the label presented influenced participants' judgments of the expressions. Across both studies, higher arousal labels were associated with: 1) higher ratings of arousal for sad, angry, and scared expressions, and 2) higher ratings of dominance for angry, proud, and disgust expressions. These results indicate that emotion labels influence judgments of facial expressions.
  • Corrigendum to: The epidemiology of alcohol use disorders cross-nationally: findings from the World Mental Health Surveys [Addict. Behav. 102 (2020) 106128] (Addictive Behaviors (2020) 102, (S0306460319304897), (10.1016/j.addbeh.2019.106128))

    The authors regret that the abovementioned article published online September 16, 2019, had an error in the author affiliations. The edited author affiliations are shown above. The authors also regret that the names of the WHO World Mental Health Survey Collaborators were omitted from the end of the article. “The WHO World Mental Health Survey collaborators are Sergio Aguilar-Gaxiola, MD, PhD; Ali Al-Hamzawi, MD; Mohammed Salih Al-Kaisy, MD; Jordi Alonso, MD, PhD; Laura Helena Andrade, MD, PhD; Lukoye Atwoli, MD, PhD; Corina Benjet, PhD; Guilherme Borges, ScD; Evelyn J. Bromet, PhD; Ronny Bruffaerts, PhD; Brendan Bunting, PhD; Jose Miguel Caldas-de-Almeida, MD, PhD; Graça Cardoso, MD, PhD; Somnath Chatterji, MD; Alfredo H. Cia, MD; Louisa Degenhardt, PhD; Koen Demyttenaere, MD, PhD; Silvia Florescu, MD, PhD; Giovanni de Girolamo, MD; Oye Gureje, MD, DSc, FRCPsych; Josep Maria Haro, MD, PhD; Meredith Harris, PhD; Hristo Hinkov, MD, PhD; Chi-yi Hu, MD, PhD; Peter de Jonge, PhD; Aimee Nasser Karam, PhD; Elie G. Karam, MD; Norito Kawakami, MD, DMSc; Ronald C. Kessler, PhD; Andrzej Kiejna, MD, PhD; Viviane Kovess-Masfety, MD, PhD; Sing Lee, MB, BS; Jean-Pierre Lepine, MD; John McGrath, MD, PhD; Maria Elena Medina-Mora, PhD; Zeina Mneimneh, PhD; Jacek Moskalewicz, PhD; Fernando Navarro-Mateu, MD, PhD; Marina Piazza, MPH, ScD; Jose Posada-Villa, MD; Kate M. Scott, PhD; Tim Slade, PhD; Juan Carlos Stagnaro, MD, PhD; Dan J. Stein, FRCPC, PhD; Margreet ten Have, PhD; Yolanda Torres, MPH, Dra.HC; Maria Carmen Viana, MD, PhD; Daniel V. Vigo, MD, DrPH; Harvey Whiteford, MBBS, PhD; David R. Williams, MPH, PhD; and Bogdan Wojtyniak, ScD.” The authors would like to apologise for any inconvenience caused.
  • Identification of susceptibility variants to benign childhood epilepsy with centro-temporal spikes (BECTS) in Chinese Han population

    Background: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease. Methods: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS. Findings: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 × 10

  • Characterisation of δ-Conotoxin TxVIA as a mammalian T-type calcium channel modulator

    The 27-amino acid (aa)-long d-conotoxin TxVIA, originally isolated from the mollusc-hunting cone snail , slows voltage-gated sodium (Na) channel inactivation in molluscan neurons, but its mammalian ion channel targets remain undetermined. In this study, we confirmed that TxVIA was inactive on mammalian Na1.2 and Na1.7 even at high concentrations (10 µM). Given the fact that invertebrate Na channel and T-type calcium channels (Ca3.x) are evolutionarily related, we examined the possibility that TxVIA may act on Ca3.x. Electrophysiological characterisation of the native TxVIA on Ca3.1, 3.2 and 3.3 revealed that TxVIA preferentially inhibits Ca3.2 current (IC = 0.24 mM) and enhances Ca3.1 current at higher concentrations. In fish bioassays TxVIA showed little effect on zebrafish behaviours when injected intramuscular at 250 ng/100 mg fish. The binding sites for TxVIA at Na1.7 and Ca3.1 revealed that their channel binding sites contained a common epitope.
  • Controlling motor neurons of every muscle for fly proboscis reaching

    We describe the anatomy of all the primary motor neurons in the fly proboscis and characterize their contributions to its diverse reaching movements. Pairing this behavior with the wealth of Drosophila’s genetic tools offers the possibility to study motor control at single-neuron resolution, and soon throughout entire circuits. As an entry to these circuits, we provide detailed anatomy of proboscis motor neurons, muscles, and joints. We create a collection of fly strains to individually manipulate every proboscis muscle through control of its motor neurons, the first such collection for an appendage. We generate a model of the action of each proboscis joint, and find that only a small number of motor neurons are needed to produce proboscis reaching. Comprehensive control of each motor element in this numerically simple system paves the way for future study of both reflexive and flexible movements of this appendage.
  • Aberrant connectivity in auditory precision encoding in schizophrenia spectrum disorder and across the continuum of psychotic-like experiences

    Background: The ability to generate a precise internal model of statistical regularities is impaired in schizophrenia. Predictive coding accounts of schizophrenia suggest that psychotic symptoms may be explained by a failure to build precise beliefs or a model of the world. The precision of this model may vary with context. For example, in a noisy environment the model will be more imprecise compared to a model built in an environment with lower noise. However compelling, this idea has not yet been empirically studied in schizophrenia. Methods: In this study, 62 participants engaged in a stochastic mismatch negativity paradigm with high and low precision. We included inpatients with a schizophrenia spectrum disorder (N = 20), inpatients with a psychiatric disorder but without psychosis (N = 20), and healthy controls (N = 22), with comparable sex ratio and age distribution. Bayesian mapping and dynamic causal modelling were employed to investigate the underlying microcircuitry of precision encoding of auditory stimuli. Results: We found strong evidence (exceedance P > 0.99) for differences in the underlying connectivity associated with precision encoding between the three groups as well as on the continuum of psychotic-like experiences assessed across all participants. Critically, we show changes in interhemispheric connectivity between the two inpatient groups, with some connections further aligning on the continuum of psychotic-like experiences. Conclusions: While our results suggest continuity in backward connectivity alterations with psychotic-like experiences regardless of diagnosis, they also point to specificity for the schizophrenia spectrum disorder group in interhemispheric connectivity alterations.
  • The structural connectivity of subthalamic deep brain stimulation correlates with impulsivity in Parkinson’s

    Subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease treats motor symptoms and improves quality of life, but can be complicated by adverse neuropsychiatric side-effects, including impulsivity. Several clinically important questions remain unclear: can 'at-risk' patients be identified prior to DBS; do neuropsychiatric symptoms relate to the distribution of the stimulation field; and which brain networks are responsible for the evolution of these symptoms? Using a comprehensive neuropsychiatric battery and a virtual casino to assess impulsive behaviour in a naturalistic fashion, 55 patients with Parkinson's disease (19 females, mean age 62, mean Hoehn and Yahr stage 2.6) were assessed prior to STN-DBS and 3 months postoperatively. Reward evaluation and response inhibition networks were reconstructed with probabilistic tractography using the participant-specific subthalamic volume of activated tissue as a seed. We found that greater connectivity of the stimulation site with these frontostriatal networks was related to greater postoperative impulsiveness and disinhibition as assessed by the neuropsychiatric instruments. Larger bet sizes in the virtual casino postoperatively were associated with greater connectivity of the stimulation site with right and left orbitofrontal cortex, right ventromedial prefrontal cortex and left ventral striatum. For all assessments, the baseline connectivity of reward evaluation and response inhibition networks prior to STN-DBS was not associated with postoperative impulsivity; rather, these relationships were only observed when the stimulation field was incorporated. This suggests that the site and distribution of stimulation is a more important determinant of postoperative neuropsychiatric outcomes than preoperative brain structure and that stimulation acts to mediate impulsivity through differential recruitment of frontostriatal networks. Notably, a distinction could be made amongst participants with clinically-significant, harmful changes in mood and behaviour attributable to DBS, based upon an analysis of connectivity and its relationship with gambling behaviour. Additional analyses suggested that this distinction may be mediated by the differential involvement of fibres connecting ventromedial subthalamic nucleus and orbitofrontal cortex. These findings identify a mechanistic substrate of neuropsychiatric impairment after STN-DBS and suggest that tractography could be used to predict the incidence of adverse neuropsychiatric effects. Clinically, these results highlight the importance of accurate electrode placement and careful stimulation titration in the prevention of neuropsychiatric side-effects after STN-DBS.
  • What do we know about the variability in survival of patients with amyotrophic lateral sclerosis?

    INTRODUCTION: ALS is a fatal neurodegenerative disease. However, patients show variability in the length of survival after symptom onset. Understanding the mechanisms of long survival could lead to possible avenues for therapy. AREAS COVERED: This review surveys the reported length of survival in ALS, the clinical features that predict survival in individual patients, and possible factors, particularly genetic factors, that could cause short or long survival. The authors also speculate on possible mechanisms. EXPERT OPINION: A small number of known factors can explain some variability in ALS survival. However, other disease-modifying factors likely exist. Factors that alter motor neurone vulnerability and immune, metabolic and muscle function could affect survival by modulating the disease process. Knowing these factors could lead to interventions to change the course of the disease. The authors suggest a broad approach is needed to quantify the proportion of variation survival attributable to genetic and non-genetic factors and to identify and estimate the effect size of specific factors. Studies of this nature could not only identify novel avenues for therapeutic research but also play an important role in clinical trial design and personalized medicine.
  • Calcium-induced calcium release and type 3 ryanodine receptors modulate the slow afterhyperpolarising current, sIAHP, and its potentiation in hippocampal pyramidal neurons

    The slow afterhyperpolarising current, sIAHP, is a Ca2+-dependent current that plays an important role in the late phase of spike frequency adaptation. sIAHP is activated by voltage-gated Ca2+ channels, while the contribution of calcium from ryanodine-sensitive intracellular stores, released by calcium-induced calcium release (CICR), is controversial in hippocampal pyramidal neurons. Three types of ryanodine receptors (RyR1-3) are expressed in the hippocampus, with RyR3 showing a predominant expression in CA1 neurons. We investigated the specific role of CICR, and particularly of its RyR3-mediated component, in the regulation of the sIAHP amplitude and time course, and the activity-dependent potentiation of the sIAHP in rat and mouse CA1 pyramidal neurons. Here we report that enhancement of CICR by caffeine led to an increase in sIAHP amplitude, while inhibition of CICR by ryanodine caused a small, but significant reduction of sIAHP. Inhibition of ryanodine-sensitive Ca2+ stores by ryanodine or depletion by the SERCA pump inhibitor cyclopiazonic acid caused a substantial attenuation in the sIAHP activity-dependent potentiation in both rat and mouse CA1 pyramidal neurons. Neurons from mice lacking RyR3 receptors exhibited a sIAHP with features undistinguishable from wild-type neurons, which was similarly reduced by ryanodine. However, the lack of RyR3 receptors led to a faster and reduced activity-dependent potentiation of sIAHP. We conclude that ryanodine receptor-mediated CICR contributes both to the amplitude of the sIAHP at steady state and its activity-dependent potentiation in rat and mouse hippocampal pyramidal neurons. In particular, we show that RyR3 receptors play an essential and specific role in shaping the activity-dependent potentiation of the sIAHP. The modulation of activity-dependent potentiation of sIAHP by RyR3-mediated CICR contributes to plasticity of intrinsic neuronal excitability and is likely to play a critical role in higher cognitive functions, such as learning and memory.
  • In situ growth of nanoflake and nanoflower-like Ni hydrated hydroxide on the surface of Ni foam as a free-standing electrode for high-performance phosphate detection

    Environmental pollution has always been a global concern, e.g. water eutrophication caused by the high concentrations of phosphorous. It is especially important to detect harmful substances conveniently, quickly and accurately. This study reports a free-standing electrode composed of Ni foam (NF) and in situ grown nanoflakes and nanoflower-like Ni hydrated hydroxide (NHH) on the NF surface (NHH/NF) by a one-step hydrothermal method for phosphate detection. The NHH/NF electrode was directly applied as a binder-free and conductive agent-free working electrode in a three electrode system and showed a wide linear detection range of 10–50,000 μM, high sensitivities of 210 and 87 μA mM cm for the phosphate concentration ranges of 10–14,000 and 14,000–50,000 μM, respectively, and a fast response time of 6 s for phosphate detection in a NaOH solution (pH≈11). The nanostructure of the NHH layer not only provided a large surface area and rapid electron transfer but also protected the NF substrate from being degraded by the electrolyte and interfering species, thereby achieving good stability and selectivity. In addition, for artificial and real wastewater detection, the good recover ability presented here improves the prospects of developing a cost-effective, simple, and accurate sensor for phosphate detection.
  • Mutations in heat shock protein beta-1 (HSPB1) are associated with a range of clinical phenotypes related to different patterns of motor neuron dysfunction: a case series

    Background: Heat shock protein beta-1 (HSPB1) is a ubiquitously expressed molecular chaperone that is important in protecting cells against cellular injury. Mutations in this protein are known to cause autosomal dominant hereditary distal axonal neuropathies, including Charcot Marie Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). However, patients with HSPB1 mutations have also been described with upper motor neuron signs. We present five patients with mutations in HSPB1 who presented with a range of clinical phenotypes related to different patterns of motor neuron dysfunction. Three of these mutations have not been previously reported. Methods: Patients were seen at our neuromuscular or amyotrophic lateral sclerosis (ALS) clinics. Gene sequencing was carried out as part of diagnostic investigations. Detailed clinical and electrophysiologic data was collected. Results: Five patients had variants of HSPB1. Three patients had a hereditary length-dependent sensori-motor axonal neuropathy consistent with Charcot Marie Tooth type 2 (CMT2); two of these patients carried novel mutations in the C-terminal region (p.Glu186* and p.Pro170Thr). One patient had the clinical picture of ALS and a novel missense mutation (p.Arg27Leu) in the N-terminal region. Another patient had the phenotype of hereditary spastic paraparesis (HSP) associated with a missense mutation (p.Gly84Arg) already described in families with CMT or dHMN. Conclusion: This study describes three novel mutations of HSPB1 and describes two patients with upper motor neurone signs associated with HSPB1 mutations.
  • Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity

  • The exceptional diversity of visual adaptations in deep-sea teleost fishes

    The deep-sea is the largest and one of the dimmest habitats on earth. In this extreme environment, every photon counts and may make the difference between life and death for its inhabitants. Two sources of light are present in the deep-sea; downwelling light, that becomes dimmer and spectrally narrower with increasing depth until completely disappearing at around 1000 m, and bioluminescence, the light emitted by animals themselves. Despite these relatively dark and inhospitable conditions, many teleost fish have made the deep-sea their home, relying heavily on vision to survive. Their visual systems have had to adapt, sometimes in astonishing and bizarre ways. This review examines some aspects of the visual system of deep-sea teleosts and highlights the exceptional diversity in both optical and retinal specialisations. We also reveal how widespread several of these adaptations are across the deep-sea teleost phylogeny. Finally, the significance of some recent findings as well as the surprising diversity in visual adaptations is discussed.
  • An epilepsy-associated SV2A mutation disrupts Synaptotagmin-1 expression and activity-dependent trafficking

    The epilepsy-linked gene , has a number of potential roles in the synaptic vesicle (SV) life cycle. However, how loss of SV2A function translates into presynaptic dysfunction and ultimately seizure activity is still undetermined. In this study, we examined whether the first SV2A mutation identified in human disease (R383Q) could provide information regarding which SV2A-dependent events are critical in the translation to epilepsy. We utilized a molecular replacement strategy in which exogenous SV2A was expressed in mouse neuronal cultures of either sex, which had been depleted of endogenous SV2A to mimic the homozygous human condition. We found that the R383Q mutation resulted in a mislocalization of SV2A from SVs to the plasma membrane, but had no effect on its activity-dependent trafficking. This SV2A mutant displayed reduced mobility when stranded on the plasma membrane and reduced binding to its interaction partner synaptotagmin-1 (Syt1). Furthermore, the R383Q mutant failed to rescue reduced expression and dysfunctional activity-dependent trafficking of Syt1 in the absence of endogenous SV2A. This suggests that the inability to control Syt1 expression and trafficking at the presynapse may be key in the transition from loss of SV2A function to seizure activity. SV2A is a synaptic vesicle (SV) protein, the absence or dysfunction of which is linked to epilepsy. However, the series of molecular events that result in this neurological disorder is still undetermined. We demonstrate here that the first human mutation in SV2A identified in an individual with epilepsy displays reduced binding to synaptotagmin-1 (Syt1), an SV protein essential for synchronous neurotransmitter release. Furthermore, this mutant cannot correct alterations in both Syt1 expression and trafficking when expressed in the absence of endogenous SV2A (to mimic the homozygous human condition). This suggests that the inability to control Syt1 expression and trafficking may be key in the transition from loss of SV2A function to seizure activity.
  • Subcortical dopamine and cognition in schizophrenia: looking beyond psychosis in preclinical models

    Schizophrenia is characterized by positive, negative and cognitive symptoms. All current antipsychotic treatments feature dopamine-receptor antagonism that is relatively effective at addressing the psychotic (positive) symptoms of schizophrenia. However, there is no clear evidence that these medications improve the negative or cognitive symptoms, which are the greatest predictors of functional outcomes. One of the most robust pathophysiological observations in patients with schizophrenia is increased subcortical dopamine neurotransmission, primarily in the associative striatum. This brain area has an important role in a range of cognitive processes. Dopamine is also known to play a major part in regulating a number of cognitive functions impaired in schizophrenia but much of this research has been focused on cortical dopamine. Emerging research highlights the strong influence subcortical dopamine has on a range of cognitive domains, including attention, reward learning, goal-directed action and decision-making. Nonetheless, the precise role of the associative striatum in the cognitive impairments observed in schizophrenia remains poorly understood, presenting an opportunity to revisit its contribution to schizophrenia. Without a better understanding of the mechanisms underlying cognitive dysfunction, treatment development remains at a standstill. For this reason, improved preclinical animal models are needed if we are to understand the complex relationship between subcortical dopamine and cognition. A range of new techniques are facillitating the discrete manipulation of dopaminergic neurotransmission and measurements of cognitive performance, which can be investigated using a variety of sensitive translatable tasks. This has the potential to aid the successful incorporation of recent clinical research to address the lack of treatment strategies for cognitive symptoms in schizophrenia. This review will give an overview on the current state of research focused on subcortical dopamine and cognition in the context of schizophrenia research. We also discuss future strategies and approaches aimed at improving the translational outcomes for the treatment of cognitive deficits in schizophrenia.
  • Impact of CYP2C19 genotype-predicted enzyme activity on hippocampal volume, anxiety, and depression

    Cytochrome P450 C19 (CYP2C19) metabolizes exogenous and endogenous compounds. Although CYP2C19 is highly expressed in the liver, it is also expressed in the brain during early life. Previous human and animal studies have linked CYP2C19 genotype-predicted enzyme activity to hippocampal volumes, depressive symptoms, and anxiety-like behaviors. We examined these promising associations in a general community sample comprising 386 Caucasian adults with no history of psychiatric or neurological illnesses. Contrary to previous findings, CYP2C19 genotype-predicted enzyme activity was not associated with hippocampal volumes, nor depressive and anxiety symptoms. Interstudy differences in CYP2C19 frequencies and/or study methodology may explain this discrepancy.
  • Risk in relatives, heritability, SNP-based heritability and genetic correlations in psychiatric disorders: a review

    The genetic contribution to psychiatric disorders is observed through the increased rates of disorders in the relatives of those affected. These increased rates are observed to be non-specific, for example children of those with schizophrenia have increased rates of schizophrenia, but also a broad range of other psychiatric diagnoses. While many factors contribute to risk, epidemiological evidence suggest that the genetic contribution carries the highest risk burden. The patterns of inheritance are consistent with a polygenic architecture of many contributing risk loci. The genetic studies of the last decade have provided empirical evidence identifying thousands of DNA variants associated with psychiatric disorders. Here, we describe how these latest results are consistent with observations from epidemiology. We provide an R tool (CHARRGe) to calculate genetic parameters from epidemiological parameters and vice versa. We discuss how the SNP-based estimates of heritability and genetic correlation relate to those estimated from family records.
  • Association of specific mental disorders with premature mortality in the Danish population using alternative measurement methods

    Importance: The association of mental disorders with premature mortality published in the Global Burden of Disease (GBD) studies has been underestimated because these analyses have recommended using only a small number of mental disorders as causes of death to estimate years of life lost (YLL). Alternative methods have been introduced, such as estimating life-years lost (LYL), to compare individuals with mental disorders with the general population. Objectives: To generate register-based YLL and LYL estimates and to use these measurement methods to assess the association of specific mental disorders with premature mortality. Design, Setting, and Participants: This population-based cohort study included all persons with and without mental disorders aged 0 to 94 years who were living in Denmark between January 1, 2000, and December 31, 2015. Data were analyzed from January to December 2019. Main Outcomes and Measures: Danish health registers were used to identify mental disorder diagnoses, dates of death, and causes of death. The YLLs were estimated for the set of mental health-associated causes of death, and all-cause and cause-specific LYLs were estimated for 18 specific mental disorders and 3 broad categories of mental disorders that were recommended for use in the GBD studies. The association between the number of comorbid mental disorders (divided into categories of persons with ≥1 type of disorder, ≥2 types of disorders, ≥3 types of disorders, and ≥4 types of disorders) and LYL estimates was also examined. Results: A total of 6 989 627 individuals (3 481 219 male persons [49.8%] and 3 508 408 female persons [50.2%]; mean [SD] age at study enrollment, 32.2 [24.4] years) were followed up for a total of 85 911 461 person-years. The YLL rates per 100 000 person-years were highest for alcohol use disorder (for male individuals, 568.7 [95% CI, 564.4-572.7]; for female individuals, 155.5 [95% CI, 153.5-157.9]) and suicide (for male individuals, 590.1 [95% CI, 583.8-596.5]; for female individuals, 202.3 [95% CI, 198.5-206.4]). Although only 3 of 18 mental and substance use disorders could be associated with YLL, all mental disorders were associated with shorter life expectancies when LYL was used for measurement. Male and female individuals diagnosed with any mental disorder had life expectancies that were shorter by 11.2 years (95% CI, 11.1-11.3 years) and 7.9 years (95% CI, 7.8-8.0 years), respectively, and remaining life expectancy decreased further among those with comorbid mental disorders. Drug use disorders were associated with the highest excess LYL estimates; however, common mental disorders, such as depressive and anxiety disorders, were also associated with substantial premature mortality. Conclusions and Relevance: Mental disorders were observed to be associated with reductions in life expectancy. This finding provides a foundation for future intervention programs designed to reduce the differential mortality gap associated with mental disorders. Register-based studies allow the calculation of precise individual-level YLLs and LYLs, and both measurement methods are informative for health care planning. Compared with YLL, the novel LYL measurement approach may more precisely capture the association of mental disorders with premature mortality and facilitates the exploration of comorbidity and specific causes of death in individuals with mental disorders.
  • HDAC inhibitors reverse mania-like behavior and modulate epigenetic regulatory enzymes in an animal model of mania induced by Ouabain

    Background: The etiology of bipolar disorder (BD) is multifactorial, involving both environmental and genetic factors. Current pharmacological treatment is associated with several side effects, which are the main reason patients discontinue treatment. Epigenetic alterations have been studied for their role in the pathophysiology of BD, as they bridge the gap between gene and environment. Objective: Evaluate the effects of histone deacetylase inhibitors on behavior and epigenetic enzymes activity in a rat model of mania induced by ouabain. Methods: Adult male rats were subjected to a single intracerebroventricular injection of ouabain (10 M) followed by 7 days of valproate (200 mg/kg) or sodium butyrate (600 mg/kg) administration. Locomotor and exploratory activities were evaluated in the open-field test. Histone deacetylase, DNA methyltransferase, and histone acetyltransferase activity were assessed in the frontal cortex, hippocampus, and striatum. Results: Ouabain induced hyperactivity in rats, which was reversed by valproate and sodium butyrate treatment. Ouabain did not alter the activity of any of the enzymes evaluated. However, valproate and sodium butyrate decreased the activity of histone deacetylase and DNA methyltransferase. Moreover, there was a positive correlation between these two enzymes. Conclusion: These results suggest that targeting epigenetic mechanisms may play an important role in mania-like behavior management.
  • Global and regional development of the human cerebral cortex: molecular architecture and occupational aptitudes

    We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.
  • Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction

    DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.
  • ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing

    A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.
  • Cohort profile: the Australian genetics of depression study

    Depression is the most common psychiatric disorder and the largest contributor to global disability. The Australian Genetics of Depression study was established to recruit a large cohort of individuals who have been diagnosed with depression at some point in their lifetime. The purpose of establishing this cohort is to investigate genetic and environmental risk factors for depression and response to commonly prescribed antidepressants.

    A total of 20 689 participants were recruited through the Australian Department of Human Services and a media campaign, 75% of whom were female. The average age of participants was 43 years±15 years. Participants completed an online questionnaire that consisted of a compulsory module that assessed self-reported psychiatric history, clinical depression using the Composite Interview Diagnostic Interview Short Form and experiences of using commonly prescribed antidepressants. Further voluntary modules assessed a wide range of traits of relevance to psychopathology. Participants who reported they were willing to provide a DNA sample (75%) were sent a saliva kit in the mail.

    95% of participants reported being given a diagnosis of depression by a medical practitioner and 88% met the criteria for a lifetime depressive episode. 68% of the sample report having been diagnosed with another psychiatric disorder in addition to depression. In line with findings from clinical trials, only 33% of the sample report responding well to the first antidepressant they were prescribed.

    A number of analyses to investigate the genetic architecture of depression and common comorbidities will be conducted. The cohort will contribute to the global effort to identify genetic variants that increase risk to depression. Furthermore, a thorough investigation of genetic and psychosocial predictors of antidepressant response and side effects is planned.
  • Genetic stratification of depression in UK Biobank

    Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations were used to test for evidence of subgroups using genetic data from seven other complex traits and disorders that were genetically correlated with depression and had sufficient power (>0.6) for detection. We found no evidence for subgroups within depression for schizophrenia, bipolar disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, anorexia nervosa, inflammatory bowel disease or obesity. This suggests that for these traits, genetic correlations with depression were driven by pleiotropic genetic variants carried by everyone rather than by a specific subgroup.
  • Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1G93A Mice Predates Disease Onset and Is A Promising Therapeutic Target

    Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1 mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1 mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1 mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.
  • Morphological malleability of the lateral line allows for surface fish (Astyanax mexicanus) adaptation to cave environments

    The lateral line is the primary modality fish use to create a hydrodynamic image of their environment. These images contribute to a variety of behaviors, from rheotaxis to escape responses. Here we discern the contributions of visual and lateral line modalities in hunting behavior of larvae that have developed under different photic conditions. In particular, cave animals have a hypertrophied sense of mechanosensation, and we studied the common animal model cavefish Astyanax mexicanus and its closest related surface relative. We raised larvae in a diurnal light-dark regimen and in complete darkness. We then examined the distribution of neuromasts in their lateral lines, and their hunting performance in light and dark conditions, with and without the contribution of the lateral line. We report that all larva depend on the lateral line for success in hunting and that surface fish raised in the dark have a greater dependency on the lateral line.
  • Brain-wide mapping of water flow perception in zebrafish

    Information about water flow, detected by lateral line organs, is critical to the behavior and survival of fish and amphibians. While certain aspects of water flow processing have been revealed through electrophysiology, we lack a comprehensive description of the neurons that respond to water flow and the network that they form. Here, we use brain-wide calcium imaging in combination with microfluidic stimulation to map out, at cellular resolution, neuronal responses involved in perceiving and processing water flow information in larval zebrafish. We find a diverse array of neurons responding to head to tail (h-t) flow, tail to head (t-h) flow, or both. Early in this pathway, in the lateral line ganglia, neurons respond almost exclusively to the simple presence of h-t or t-h flow, but later processing includes neurons responding specifically to flow onset, representing the accumulated displacement of flow during a stimulus, or encoding the speed of the flow. The neurons reporting on these more nuanced details are located across numerous brain regions, including some not previously implicated in water flow processing. A graph theory-based analysis of the brain-wide water flow network shows that a majority of this processing is dedicated to h-t flow detection, and this is reinforced by our finding that details like flow velocity and the total accumulated flow are only encoded for the h-t direction. The results represent the first brain-wide description of processing for this important modality, and provide a departure point for more detailed studies of the flow of information through this network.In aquatic animals, the lateral line is important for detecting water flow stimuli, but the brain networks that interpret this information remain mysterious. Here, we have imaged the activity of individual neurons across the entire brains of larval zebrafish, revealing all response types and their brain locations as water flow processing occurs. We find neurons that respond to the presence of water flow, and others attuned to the flow's direction, speed, duration, or the accumulated displacement of water that has passed during the stimulus. With this information, we modeled the underlying network, describing a system that is nuanced in its processing of water flow simulating head to tail motion but rudimentary in processing flow in the tail to head direction.
  • Lens eyes in protists

    Eyes are not unique to animals. As described by Nilsson and Marshall, prominent eyes, complete with retina and lens, have unexpectedly evolved in single cell dinoflagellates.
  • Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group

    Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18–75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen’s d = 0.14, 95% CI: 0.08–0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.
  • Educational attainment polygenic scores are associated with cortical total surface area and regions important for language and memory

    It is well established that higher cognitive ability is associated with larger brain size. However, individual variation in intelligence exists despite brain size and recent studies have shown that a simple unifactorial view of the neurobiology underpinning cognitive ability is probably unrealistic. Educational attainment (EA) is often used as a proxy for cognitive ability since it is easily measured, resulting in large sample sizes and, consequently, sufficient statistical power to detect small associations. This study investigates the association between three global (total surface area (TSA), intra-cranial volume (ICV) and average cortical thickness) and 34 regional cortical measures with educational attainment using a polygenic scoring (PGS) approach. Analyses were conducted on two independent target samples of young twin adults with neuroimaging data, from Australia (N ​= ​1097) and the USA (N ​= ​723), and found that higher EA-PGS were significantly associated with larger global brain size measures, ICV and TSA (R ​= ​0.006 and 0.016 respectively, p ​< ​0.001) but not average thickness. At the regional level, we identified seven cortical regions—in the frontal and temporal lobes—that showed variation in surface area and average cortical thickness over-and-above the global effect. These regions have been robustly implicated in language, memory, visual recognition and cognitive processing. Additionally, we demonstrate that these identified brain regions partly mediate the association between EA-PGS and cognitive test performance. Altogether, these findings advance our understanding of the neurobiology that underpins educational attainment and cognitive ability, providing focus points for future research.
  • A pilot trial of cognitive behavioral therapy for caregivers after deep brain stimulation for Parkinson's Disease

    Subthalamic deep brain stimulation for Parkinson's disease may not ameliorate burden among caregivers. An 8-session, manualized program of cognitive-behavioral therapy (CBT) was delivered to a pilot sample of 10 caregivers (6 females, mean age: 60, age range: 34-79). Primary outcome measures were caregiver burden (Zarit Burden Interview) and caregiver quality of life (Parkinson's Disease Questionnaire-Carer). Secondary outcome measures comprised ratings of depression and anxiety in the caregiver, in addition to relationship quality. Caregiver burden ( = 2.91 = .017) and caregiver anxiety ( = 2.82 = .020) symptoms were significantly reduced at completion of the program, and these benefits were maintained 3 months later. Caregiver quality of life had significantly improved by the end of the intervention ( = 3.02 = .015), but this effect was not sustained after 3 months. The longitudinal influence of participation in the program on caregiver burden was confirmed in a linear, mixed-effects model, χ (3) = 15.1, = .0017). The intervention was well received by participants, and qualitative feedback was obtained. These results indicate that caregiver burden is modifiable in this cohort with a short course of CBT, that benefits are maintained after termination of the program, and that psychological treatment is acceptable to participants. Larger, controlled trials are justified.
  • Altered brain endothelial cell phenotype from a familial alzheimer mutation and its potential implications for amyloid clearance and drug delivery

    The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3-5 kDa dextran as a model cargo and the amyloid-β (Aβ) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery.
  • Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders

    Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium-schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genome-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. We show that decreased expression of VPS29 in the brain may increase risk to SCZ only and increased expression of CSE1L is associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7 in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.
  • Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

    De novo germline mutations in the RNA helicase DDX3X account for 1%–3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.Using human and mouse genetics, Lennox et al. identify 107 mutations in DDX3X, demonstrating DDX3X is essential for cortical development. A striking correlation between the severity of clinical mutations and abnormal RNA metabolism highlights unappreciated mechanisms of DDX3X syndrome.
  • Platelets in Neurodegenerative Conditions—Friend or Foe?

    It is now apparent that platelet function is more diverse than originally thought, shifting the view of platelets from blood cells involved in hemostasis and wound healing to major contributors to numerous regulatory processes across different tissues. Given their intriguing ability to store, produce and release distinct subsets of bioactive molecules, including intercellular signaling molecules and neurotransmitters, platelets may play an important role in orchestrating healthy brain function. Conversely, a number of neurodegenerative conditions have recently been associated with platelet dysfunction, further highlighting the tissue-independent role of these cells. In this review we summarize the requirements for platelet-neural cell communication with a focus on neurodegenerative diseases, and discuss the therapeutic potential of healthy platelets and the proteins which they release to counteract these conditions.
  • Grab‐AD : generalizability and reproducibility of altered brain activity and diagnostic classification in Alzheimer's Disease

    Alzheimer's disease (AD) is associated with disruptions in brain activity and networks. However, there is substantial inconsistency among studies that have investigated functional brain alterations in AD; such contradictions have hindered efforts to elucidate the core disease mechanisms. In this study, we aim to comprehensively characterize AD-associated functional brain alterations using one of the world's largest resting-state functional MRI (fMRI) biobank for the disorder. The biobank includes fMRI data from six neuroimaging centers, with a total of 252 AD patients, 221 mild cognitive impairment (MCI) patients and 215 healthy comparison individuals. Meta-analytic techniques were used to unveil reliable differences in brain function among the three groups. Relative to the healthy comparison group, AD was associated with significantly reduced functional connectivity and local activity in the default-mode network, basal ganglia and cingulate gyrus, along with increased connectivity or local activity in the prefrontal lobe and hippocampus (p < .05, Bonferroni corrected). Moreover, these functional alterations were significantly correlated with the degree of cognitive impairment (AD and MCI groups) and amyloid-β burden. Machine learning models were trained to recognize key fMRI features to predict individual diagnostic status and clinical score. Leave-one-site-out cross-validation established that diagnostic status (mean area under the receiver operating characteristic curve: 0.85) and clinical score (mean correlation coefficient between predicted and actual Mini-Mental State Examination scores: 0.56, p < .0001) could be predicted with high accuracy. Collectively, our findings highlight the potential for a reproducible and generalizable functional brain imaging biomarker to aid the early diagnosis of AD and track its progression.