Recent QBI publications

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • The epidemiology of drug use disorders cross-nationally: findings from the WHO's World Mental Health Surveys

    Background: Illicit drug use and associated disease burden are estimated to have increased over the past few decades, but large gaps remain in our knowledge of the extent of use of these drugs, and especially the extent of problem or dependent use, hampering confident cross-national comparisons. The World Mental Health (WMH) Surveys Initiative involves a standardised method for assessing mental and substance use disorders via structured diagnostic interviews in representative community samples of adults. We conducted cross-national comparisons of the prevalence and correlates of drug use disorders (DUDs) in countries of varied economic, social and cultural nature. Methods and findings: DSM-IV DUDs were assessed in 27 WMH surveys in 25 countries. Across surveys, the prevalence of lifetime DUD was 3.5%, 0.7% in the past year. Lifetime DUD prevalence increased with country income: 0.9% in low/lower-middle income countries, 2.5% in upper-middle income countries, 4.8% in high-income countries. Significant differences in 12-month prevalence of DUDs were found across country in income groups in the entire cohort, but not when limited to users. DUDs were more common among men than women and younger than older respondents. Among those with a DUD and at least one other mental disorder, onset of the DUD was usually preceded by the ‘other’ mental disorder. Conclusions: Substantial cross-national differences in DUD prevalence were found, reflecting myriad social, environmental, legal and other influences. Nonetheless, patterns of course and correlates of DUDs were strikingly consistent. These findings provide foundational data on country-level comparisons of DUDs.
  • A hyperactive form of unc-13 enhances Ca2+ sensitivity and synaptic vesicle release probability in C. elegans

    Munc13 proteins play several roles in regulating short-term synaptic plasticity. However, the underlying molecular mechanisms remain largely unclear. Here we report that C. elegans UNC-13L, a Munc13-1 ortholog, has three domains that inhibit synaptic vesicle (SV) exocytosis. These include the X (sequence between C2A and C1), C1, and C2B domains. Deleting all three inhibitory domains produces a hyperactive UNC-13 (sUNC-13) that exhibits dramatically increased neurotransmitter release, Ca sensitivity of release, and release probability. The vesicular pool in unc-13 mutants rescued by sUNC-13 exhibits a faster synaptic recovery and replenishment rate, demonstrating an important role of sUNC-13 in regulating synaptic plasticity. Analysis of double mutants suggests that sUNC-13 enhances tonic release by increasing the open probability of UNC-64/syntaxin-1A, whereas its effects on evoked release appear to be mediated by additional functions, presumably by further regulating the activity of the assembled soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) complex.
  • Syntaxin1A neomorphic mutations promote rapid recovery from isoflurane anesthesia in Drosophila melanogaster

    WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Syntaxin1A is a presynaptic molecule that plays a key role in vesicular neurotransmitter releaseMutations of syntaxin1A result in resistance to both volatile and intravenous anestheticsTruncated syntaxin1A isoforms confer drug resistance in cell culture and nematode models of anesthesia WHAT THIS ARTICLE TELLS US THAT IS NEW: Resistance to isoflurane anesthesia can be produced by transiently expressing truncated syntaxin1A proteins in adult Drosophila fliesElectrophysiologic and behavioral studies in Drosophila show that mutations in syntaxin1A facilitate recovery from isoflurane anesthesiaThese observations suggest that presynaptic mechanisms, via syntaxin1A-mediated regulation of neurotransmitter release, are involved in general anesthesia maintenance and recovery BACKGROUND:: Mutations in the presynaptic protein syntaxin1A modulate general anesthetic effects in vitro and in vivo. Coexpression of a truncated syntaxin1A protein confers resistance to volatile and intravenous anesthetics, suggesting a target mechanism distinct from postsynaptic inhibitory receptor processes. Hypothesizing that recovery from anesthesia may involve a presynaptic component, the authors tested whether syntaxin1A mutations facilitated recovery from isoflurane anesthesia in Drosophila melanogaster. METHODS: A truncated syntaxin1A construct was expressed in Drosophila neurons. The authors compared effects on isoflurane induction versus recovery in syntaxin1A mutant animals by probing behavioral responses to mechanical stimuli. The authors also measured synaptic responses from the larval neuromuscular junction using sharp intracellular recordings, and performed Western blots to determine whether the truncated syntaxin1A is associated with presynaptic core complexes. RESULTS: Drosophila expressing a truncated syntaxin1A (syx, n = 40) were resistant to isoflurane induction for a behavioral responsiveness endpoint (ED50 0.30 ± 0.01% isoflurane, P < 0.001) compared with control (0.240 ± 0.002% isoflurane, n = 40). Recovery from isoflurane anesthesia was also faster, with syx-expressing flies showing greater levels of responsiveness earlier in recovery (reaction proportion 0.66 ± 0.48, P < 0.001, n = 68) than controls (0.22 ± 0.42, n = 68 and 0.33 ± 0.48, n = 66). Measuring excitatory junction potentials of larvae coexpressing the truncated syntaxin1A protein showed a greater recovery of synaptic function, compared with controls (17.39 ± 3.19 mV and 10.29 ± 4.88 mV, P = 0.014, n = 8 for both). The resistance-promoting truncated syntaxin1A was not associated with presynaptic core complexes, in the presence or absence of isoflurane anesthesia. CONCLUSIONS: The same neomorphic syntaxin1A mutation that confers isoflurane resistance in cell culture and nematodes also produces isoflurane resistance in Drosophila. Resistance in Drosophila is, however, most evident at the level of recovery from anesthesia, suggesting that the syntaxin1A target affects anesthesia maintenance and recovery processes rather than induction. The absence of truncated syntaxin1A from the presynaptic complex suggests that the resistance-promoting effect of this molecule occurs before core complex formation.
  • Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior

    Twin studies and other analyses of inheritance of sexual orientation in humans has indicated that same-sex sexual behavior has a genetic component. Previous searches for the specific genes involved have been underpowered and thus unable to detect genetic signals. Ganna et al. perform a genome-wide association study on 493,001 participants from the United States, the United Kingdom, and Sweden to study genes associated with sexual orientation (see the Perspective by Mills). They find multiple loci implicated in same-sex sexual behavior indicating that, like other behavioral traits, nonheterosexual behavior is polygenic.
  • Stria terminalis, amygdala, and temporoparietal junction networks facilitate efficient emotion processing under expectations

    Rapid emotion processing is an ecologically essential ability for survival in social environments in which threatening or advantageous encounters dynamically and rapidly occur. Efficient emotion recognition is subserved by different processes, depending on one's expectations; however, the underlying functional and structural circuitry is still poorly understood. In this study, we delineate brain networks that subserve fast recognition of emotion in situations either congruent or incongruent with prior expectations. For this purpose, we used multimodal neuroimaging and investigated performance on a dynamic emotion perception task. We show that the extended amygdala structural and functional networks relate to speed of emotion processing under threatening conditions. Specifically, increased microstructure of the right stria terminalis, an amygdala white-matter pathway, was related to faster detection of emotion during actual presentation of anger or after cueing anger. Moreover, functional connectivity of right amygdala with limbic regions was related to faster detection of anger congruent with cue, suggesting selective attention to threat. On the contrary, we found that faster detection of anger incongruent with cue engaged the ventral attention "reorienting" network. Faster detection of happiness, in either expectancy context, engaged a widespread frontotemporal-subcortical functional network. These findings shed light on the functional and structural circuitries that facilitate speed of emotion recognition and, for the first time, elucidate a role for the stria terminalis in human emotion processing.
  • Physical activity of people with mental disorders compared to the general population: a systematic review of longitudinal cohort studies

    We investigated if (a) people with lower physical activity have an increased risk of subsequent mental disorders (compared to those with higher physical activity); and (b) people with mental disorders have reduced subsequent physical activity (compared to those without mental disorders).

    A systematic review of population-based longitudinal studies examining physical activity and mental disorders was conducted. Mental disorders were defined by International Classification of Diseases or Diagnostic and Statistical Manual of Mental Disorders. The results were described in a narrative summary.

    Twenty-two studies were included. The majority (19) examined mood disorders and physical activity. Only two studies found consistent association between lower physical activity and a reduced risk of subsequent mental disorders. One study found the bidirectional association between physical activity and major depression. Twelve studies found mixed results (i.e., no consistency in direction and significance of the findings), and seven studies found no association between the variables of interest.

    There is a lack of consistent evidence linking physical activity to be either a risk factor or consequence of mental disorders.

  • Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing

    Background DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed 'epigenetic clocks'. The deviation of predicted age from the actual age ('age acceleration residual', AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association. Methods In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues. Results We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, ) exhibits no association with mortality in both LBC1921 (hazard ratio = 1.08, 95% CI 0.91-1.27) and LBC1936 (hazard ratio = 1.00, 95% CI 0.79-1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor. Conclusions This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.
  • Rapid recalibration of temporal order judgements: response bias accounts for contradictory results

    Recent history influences subsequent perception, decision-making and motor behaviours. In this article, we address a discrepancy in the effects of recent sensory history on the perceived timing of auditory and visual stimuli. In the synchrony judgement (SJ) task, similar timing relationships in consecutive trials seem more synchronous (i.e. less like the repeated temporal order). This effect is known as rapid recalibration and is consistent with a negative perceptual aftereffect. Interestingly, the opposite is found in the temporal order judgement (TOJ) task (positive rapid recalibration). We aimed to determine whether a simple bias to repeat judgements on consecutive trials (choice-repetition bias) could account for the discrepant results in these tasks. Preliminary simulations and analyses indicated that a choice-repetition bias could produce apparently positive rapid recalibration in the TOJ and not the SJ task. Our first experiment revealed no evidence of rapid recalibration of TOJs, but negative rapid recalibration of associated confidence. This suggests that timing perception was rapidly recalibrated, but that the negative recalibration effect was obfuscated by a positive bias effect. In our second experiment, we experimentally mitigated the choice-repetition bias effect and found negative rapid recalibration of TOJs. We therefore conclude that timing perception is negatively rapidly recalibrated, and this is observed consistently across timing tasks. These results contribute to a growing body of evidence that indicates multisensory perception is constantly undergoing recalibration, such that perceptual synchrony is maintained. This work also demonstrates that participants' task responses reflect judgements that are contaminated by independent biases of perception and decision-making.
  • Absolute and relative estimates of genetic and environmental variance in brain structure volumes

    Comparing estimates of the amount of genetic and environmental variance for different brain structures may elucidate differences in the genetic architecture or developmental constraints of individual brain structures. However, most studies compare estimates of relative genetic (heritability) and environmental variance in brain structure, which do not reflect differences in absolute variance between brain regions. Here we used a population sample of young adult twins and singleton siblings of twins (n = 791; M = 23 years, Queensland Twin IMaging study) to estimate the absolute genetic and environmental variance, standardised by the phenotypic mean, in the size of cortical, subcortical, and ventricular brain structures. Mean-standardised genetic variance differed widely across structures [23.5-fold range 0.52% (hippocampus) to 12.28% (lateral ventricles)], but the range of estimates within cortical, subcortical, or ventricular structures was more moderate (two to fivefold range). There was no association between mean-standardised and relative measures of genetic variance (i.e., heritability) in brain structure volumes. We found similar results in an independent sample (n = 1075, M = 29 years, Human Connectome Project). These findings open important new lines of enquiry: namely, understanding the bases of these variance patterns, and their implications regarding the genetic architecture, evolution, and development of the human brain.
  • Comparing Current Steering Technologies for Directional Deep Brain Stimulation Using a Computational Model That Incorporates Heterogeneous Tissue Properties

    Objective A computational model that accounts for heterogeneous tissue properties was used to compare multiple independent current control (MICC), multi-stim set (MSS), and concurrent activation (co-activation) current steering technologies utilized in deep brain stimulation (DBS) on volume of tissue activated (VTA) and power consumption. Methods A computational model was implemented in Sim4Life v4.0 with the multimodal image-based detailed anatomical (MIDA) model, which accounts for heterogeneous tissue properties. A segmented DBS lead placed in the subthalamic nucleus (STN). Three milliamperes of current (with a 90 mu s pseudo-biphasic waveform) was distributed between two electrodes with various current splits. The laterality, directional accuracy, volume, and shape of the VTAs using MICC, MSS and co-activation, and their power consumption were computed and compared. Results MICC, MSS, and coactivation resulted in less laterality of steering than single-segment activation. Both MICC and MSS show directional inaccuracy (more pronounced with MSS) during radial current steering. Co-activation showed greater directional accuracy than MICC and MSS at centerline between the two activated electrodes. MSS VTA volume was smaller and more compact with less current spread outside the active electrode plane than MICC VTA. There was no consistent pattern of power drain between MSS and MICC, but electrode co-activation always used less power than either fractionating paradigm. Conclusion While current fractionalization technologies can achieve current steering between two segmented electrodes, this study shows that there are important limitations in accuracy and focus of tissue activation when tissue heterogeneity is accounted for.
  • The systemic exercise-released chemokine lymphotactin/XCL1 modulates in vitro adult hippocampal precursor cell proliferation and neuronal differentiation

    Physical exercise has well-established anti-inflammatory effects, with neuro-immunological crosstalk being proposed as a mechanism underlying the beneficial effects of exercise on brain health. Here, we used physical exercise, a strong positive modulator of adult hippocampal neurogenesis, as a model to identify immune molecules that are secreted into the blood stream, which could potentially mediate this process. Proteomic profiling of mouse plasma showed that levels of the chemokine lymphotactin (XCL1) were elevated after four days of running. We found that XCL1 treatment of primary cells isolated from both the dentate gyrus and the subventricular zone of the adult mice led to an increase in the number of neurospheres and neuronal differentiation in neurospheres derived from the dentate gyrus. In contrast, primary dentate gyrus cells isolated from XCL1 knockout mice formed fewer neurospheres and exhibited a reduced neuronal differentiation potential. XCL1 supplementation in a dentate gyrus-derived neural precursor cell line promoted neuronal differentiation and resulted in lower cell motility and a reduced number of cells in the S phase of the cell cycle. This work suggests an additional function of the chemokine XCL1 in the brain and underpins the complexity of neuro-immune interactions that contribute to the regulation of adult hippocampal neurogenesis.
  • Genotype-by-environment interactions inferred from genetic effects on phenotypic variability in the UK Biobank

    Genotype-by-environment interaction (GEI) is a fundamental component in understanding complex trait variation. However, it remains challenging to identify genetic variants with GEI effects in humans largely because of the small effect sizes and the difficulty of monitoring environmental fluctuations. Here, we demonstrate that GEI can be inferred from genetic variants associated with phenotypic variability in a large sample without the need of measuring environmental factors. We performed a genome-wide variance quantitative trait locus (vQTL) analysis of ~5.6 million variants on 348,501 unrelated individuals of European ancestry for 13 quantitative traits in the UK Biobank and identified 75 significant vQTLs with P < 2.0 × 10 for 9 traits, especially for those related to obesity. Direct GEI analysis with five environmental factors showed that the vQTLs were strongly enriched with GEI effects. Our results indicate pervasive GEI effects for obesity-related traits and demonstrate the detection of GEI without environmental data.
  • The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis

    Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B(TrkB). In addition, BDNF/TrkB neuroprotective functions can also be elicited indirectly via activation of adenosine 2A receptors (A(2a)Rs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A(2a)Rs, can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although enhancing BDNF has been a major goal for protection of dying motor neurons (MNs), this has not been successful. Indeed, there is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. For example, in ALS, early synaptic hyper-excitability of MNs is thought to enhance BDNF-mediated signaling, thereby causing glutamate excitotoxicity, and ultimately MN death. Moreover, direct inhibition of TrkB and A(2a)Rs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A(2a)Rs receptors may be important in early disease pathogenesis in ALS. This review highlights the relevance of pathophysiological actions of BDNF/TrkB under certain circumstances, so that manipulation of BDNF/TrkB and A(2a)Rs may give rise to alternate neuroprotective therapeutic strategies in the treatment of neural diseases such as ALS.
  • Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium

    Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10), methionine (p-value = 9.2 × 10), tyrosine (p-value = 2.1 × 10), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.
  • Segmenting processes in the human lateral geniculate nucleus

  • GWAS of suicide attempt in psychiatric disorders and association with major depression polygenic risk scores

    Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R= 0.25%), bipolar disorder (R=0.24%), and schizophrenia (R= 0.40%). Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
  • An evaluation of the Behavioral Inhibition and Behavioral Activation System (BIS-BAS) model of pain

    Objective: This study evaluated the behavioral inhibition and activation system (BIS-BAS) model of pain. Frontal alpha asymmetry (FAA) as a possible neurophysiological correlate of the BIS-BAS was also explored, as was the role of personality factors. Research Method: A cross-sectional study was completed at the University of (the University of Queensland). The sample was N = 69 adults with chronic low back pain. Self-report and data were collected as a part of a treatment outcome study. Correlational analyses were conducted between theorized BIS-BAS-related measures of cognitions (catastrophizing, control beliefs), emotion (depression, anxiety, happiness), and behavior (avoidance, engagement). Correlations and hierarchical regression were used to explore the association between these measures, pain intensity, personality factors, and FAA. Results: As hypothesized, the correlations between the BIS and BAS measures were all negative and mostly significant (ps < .05). The BIS-related measures were significantly positively associated with each other and Neuroticism (ps <.01). The BAS-related measures were positively correlated with each other and Extraversion. with most of these associations statistically significant. While pain intensity was significantly associated with several BIS and BAS measures (ps < .05), FAA was not significantly associated with pain or any BIS-BAS domain. BAS-related measures were most strongly associated with pain intensity (Delta R-2 = .13). Conclusions: Few studies have concurrently investigated the intersection between brain state, pain-related variables and psychosocial factors. This is the first study to test these associations from the perspective of a BIS-BAS model of pain. The findings provide preliminary support for the central tenets of this framework. The clinical implications of the findings are discussed.
  • Nonlinear time series analysis using ordinal networks with select applications in biomedical signal processing

  • Assortative mating in autism spectrum disorder: toward an evidence base from DNA data, but not there yet

  • Steady-state visual evoked potentials reveal enhanced neural responses to illusory surfaces during a concurrent visual attention task

    Under natural viewing conditions, visual stimuli are often obscured by occluding surfaces. To aid object recognition, the visual system actively reconstructs the missing information, as exemplified in the classic Kanizsa illusion, a phenomenon termed "modal completion". Single-cell recordings in monkeys have shown that neurons in early visual cortex respond to illusory contours, but it has proven difficult to measure the neural correlates of modal completion in humans. We used electroencephalography (EEG) to measure steady-state visual-evoked potentials (SSVEPs) from disks with quarter segments removed to induce an illusory shape (or rotated to eliminate the illusory square in control trials). Opposing pairs of inducers were tagged with one of two flicker frequencies (2.5 or 4 Hz). During stimulus presentations, participants performed an attention task at fixation that required them to judge the orientation of a briefly flashed central bar while ignoring congruent (same orientation) or incongruent (different orientation) flanker bars that appeared on or off the illusory surface. Importantly, the occurrence of any illusory shape was never task relevant. Frequency-based analyses revealed that SSVEP amplitudes were reliably enhanced for trials in which an illusory square appeared, relative to control trials, at 4, 5 and 8 Hz and at an intermodulation frequency of 13 Hz. Participants' reaction times in the flanker task were significantly slower for incongruent versus congruent trials, and this distractor interference effect occurred only in the presence of an illusory surface and not in the control condition. Our results reveal a robust neural correlate of modal completion in the human visual system and provide evidence that visual completion can affect attentional control processes as deployed in a flanker task.
  • Delineating the topography of amyloid-associated cortical atrophy in Down syndrome

    Older adults with Down syndrome (DS) often have Alzheimer's disease (AD) neuropathologies. Although positron emission tomography imaging studies of amyloid deposition (beta amyloid, Aβ) have been associated with worse clinical prognosis and cognitive impairment, their relationships with cortical thickness remain unclear in people with DS. In a sample of 44 DS adults who underwent cognitive assessments, [C]-PiB positron emission tomography, and T1-weighted magnetization-prepared rapid gradient echo, we used mixed effect models to evaluate the spatial relationships between Aβ binding with patterns of cortical thickness. Partial Spearman correlations were used to delineate the topography of local Aβ-associated cortical thinning. [C]-PiB nondisplaceable binding potential was negatively associated with decreased cortical thickness. Locally, regional [C]-PiB retention was negatively correlated with cortical thickness in widespread cortices, predominantly in temporoparietal regions. Contrary to the prevailing evidence in established AD, we propose that our findings implicate Aβ in spatial patterns of atrophy that recapitulated the “cortical signature” of neurodegeneration in AD, conferring support to recent recommendations for earlier disease-interventions.
  • Neural and behavioral markers of observed pain of older adults

    To contribute to better understanding of empathy of younger adults for the pain of older adults, this study examined whether brain responses and behavioral ratings of young adult participants to the observed physical pain of older people differed from that to younger people. fMRI was used to measure participants’ brain responses to seeing younger and older people receiving a painful compared with non-painful touch, while they rated both the level of perceived pain observed and their own level of personal discomfort from observing the painful touch. The young participants showed greater brain activation when observing younger versus older people receiving painful stimuli, and they rated the needle-touch to the younger people to appear more painful and more personally distressing. Furthermore, those participants reporting a greater level of contact with older adults at work showed less brain activation in the left insula cortex, a typical neural marker for observed pain, when observing painful touch to the older people. These have implications for understanding both the emotional responses and perception of pain of young adults when observing pain in the elderly.
  • The efficacy of transcranial direct current stimulation to prefrontal areas is related to underlying cortical morphology

    Applying a weak electrical current to the cortex can have effects on a range of behaviours. Techniques such as transcranial direct current stimulation (tDCS) have been widely used in both research and clinical settings. However, there is significant variability across individuals in terms of their responsiveness to stimulation, which poses practical challenges to the application of tDCS, but also provides a unique opportunity to study the link between the brain and behaviour. Here, we assessed the role of individual differences in cortical morphology specifically in prefrontal cortical regions of interest - for determining the influence of tDCS on decision-making performance. Specifically, we employed magnetic resonance imaging (MRI) and a previously replicated paradigm in which we modulated learning in a simple decision-making task by applying tDCS to the left prefrontal cortex in human subjects of both sexes. Cortical thickness of the left (but not right) prefrontal cortex accounted for almost 35% of the variance in stimulation efficacy across subjects. This is the first demonstration that variations in cortical architecture are associated with reliable differences in the effects of tDCS on cognition. Our findings have important implications for predicting the likely efficacy of different non-invasive brain stimulation treatments on a case by case basis.
  • Hyperconnectivity in perisylvian language pathways in schizophrenia with auditory verbal hallucinations: a multi-site diffusion MRI study

    Auditory verbal hallucinations (AVH) are one of the cardinal symptoms of schizophrenia, and are proposed to be associatedwith altered integrity of the left perisylvian language pathways. There is considerable heterogeneity in the pattern of white matter abnormalities across previous studies. We investigated the white matter integrity of the perisylvian language pathways in schizophrenia patientswith AVH based on a relatively large sample dataset fromfour different sites. 113 schizophrenia patientswith AVH, 96 patientswithout AVH(nAVH), and 269 healthy controls (HC) underwent diffusion-weighted imaging. Between-group comparisonswere performed on the fractional anisotropy (FA) values of the anterior, posterior, and long segment fasciculi within the perisylvian language network. Analysis of covariance among the 3 groups revealed the long segment of the left perisylvian language pathways was significantly different in FA value. Post hoc analysis showed that compared with the HC group, the AVH group had significantly higher FA measurements in the left long segment. The nAVH group showed intermediate FA values for this segment compared to the AVH and HC group but did not differ significantly from either group. Furthermore, the prospective meta-analyses also revealed that FA value of the left long segment was significantly higher in the AVH group compared to the HC group. Our findings suggest the hyperconnectivity pattern of the left perisylvian language pathways in the presence of AVH in schizophrenia and support the self-monitoring of inner speech model.
  • Maternal vitamin D deficiency during rat gestation elicits a milder phenotype compared to the mouse model: implications for the placental glucocorticoid barrier

    Maternal vitamin D deficiency disturbs fetal development and programmes neurodevelopmental complications in offspring, possibly through increased fetal glucocorticoid exposure. We aimed to determine whether prenatal exposure to excess glucocorticoids underlies our rat model of early-life vitamin D deficiency, leading to altered adult behaviours. Vitamin D deficiency reduced the expression of the glucocorticoid-inactivating enzyme Hsd11b2 in the female placenta, but did not alter maternal glucocorticoid levels, feto-placental weights, or placental expression of other glucocorticoid-related genes at mid-gestation. This differs to the phenotype previously observed in vitamin D deficient mice, and highlights important modelling considerations.
  • The search for improved animal models of Alzheimer's disease and novel strategies for therapeutic intervention

  • Cross-national patterns of substance use disorder treatment and associations with mental disorder comorbidity in the WHO World Mental Health Surveys

    To examine cross-national patterns of 12-month substance use disorder (SUD) treatment and minimally adequate treatment (MAT), and associations with mental disorder comorbidity.

    Cross-sectional, representative household surveys.

    Twenty-seven surveys from 25 countries of the WHO World Mental Health Survey Initiative.

    A total of 2446 people with past-year DSM-IV SUD diagnoses (alcohol or illicit drug abuse and dependence).

    Outcomes were SUD treatment, defined as having either received professional treatment or attended a self-help group for substance-related problems in the past 12 months, and MAT, defined as having either four or more SUD treatment visits to a health-care professional, six or more visits to a non-health-care professional or being in ongoing treatment at the time of interview. Covariates were mental disorder comorbidity and several socio-economic characteristics. Pooled estimates reflect country sample sizes rather than population sizes.

    Of respondents with past-year SUD, 11.0% [standard error (SE) = 0.8] received past 12-month SUD treatment. SUD treatment was more common among people with comorbid mental disorders than with pure SUDs (18.1%, SE = 1.6 versus 6.8%, SE = 0.7), as was MAT (84.0%, SE = 2.5 versus 68.3%, SE = 3.8) and treatment by health-care professionals (88.9%, SE = 1.9 versus 78.8%, SE = 3.0) among treated SUD cases. Adjusting for socio-economic characteristics, mental disorder comorbidity doubled the odds of SUD treatment [odds ratio (OR) = 2.34; 95% confidence interval (CI) = 1.71-3.20], MAT among SUD cases (OR = 2.75; 95% CI = 1.90-3.97) and MAT among treated cases (OR = 2.48; 95% CI = 1.23-5.02). Patterns were similar within country income groups, although the proportions receiving SUD treatment and MAT were higher in high- than low-/middle-income countries.

    Few people with past-year substance use disorders receive adequate 12-month substance use disorder treatment, even when comorbid with a mental disorder. This is largely due to the low proportion of people receiving any substance use disorder treatment, as the proportion of patients whose treatment is at least minimally adequate is high.
  • The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness

  • p110δ PI 3-kinase inhibition perturbs APP and TNFα trafficking, reduces plaque burden, dampens neuroinflammation and prevents cognitive decline in an Alzheimer's disease mouse model

    Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-β (Aβ) peptide. Accumulation of Aβ, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. Here, we report that inactivation of the p110δ isoform of phosphoinositide 3-kinase (PI3K) reduces anterograde axonal trafficking of APP in hippocampal neurons and dampens secretion of the inflammatory cytokine tumor necrosis factor alpha (TNFα) by microglial cells in the familial AD APP/PS1 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3Kδ (δ) had reduced Aβ peptides levels and plaques in the brain and an abrogated inflammatory response compared to APP/PS1 littermates. Mechanistic investigations reveal that PI3Kδ inhibition decreases the axonal transport of APP by eliciting the formation of highly-elongated tubular-shaped APP-containing carriers, reducing the levels of secreted Aβ peptide. Importantly, APP/PS1/δ mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3Kδ as a new approach to protect against AD pathology due to its dual action of dampening microglial-dependent neuroinflammation and reducing plaque burden by inhibition of neuronal APP trafficking and processing.During Alzheimer's disease, the accumulation of the toxic Aβ peptide in plaques is associated with a chronic excessive inflammatory response. Uncovering new drug targets that simultaneously reduce both Aβ plaque load and neuroinflammation holds therapeutic promises. Using a combination of genetic and pharmacological approaches, we found that the p110δ isoform of PI 3-kinase (PI3Kδ) is involved in anterograde trafficking of the amyloid precursor protein (APP) in neurons, and in the secretion of TNFα from microglial cells. Genetic inactivation of PI3Kδ reduces Aβ plaque deposition and abrogates the inflammatory response, resulting in a complete rescue of the life span and spatial memory performance. We conclude that inhibiting PI3Kδ represents a novel therapeutic approach to ameliorate AD pathology, by dampening plaque accumulation and microglial-dependent neuroinflammation.
  • Is there a role for antibodies targeting muscarinic acetylcholine receptors in the pathogenesis of schizophrenia?

    Muscarinic receptor dysfunction has been suggested to play an important role in the pathophysiology of schizophrenia. Recently, it has also become clear that immune reactivity directed against neurotransmitter receptors may play a pathogenic role in some cases of schizophrenia. The aim of this review is to summarize the case for muscarinic receptor dysfunction in schizophrenia and the evidence supporting the hypothesis that this dysfunction is related to the development of muscarinic receptor-targeting antibodies.

    The article reviews studies of muscarinic receptors and the presence and potential role(s) of anti-muscarinic acetylcholine receptor antibodies in people with schizophrenia.

    There is accumulating evidence that altered or deficient muscarinic signalling underlies some of the key clinical features of schizophrenia. Although the number of studies investigating anti-muscarinic acetylcholine receptor antibodies in schizophrenia is relatively small, they consistently demonstrate that such antibodies are present in a proportion of patients. This evidence suggests that these antibodies could have pathogenic effects or exist as a biomarker to an unknown pathophysiological process in schizophrenia.

    The presence of elevated levels of anti-muscarinic acetylcholine receptor antibodies may identify a subgroup of people with schizophrenia, potentially informing aetiopathogenesis, clinical presentation and treatment. To date, all studies have examined antibodies in participants with chronic schizophrenia, who have likely received antipsychotic medication for many years. As these medications modulate immune functions and regulate receptor densities, it is recommended that future studies screen for the presence of anti-muscarinic antibodies in people experiencing their first episode of psychosis.
  • The CuePed Trial: how does environmental complexity impact cue effectiveness? A comparison of tonic and phasic visual cueing in simple and complex environments in a Parkinson’s Disease population with freezing of gait

    Background. The optimal prescription of cueing for the treatment of freezing of gait (FoG) in Parkinson's disease (PD) is currently a difficult problem for clinicians due to the heterogeneity of cueing modalities, devices, and the limited comparative trial evidence. There has been a rise in the development of motion-sensitive, wearable cueing devices for the treatment of FoG in PD. These devices generally produce cues after signature gait or electroencephalographic antecedents of FoG episodes are detected (phasic cues). It is not known whether these devices offer benefit over simple (tonic) cueing devices. Methods. We assembled 20 participants with PD and FoG and familiarized them with a belt-worn, laser-light cueing device (Agilitas (TM)). The device was designed with 2 cueing modalities-gait-dependent or phasic cueing and gait-independent or tonic cueing. Participants used the device sequentially in the off, phasic, or tonic modes, across 2 tasks-a 2-minute walk and an obstacle course. Results. A significant improvement in mean distance walked during the 2-minute walk test was observed for the tonic mode (127.3m) compared with the off (111.4m) and phasic (116.1m) conditions. In contrast, there was a nonsignificant trend toward improvement in FoG frequency, duration, and course time when the device was switched from off to tonic and to phasic modes for the obstacle course. Conclusions. Parkinson's disease patients with FoG demonstrated an improvement in distance walked during the two-minute walk test when a cueing device was switched from off to phasic and to tonic modes of operation. However, this benefit was lost when patients negotiated an obstacle course.
  • STXBP1 encephalopathy: connecting neurodevelopmental disorders with α-synucleinopathies?

    De novo pathogenic variants in STXBP1 encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.
  • Ultrafast fMRI of the rodent brain using simultaneous multi-slice EPI

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

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

    Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%. Mortality rates are higher than those in other psychiatric disorders, and outcomes are unacceptably poor. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
  • Paternal-age-related de novo mutations and risk for five disorders

    There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.
  • Spectral changes associated with transmission of OLED emission through human skin

    A recent and emerging application of organic light emitting diodes (OLEDs) is in wearable technologies as they are flexible, stretchable and have uniform illumination over a large area. In such applications, transmission of OLED emission through skin is an important part and therefore, understanding spectral changes associated with transmission of OLED emission through human skin is crucial. Here, we report results on transmission of OLED emission through human skin samples for yellow and red emitting OLEDs. We found that the intensity of transmitted light varies depending on the site from where the skin samples are taken. Additionally, we show that the amount of transmitted light reduces by ~ 35-40% when edge emissions from the OLEDs are blocked by a mask exposing only the light emitting area of the OLED. Further, the emission/electroluminescence spectra of the OLEDs widen significantly upon passing through skin and the full width at half maximum increases by >20 nm and >15 nm for yellow and red OLEDs, respectively. For comparison, emission profile and intensities of transmitted light for yellow and red inorganic LEDs are also presented. Our results are highly relevant for the rapidly expanding area of non-invasive wearable technologies that use organic optoelectronic devices for sensing.
  • The effect of X-linked dosage compensation on complex trait variation

    Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and 1600 gene expression traits from a sample of 2000 individuals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h = 0.63%) compared to females (mean h = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight examples of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for.