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.
  • 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.
  • 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.
  • 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.
  • 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

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Cerebral blood flow in community-based older twins is moderately heritable: an arterial spin labeling perfusion imaging study

    Adequate cerebral blood flow (CBF) is necessary to maintain brain metabolism and function. Arterial spin labeling (ASL) is an emerging MRI technique offering a non-invasive and reliable quantification of CBF. The genetic basis of CBF has not been well documented, and one approach to investigate this is to examine its heritability. The current study aimed to examine the heritability of CBF using ASL data from a cohort of community-dwelling older twins (41 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs; age range, 65-93 years; 56.4% female). The results showed that the cortex had higher CBF than subcortical gray matter (GM) regions, and CBF in the GM regions of the anterior cerebral artery (ACA) territory was lower than that of the middle (MCA) and posterior (PCA) cerebral arteries. After accounting for the effects of age, sex and scanner, moderate heritability was identified for global CBF (h(2) = 0.611; 95% CI = 0.380-0.761), as well as for cortical and subcortical GM and the GM in the major arterial territories (h(2) = 0.500-0.612). Strong genetic correlations (GCs) were found between CBF in subcortical and cortical GM regions, as well as among the three arterial territories (ACA, MCA, PCA), suggesting a largely convergent genetic control for the CBF in brain GM. The moderate heritability of CBF warrants future investigations to uncover the genetic variants and genes that regulate CBF.
  • Publisher correction: Multi-trait analysis of genome-wide association summary statistics using MTAG

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.
  • Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling

    Tau is a scaffolding protein that serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We have recently shown that amyloid-β, the second hallmark of AD, induces protein synthesis of tau. Importantly, this activation was found to be tau-dependent, raising the question of whether FTD-tau by itself affects protein synthesis. We therefore applied non-canonical amino acid labelling to visualise and identify newly synthesised proteins in the K369I tau transgenic K3 mouse model of FTD This revealed massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH-MS proteomics, we identified changes in 247 proteins of the proteome of K3 mice. These included decreased synthesis of the ribosomal proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis.
  • Students’, colleagues’ and research partners’ experience about work and accomplishments from collaborating with Robin Thompson

  • Publisher Correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.
  • Revisiting the role of the innate immune complement system in ALS

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

    Sleep optimizes waking behavior, however, waking experience may also influence sleep. We used the fruit fly Drosophila melanogaster to investigate the relationship between visual experience and sleep in wild-type and mutant flies. We found that the classical visual mutant, optomotor-blind (omb), which has undeveloped horizontal system/vertical system (HS/VS) motion-processing cells and are defective in motion and visual salience perception, showed dramatically reduced and less consolidated sleep compared to wild-type flies. In contrast, optogenetic activation of the HS/VS motion-processing neurons in wild-type flies led to an increase in sleep following the activation, suggesting an increase in sleep pressure. Surprisingly, exposing wild-type flies to repetitive motion stimuli for extended periods did not increase sleep pressure. However, we observed that exposing flies to more complex image sequences from a movie led to more consolidated sleep, particularly when images were randomly shuffled through time. Our results suggest that specific forms of visual experience that involve motion circuits and complex, nonrepetitive imagery, drive sleep need in Drosophila.
  • “Arte et Labore” - a Blackburn Rovers fan's legacy in human complex trait genetics

    Through his own research contributions on the modelling and genetic analysis of quantitative traits and through his former students and postdocs, Robin Thompson has indirectly left a major legacy in human genetics. In this short note, we highlight examples of the long-lasting relevance and impact of Robin's work in human genetics. A lone early study of marker-assisted selection developed many of the tools and approaches later exploited (often after reinvention) by the human genetics community in GWAS studies and for prediction. Furthermore, a particularly clear example of the pervasive impact of Robin's work is that REML has become the default method to estimate variance components and that genetic predictions exploiting linkage disequilibrium in the population are starting to become used in precision medicine applications.
  • MIR137 polygenic risk is associated with schizophrenia and affects functional connectivity of the dorsolateral prefrontal cortex

    Background Genome-wide association studies (GWAS) have consistently revealed that a variant of microRNA 137 (MIR137) shows a quite significant association with schizophrenia. Identifying the network of genes regulated by MIR137 could provide insights into the biological processes underlying schizophrenia. In addition, DLPFC functional connectivity, a robust correlate of MIR137, may provide plausible endophenotypes. However, the regulatory role of the MIR137 gene network in the disrupted functional connectivity remains unclear. Here, we tested the effects of the MIR137 regulated genes on the risk for schizophrenia and DLPFC functional connectivity.MethodsTo evaluate the additive effects of the MIR137 regulated genes (N = 1274), we calculated a MIR137 polygenic risk score (PRS) for schizophrenia and tested its association with the risk for schizophrenia in the genomic data of a Han Chinese population that included schizophrenia patients (N = 589) and normal controls (N = 575). We then investigated the association between MIR137 PRS and DLPFC functional connectivity in two independent young healthy cohorts (N = 356 and N = 314).ResultsWe found that the MIR137 PRS successfully captured the differences in genetic structure between the patients and controls, but the single gene MIR137 did not. We then consistently found that a higher MIR137 PRS was correlated with lower functional connectivities between the DLPFC and both the superior parietal cortex and the inferior temporal cortex in two independent cohorts.ConclusionThe findings suggested that these two functional connectivities of the DLPFC could be important endophenotypes linking the MIR137-regulated genetic structure to schizophrenia.
  • STIM1 is required for remodeling of the endoplasmic reticulum and microtubule cytoskeleton in steering growth cones

    The spatial and temporal regulation of calcium signaling in neuronal growth cones is essential for axon guidance. In growth cones, the endoplasmic reticulum (ER) is a significant source of calcium signals. However, it is not clear whether the ER is remodeled during motile events to localize calcium signals in steering growth cones. The expression of the ER-calcium sensor, stromal interacting molecule 1 (STIM1) is necessary for growth cone steering toward the calcium-dependent guidance cue BDNF, with STIM1 functioning to sustain calcium signals through store-operated calcium entry. However, STIM1 is also required for growth cone steering away from semaphorin-3a, a guidance cue that does not activate ER-calcium release, suggesting multiple functions of STIM1 within growth cones (Mitchell et al., 2012). STIM1 also interacts with microtubule plus-end binding proteins EB1/EB3 (Grigoriev et al., 2008). Here, we show that STIM1 associates with EB1/EB3 in growth cones and that STIM1 expression is critical for microtubule recruitment and subsequent ER remodeling to the motile side of steering growth cones. Furthermore, we extend our data , demonstrating that zSTIM1 is required for axon guidance in actively navigating zebrafish motor neurons, regulating calcium signaling and filopodial formation. These data demonstrate that, in response to multiple guidance cues, STIM1 couples microtubule organization and ER-derived calcium signals, thereby providing a mechanism where STIM1-mediated ER remodeling, particularly in filopodia, regulates spatiotemporal calcium signals during axon guidance. Defects in both axon guidance and endoplasmic reticulum (ER) function are implicated in a range of developmental disorders. During neuronal circuit development, the spatial localization of calcium signals controls the growth cone cytoskeleton to direct motility. We demonstrate a novel role for stromal interacting molecule 1 (STIM1) in regulating microtubule and subsequent ER remodeling in navigating growth cones. We show that STIM1, an activator of store-operated calcium entry, regulates the dynamics of microtubule-binding proteins EB1/EB3, coupling ER to microtubules, within filopodia, thereby steering growth cones. The STIM1-microtubule-ER interaction provides a new model for spatial localization of calcium signals in navigating growth cones in the nascent nervous system.
  • Ultrasound-mediated blood-brain barrier opening enhances delivery of therapeutically relevant formats of a tau-specific antibody

    The microtubule-associated protein tau is an attractive therapeutic target for the treatment of Alzheimer's disease and related tauopathies as its aggregation strongly correlates with disease progression and is considered a key mediator of neuronal toxicity. Delivery of most therapeutics to the brain is, however, inefficient, due to their limited ability to cross the blood-brain barrier (BBB). Therapeutic ultrasound is an emerging non-invasive technology which transiently opens the BBB in a focused manner to allow peripherally delivered molecules to effectively enter the brain. In order to open a large area of the BBB, we developed a scanning ultrasound (SUS) approach by which ultrasound is applied in a sequential pattern across the whole brain. We have previously shown that delivery of an anti-tau antibody in a single-chain variable fragment (scFv) format to the brain is increased with SUS allowing for an enhanced therapeutic effect. Here we compared the delivery of an anti-tau antibody, RN2N, in an scFv, fragment antigen-binding (Fab) and full-sized immunoglobulin G (IgG) format, with and without sonication, into the brain of pR5 tau transgenic mice, a model of tauopathy. Our results revealed that the full-sized IgG reaches a higher concentration in the brain compared with the smaller formats by bypassing renal excretion. No differences in either the ultrasound-mediated uptake or distribution in the brain from the sonication site was observed across the different antibody formats, suggesting that ultrasound can be used to successfully increase the delivery of therapeutic molecules of various sizes into the brain for the treatment of neurological diseases.
  • Frontotemporal dementia mutant Tau promotes aberrant Fyn nanoclustering in hippocampal dendritic spines

    The Src kinase Fyn plays critical roles in memory formation and Alzheimer's disease. Its targeting to neuronal dendrites is regulated by Tau via an unknown mechanism. As nanoclustering is essential for efficient signaling, we used single-molecule tracking to characterize the nanoscale distribution of Fyn in mouse hippocampal neurons, and manipulated the expression of Tau to test whether it controls Fyn nanoscale organization. We found that dendritic Fyn exhibits at least three distinct motion states, two of them associated with nanodomains. Fyn mobility decreases in dendrites during neuronal maturation, suggesting a dynamic synaptic reorganization. Removing Tau increases Fyn mobility in dendritic shafts, an effect that is rescued by re-expressing wildtype Tau. By contrast, expression of frontotemporal dementia P301L mutant Tau immobilizes Fyn in dendritic spines, affecting its motion state distribution and nanoclustering. Tau therefore controls the nanoscale organization of Fyn in dendrites, with the pathological Tau P301L mutation potentially contributing to synaptic dysfunction by promoting aberrant Fyn nanoclustering in spines.
  • Interspecies differences in the connectivity of ventral striatal components between humans and macaques

    Although the evolutionarily conserved functions of the ventral striatal components have been used as a priori knowledge for further study, whether these functions are conserved between species remains unclear. In particular, whether macroscopic connectivity supports this given the disproportionate volumetric differences between species in the brain regions that project to the ventral striatum, including the prefrontal and limbic areas, has not been established In this study, the human and macaque striatum was first tractographically parcellated to define the ventral striatum and its two subregions, the nucleus accumbens (Acb)-like and the neurochemically unique domains of the Acb and putamen (NUDAPs)-like divisions. Our results revealed a similar topographical distribution of the connectivity-based ventral striatal components in the two primate brains. Successively, a set of targets was extracted to construct a connectivity fingerprint to characterize these parcellation results, enabling cross-species comparisons. Our results indicated that the connectivity fingerprints of the ventral striatum-like divisions were dissimilar in the two species. We localized this difference to specific targets to analyze possible interspecies functional modifications. Our results also revealed interspecies-convergent connectivity ratio fingerprints of the target group to these two ventral striatum-like subregions. This convergence may suggest synchronous connectional changes of these ventral striatal components during primate evolution.
  • Proteomics approaches for biomarker and drug target discovery in ALS and FTD

    Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing in prevalence but lack targeted therapeutics. Although the pathological mechanisms behind these diseases remain unclear, both ALS and FTD are characterized pathologically by aberrant protein aggregation and inclusion formation within neurons, which correlates with neurodegeneration. Notably, aggregation of several key proteins, including TAR DNA binding protein of 43 kDa (TDP-43), superoxide dismutase 1 (SOD1), and tau, have been implicated in these diseases. Proteomics methods are being increasingly applied to better understand disease-related mechanisms and to identify biomarkers of disease, using model systems as well as human samples. Proteomics-based approaches offer unbiased, high-throughput, and quantitative results with numerous applications for investigating proteins of interest. Here, we review recent advances in the understanding of ALS and FTD pathophysiology obtained using proteomics approaches, and we assess technical and experimental limitations. We compare findings from various mass spectrometry (MS) approaches including quantitative proteomics methods such as stable isotope labeling by amino acids in cell culture (SILAC) and tandem mass tagging (TMT) to approaches such as label-free quantitation (LFQ) and sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) in studies of ALS and FTD. Similarly, we describe disease-related protein-protein interaction (PPI) studies using approaches including immunoprecipitation mass spectrometry (IP-MS) and proximity-dependent biotin identification (BioID) and discuss future application of new techniques including proximity-dependent ascorbic acid peroxidase labeling (APEX), and biotinylation by antibody recognition (BAR). Furthermore, we explore the use of MS to detect post-translational modifications (PTMs), such as ubiquitination and phosphorylation, of disease-relevant proteins in ALS and FTD. We also discuss upstream technologies that enable enrichment of proteins of interest, highlighting the contributions of new techniques to isolate disease- relevant protein inclusions including flow cytometric analysis of inclusions and trafficking (FloIT). These recently developed approaches, as well as related advances yet to be applied to studies of these neurodegenerative diseases, offer numerous opportunities for discovery of potential therapeutic targets and biomarkers for ALS and FTD.
  • Correction: GWAS on family history of Alzheimer’s disease

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.
  • Regional differences in the inflammatory and heat shock response in glia: implications for ALS

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

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. ALS exhibits high phenotypic variability including age and site of onset, and disease duration. To uncover epigenetic and transcriptomic factors that may modify an ALS phenotype, we used a cohort of Australian monozygotic twins (n = 3 pairs) and triplets (n = 1 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to C9orf72 and SOD1. Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins/triplets and control twins (n = 2 pairs), implicated genes with consistent longitudinal differential DNA methylation and/or gene expression. Two identified genes, RAD9B and C8orf46, showed significant differential methylation in an extended cohort of >1000 ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated CCNF, DPP6, RAMP3, and CCS, which have been previously associated with ALS. Longitudinal transcriptome data showed an 8-fold enrichment of immune function genes and under-representation of transcription and protein modification genes in ALS. Examination of these changes in a large Australian sporadic ALS cohort suggest a broader role in ALS. Furthermore, we observe that increased methylation age is a signature of ALS in older patients.
  • Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity (Nature Genetics, (2018), 50, 1, (26-41), 10.1038/s41588-017-0011-x)

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.
  • Newborn vitamin D levels in relation to autism spectrum disorders and intellectual disability: a case–control study in California

    Vitamin D deficiency has been increasing concurrently with prevalence of autism spectrum disorders (ASD), and emerging evidence suggests vitamin D is involved in brain development. Most prior studies of ASD examined vitamin D levels in children already diagnosed, but a few examined levels during perinatal development, the more likely susceptibility period. Therefore, we examined newborn vitamin D levels in a case–control study conducted among births in 2000–2003 in southern California. Children with ASD (N = 563) or intellectual disability (ID) (N = 190) were identified from the Department of Developmental Services and compared to population controls (N = 436) identified from birth certificates. 25-hydroxyvitamin D (25(OH)D) was measured in archived newborn dried blood spots by a sensitive assay and corrected to sera equivalents. We categorized 25(OH) D levels as deficient (<50 nmol/L), insufficient (50–74 nmol/L), and sufficient (≥75 nmol/L), and also examined continuous levels, using logistic regression. The adjusted odds ratios (AOR) and 95% confidence intervals for ASD were 0.96 (0.64–1.4) for 25(OH)D deficiency (14% of newborns) and 1.2 (0.86–1.6) for insufficiency (26% of newborns). The AORs for continuous 25(OH)D (per 25 nmol/L) were 1.0 (0.91–1.09) for ASD and 1.14 (1.0–1.30) for ID. Thus, in this relatively large study of measured newborn vitamin D levels, our results do not support the hypothesis of lower 25(OH)D being associated with higher risk of ASD (or ID), although we observed suggestion of interactions with sex and race/ethnicity. 25(OH)D levels were relatively high (median 84 nmol/L in controls), so results may differ in populations with higher prevalence of low vitamin D levels. Autism Res 2019, 12: 989–998.
  • Promoting and protecting trainee welfare in an imperfect world

  • Comparison study of passive acoustic mapping and high-speed photography for monitoring in situ cavitation bubbles

    The spatiotemporal accuracy of passive acoustic mapping (PAM) for monitoring in situ cavitation bubbles has not been assessed directly via optical means. Here, the cavitation bubbles are monitored from two image sequences obtained simultaneously with PAM and high-speed photography (HSP). The temporal accuracy of PAM for detecting cavitation nucleation and the spatial resolution for cavitation localization are compared with those measured from HSP. The results show that PAM has a temporal accuracy of 20 μs. Mean differences in the spatial locations of PAM and HSP are as small as 10.0 and 30.5 μm along the lateral and axial directions, respectively.
  • Publisher Correction: Gene expression imputation across multiple brain regions provides insights into schizophrenia risk (Nature Genetics, (2019), 51, 4, (659-674), 10.1038/s41588-019-0364-4)

    In the HTML version of the article originally published, the author group ‘The Schizophrenia Working Group of the Psychiatric Genomics Consortium’ was displayed incorrectly. The error has been corrected in the HTML version of the article.
  • Neonatal vitamin D status in relation to autism spectrum disorder and developmental delay in the CHARGE case–control study

    Vitamin D appears essential for normal neurodevelopment and cognitive and behavioral function. We examined neonatal vitamin D in relation to the child's later diagnosis of autism spectrum disorder (ASD) or developmental delay (DD). Children aged 24–60 months enrolled in the population-based CHARGE case–control study were evaluated clinically for ASD (n = 357), DD (n = 134), or typical development (TD, n = 234) at the MIND Institute (Sacramento, CA) using standardized assessments. Total 25-hydroxyvitamin D (25[OH]D) was measured using sensitive isotope dilution liquid chromatography–tandem mass spectrometry in archived dried blood spots collected for the California Department of Public Health's Newborn Screening Program. Multinomial logistic regression was used to calculate ORs as measures of the associations between 25 nmol/L change in 25(OH)D and ASD and DD. Associations between 25(OH)D and scores on Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales were assessed using robust linear regression. Effect modification was examined using stratified models and interaction product terms. Unadjusted mean (SD) 25(OH)D was lower for DD (73.2 [37.6]) than for TD (82.7 [39.3]) and ASD (80.1 [37.4]). After adjustment for maternal prepregnancy body mass index and education, a 25 nmol/L increase in total 25(OH)D was not associated with ASD (OR = 0.97; CI: 0.87–1.08) or DD (OR = 0.91; 95% CI: 0.78–1.06). Neonatal 25(OH)D was associated with significantly reduced ASD only in females (adjusted OR = 0.74; 95% CI: 0.55–0.99, P = 0.03), and significantly reduced DD only in non-Hispanic white children (adjusted OR = 0.79; 95% CI: 0.63–0.98, P = 0.11 for Hispanic, P = 0.31 for other), driven by DD children with trisomy 21. This study provides evidence that neonatal vitamin D could be associated with ASD in females and with DD in non-Hispanic white children. Autism Res 2019.
  • Bone-marrow mononuclear cell therapy in a mouse model of amyotrophic lateral sclerosis: Functional outcomes from different administration routes

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

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

    Animal visual systems adapt to environmental light on various timescales. In scotopic conditions, evolutionary time-scale adaptations include spectral tuning to a narrower light spectrum, loss (or inactivation) of visual genes, and pure-rod or rod-dominated retinas. Some fishes inhabiting shallow coral reefs may show activity during the day and at night. It is unclear whether these fishes show adaptations typical of exclusively nocturnal or deep-sea fishes, or of diurnally active shallow-water species. Here, we investigated visual pigment diversity in cardinalfishes (Apogonidae). Most cardinalfishes are nocturnal foragers, yet they aggregate in multispecies groups in and around coral heads during the day, engaging in social and predator avoidance behaviours. We sequenced retinal transcriptomes of 28 species found on the Great Barrier Reef, assessed the diversity of expressed opsin genes and predicted the spectral sensitivities of resulting photopigments using sequence information. Predictions were combined with microspectrophotometry (MSP) measurements in seven cardinalfish species. Retinal opsin expression was rod opsin (RH1) dominated (>87%), suggesting the importance of scotopic vision. However, all species retained expression of multiple cone opsins also, presumably for colour vision. We found five distinct quantitative expression patterns among cardinalfishes, ranging from short-wavelength-shifted to long-wavelength-shifted. These results indicate that cardinalfishes are both well adapted to dim-light conditions and have retained a sophisticated colour vision sense. Other reef fish families also show both nocturnal and diurnal activity while most are strictly one or the other. It will be interesting to compare these behavioural differences across different phylogenetic groups using the criteria and methods developed here.
  • New insight into human sweet taste: a genome-wide association study of the perception and intake of sweet substances

    Individual differences in human perception of sweetness are partly due to genetics; however, which genes are associated with the perception and the consumption of sweet substances remains unclear.

    The aim of this study was to verify previous reported associations within genes involved in the peripheral receptor systems (i.e., TAS1R2, TAS1R3, and GNAT3) and reveal novel loci.

    We performed genome-wide association scans (GWASs) of the perceived intensity of 2 sugars (glucose and fructose) and 2 high-potency sweeteners (neohesperidin dihydrochalcone and aspartame) in an Australian adolescent twin sample (n = 1757), and the perceived intensity and sweetness and the liking of sucrose in a US adult twin sample (n = 686). We further performed GWASs of the intake of total sugars (i.e., total grams of all dietary mono- and disaccharides per day) and sweets (i.e., handfuls of candies per day) in the UK Biobank sample (n = ≤174,424 white-British individuals). All participants from the 3 independent samples were of European ancestry.

    We found a strong association between the intake of total sugars and the single nucleotide polymorphism rs11642841 within the FTO gene on chromosome 16 (P = 3.8 × 10-8) and many suggestive associations (P < 1.0 × 10-5) for each of the sweet perception and intake phenotypes. We showed genetic evidence for the involvement of the brain in both sweet taste perception and sugar intake. There was limited support for the associations with TAS1R2, TAS1R3, and GNAT3 in all 3 European samples.

    Our findings indicate that genes additional to those involved in the peripheral receptor system are also associated with the sweet taste perception and intake of sweet-tasting foods. The functional potency of the genetic variants within TAS1R2, TAS1R3, and GNAT3 may be different between ethnic groups and this warrants further investigations.
  • Parkinson's disease age at onset genome-wide association study: defining heritability, genetic loci, and α-synuclein mechanisms

    Background: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives: To identify the genetic determinants of PD age at onset. Methods: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease.
  • Peripheral Nerve Regeneration Is Independent From Schwann Cell p75(NTR) Expression

    Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75(NTR) has been identified as a positive modulator for Schwann cell myelination during development and implicated in promoting nerve regeneration after injury. However, most studies base this conclusion on results obtained from complete p75(NTR) knockout mouse models and cannot dissect the specific role of p75(NTR) expressed by Schwann cells. In this present study, a conditional knockout model selectively deleting p75(NTR) expression in Schwann cells was generated, where p75(NTR) expression is replaced with that of an mCherry reporter. Silencing of Schwann cell p75(NTR) expression was confirmed in the sciatic nerve in vivo and in vitro, without altering axonal expression of p75(NTR). No difference in sciatic nerve myelination during development or following sciatic nerve crush injury was observed, as determined by quantification of both myelinated and unmyelinated nerve fiber densities, myelinated axonal diameter and myelin thickness. However, the absence of Schwann cell p75(NTR) reduced motor nerve conduction velocity after crush injury. Our data indicate that the absence of Schwann cell p75(NTR) expression in vivo is not critical for axonal regrowth or remyelination following sciatic nerve crush injury, but does play a key role in functional recovery. Overall, this represents the first step in redefining the role of p75(NTR) in the peripheral nervous system, suggesting that the Schwann cell-axon unit functions as a syncytium, with the previous published involvement of p75(NTR) in remyelination most likely depending on axonal/neuronal p75(NTR) and/or mutual glial-axonal interactions.
  • Loss of appetite is associated with a loss of weight and fat mass in patients with amyotrophic lateral sclerosis

    Objective: Weight loss in amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. It has different possible causes, including loss of appetite. Our objective is to determine the prevalence and impact of loss of appetite on change in body weight and composition in patients with ALS. Methods: We conducted a prospective case-control study, comparing demographic, clinical, appetite and prognostic features between 62 patients with ALS and 45 healthy non-neurodegenerative disease (NND) controls. To determine the impact of loss of appetite on weight throughout disease course, we conducted serial assessments at similar to three to four-month intervals. Results: Loss of appetite is more prevalent in patients with ALS than NND controls (29 vs. 11.1%, odds ratio = 3.27 (1.1-9.6); p < 0.01). In patients with ALS, loss of appetite is associated with greater weight loss and greater loss of fat mass. Appetite scores in patients with ALS worsens as disease progresses and are correlated with worsening ALS Functional Rating Scale-Revised scores. Conclusion: We confirm that loss of appetite is prevalent in patients with ALS and is significantly associated with weight loss and loss of fat mass. Appetite worsens with disease progression. Identification and early interventions to address loss of appetite in patients with ALS may prevent or slow weight loss; this could improve disease outcome.