QBI research publications

  • Computer-aided measurement system using image processing for measuring Cobb angle in scoliosis

    Background: One of the spine deformities is scoliosis, and Cobb angle is generally used to assess it. Objectives: In this study, a computer-aided measurement system (CAMS) was presented as a new repeatable and reproducible approach to assess the Cobb angle in idiopathic scoliosis patients. Methods: Python libraries, including OpenCV and Numpy were used for image processing and design of the software. To assess the repeatability and reproducibility of the CAMS, a series of 98 anterior-posterior radiographs from patients with idiopathic scoliosis were used. Assessments were done by five independent observers. Each radiograph was assessed by each observer three times with a minimum break of two weeks among assessment. The single measure intraclass correlation coefficient (ICC), the mean absolute difference (MAD), and the standard error measurement (SEM) values were used for intra-and inter-observer reliability. Results: The inter-observer analysis indicated that the ICCs ranged from 0.94-0.99, and the MAD between manual and CAMS were less than 3°. For intra-observer measurements, the combined SEM between all observers for the manual and CAMS was 1.79° and 1.27°, respectively. An ICC value of 0.97 with 95% confidence interval (CI) was excellent in CAMS for inter-observer reliability. The MAD of CAMS was 2.18 ± 2.01 degrees. Conclusions: The CAMS is an effective and reliable approach for assessing scoliotic curvature in the standing radiographs of thoraco-lumbar. Moreover, CAMS can accelerate clinical visits, and its calculation results are reliable.
  • Interleukin-8 and depressive responses to an inflammatory challenge: secondary analysis of a randomized controlled trial

    Emerging evidence suggests that interleukin (IL)-8 has a protective role in the context of depression. Higher levels of IL-8 are associated with lower depressive symptom severity among depressed patients, and treatment-related increases in IL-8 correlate with a positive response in depressed patients. This study (a secondary analysis of a completed randomized controlled trial) aimed to examine whether higher levels of IL-8 mitigate increases in depressed mood in response to an experimental model of inflammation induced depression. Given epidemiologic relationships identified between IL-6, tumor necrosis factor (TNF)- α, and subsequent depression, levels of these pro-inflammatory cytokines were also explored as potential moderators of depressed mood response to endotoxin. Secondary analyses were completed on data from healthy adults (n = 114) who completed a double-blind, placebo-controlled randomized trial in which participants were randomly assigned to receive either a single infusion of low-dose endotoxin (derived from Escherichia coli; 0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline). IL-8, as well as IL-6 and TNF- α, were measured at baseline prior to infusion, and depressed mood and feelings of social disconnection were assessed approximately hourly. Baseline levels of IL-8, but not IL-6 or TNF-α, moderated depressed mood (β = − 0.274, p =.03) and feelings of social disconnection (β = − 0.307, p =.01) responses, such that higher baseline IL-8 was associated with less increase in depressed mood and feelings of social disconnection in the endotoxin, but not placebo, condition. IL-8 had threshold effects, in which highest quartile IL-8 (≥ 2.7 pg/mL) attenuated increases in depressed mood in response to endotoxin as compared to lower IL-8 quartiles (p =.02). These findings suggest that IL-8 may be a biological factor that mitigates risk of inflammation-associated depression. Clinical trials registration: ClinicalTrials.gov NCT01671150, registration date 23/08/2012.
  • Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors

    Background: Genetic variants in the subunits of the gamma-aminobutyric acid type A (GABA) receptors are implicated in the onset of multiple pathologic conditions including genetic epilepsy. Previous work showed that pathogenic GABA subunits promote misfolding and inefficient assembly of the GABA receptors, limiting receptor expression and activity at the plasma membrane. However, GABA receptors containing variant subunits can retain activity, indicating that enhancing the folding, assembly, and trafficking of these variant receptors offers a potential opportunity to mitigate pathology associated with genetic epilepsy. Results: Here, we demonstrate that pharmacologically enhancing endoplasmic reticulum (ER) proteostasis using small molecule activators of the ATF6 (Activating Transcription Factor 6) signaling arm of the unfolded protein response (UPR) increases the assembly, trafficking, and surface expression of variant GABA receptors. These improvements are attributed to ATF6-dependent remodeling of the ER proteostasis environment, which increases protein levels of pro-folding ER proteostasis factors including the ER chaperone BiP (Immunoglobulin Binding Protein) and trafficking receptors, such as LMAN1 (Lectin Mannose-Binding 1) and enhances their interactions with GABA receptors. Importantly, we further show that pharmacologic ATF6 activators increase the activity of GABA receptors at the cell surface, revealing the potential for this strategy to restore receptor activity to levels that could mitigate disease pathogenesis. Conclusions: These results indicate that pharmacologic ATF6 activators offer an opportunity to restore GABA receptor activity in diseases including genetic epilepsy and point to the potential for similar pharmacologic enhancement of ER proteostasis to improve trafficking of other disease-associated variant ion channels implicated in etiologically-diverse diseases.
  • Retrospective genomics highlights changes in genetic composition of tiger sharks (Galeocerdo cuvier) and potential loss of a south-eastern Australia population

    Over the last century, many shark populations have declined, primarily due to overexploitation in commercial, artisanal and recreational fisheries. In addition, in some locations the use of shark control programs also has had an impact on shark numbers. Still, there is a general perception that populations of large ocean predators cover wide areas and therefore their diversity is less susceptible to local anthropogenic disturbance. Here we report on temporal genomic analyses of tiger shark (Galeocerdo cuvier) DNA samples that were collected from eastern Australia over the past century. Using Single Nucleotide Polymorphism (SNP) loci, we documented a significant change in genetic composition of tiger sharks born between ~1939 and 2015. The change was most likely due to a shift over time in the relative contribution of two well-differentiated, but hitherto cryptic populations. Our data strongly indicate a dramatic shift in the relative contribution of these two populations to the overall tiger shark abundance on the east coast of Australia, possibly associated with differences in direct or indirect exploitation rates.
  • The time-course of feature-based attention effects dissociated from temporal expectation and target-related processes

    Selective attention prioritises relevant information amongst competing sensory input. Time-resolved electrophysiological studies have shown stronger representation of attended compared to unattended stimuli, which has been interpreted as an effect of attention on information coding. However, because attention is often manipulated by making only the attended stimulus a target to be remembered and/or responded to, many reported attention effects have been confounded with target-related processes such as visual short-term memory or decision-making. In addition, attention effects could be influenced by temporal expectation about when something is likely to happen. The aim of this study was to investigate the dynamic effect of attention on visual processing using multivariate pattern analysis of electroencephalography (EEG) data, while (1) controlling for target-related confounds, and (2) directly investigating the influence of temporal expectation. Participants viewed rapid sequences of overlaid oriented grating pairs while detecting a “target” grating of a particular orientation. We manipulated attention, one grating was attended and the other ignored (cued by colour), and temporal expectation, with stimulus onset timing either predictable or not. We controlled for target-related processing confounds by only analysing non-target trials. Both attended and ignored gratings were initially coded equally in the pattern of responses across EEG sensors. An effect of attention, with preferential coding of the attended stimulus, emerged approximately 230 ms after stimulus onset. This attention effect occurred even when controlling for target-related processing confounds, and regardless of stimulus onset expectation. These results provide insight into the effect of feature-based attention on the dynamic processing of competing visual information.
  • Rapid development of an integrated remote programming platform for neuromodulation systems through the biodesign process

    Treating chronic symptoms for pain and movement disorders with neuromodulation therapies involves fine-tuning of programming parameters over several visits to achieve and maintain symptom relief. This, together with challenges in access to trained specialists, has led to a growing need for an integrated wireless remote care platform for neuromodulation devices. In March of 2021, we launched the first neuromodulation device with an integrated remote programming platform. Here, we summarize the biodesign steps taken to identify the unmet patient need, invent, implement, and test the new technology, and finally gain market approval for the remote care platform. Specifically, we illustrate how agile development aligned with the evolving regulatory requirements can enable patient-centric digital health technology in neuromodulation, such as the remote care platform. The three steps of the biodesign process applied for remote care platform development are: (1) Identify, (2) Invent, and (3) Implement. First, we identified the unmet patient needs through market research and voice-of-customer (VOC) process. Next, during the concept generation phase of the invention step, we integrated the results from the VOC into defining requirements for prototype development. Subsequently, in the concept screening phase, ten subjects with PD participated in a clinical pilot study aimed at characterizing the safety of the remote care prototype. Lastly, during the implementation step, lessons learned from the pilot experience were integrated into final product development as new features. Following final product development, we completed usability testing to validate the full remote care system and collected preliminary data from the limited market release experience. The VOC data, during prototype development, helped us identify thresholds for video quality and needs priorities for clinicians and patients. During the pilot study, one subject reported anticipated remote–care-related adverse events that were resolved without sequelae. For usability analysis following final product development, the failure rates for task completion for both user groups were about 1%. Lastly, during the initial 4 weeks of the limited market release experience, a total of 858 remote care sessions were conducted with a 93% success rate. Overall, we developed a remote care platform by adopting a user-centric approach. Although the system intended to address pre-COVID19 challenges associated with disease management, the unforeseen overlap of the study with the pandemic elevated the importance of such a system and an innovative development process enabled us to advance a patient-centric platform to gain regulatory approval and successfully launch the remote care platform to market.
  • On the relations between letter, word, and sentence-level processing during reading

    Much prior research on reading has focused on a specific level of processing, with this often being letters, words, or sentences. Here, for the first time in adult readers, we provide a combined investigation of these three key component processes of reading comprehension. We did so by testing the same group of participants in three tasks thought to reflect processing at each of these levels: alphabetic decision, lexical decision, and grammatical decision. Participants also performed a non-reading classification task, with an aim to partial-out common binary decision processes from the correlations across the three main tasks. We examined the pairwise partial correlations for response times (RTs) in the three reading tasks. The results revealed strong significant correlations across adjacent levels of processing (i.e., letter-word; word-sentence) and a non-significant correlation between non-adjacent levels (letter-sentence). The results provide an important new benchmark for evaluating computational models that describe how letters, words, and sentences contribute to reading comprehension.
  • Plasma biomarkers inclusive of α-synuclein/amyloid-beta40 ratio strongly correlate with Mini-Mental State Examination score in Parkinson’s disease and predict cognitive impairment

    Plasma biomarkers for Parkinson’s disease (PD) diagnosis that carry predictive value for cognitive impairment are valuable. We explored the relationship of Mini-Mental State Examination (MMSE) score with plasma biomarkers in PD patients and compared results to vascular dementia (VaD) and normal controls. The predictive accuracy of an individual biomarker on cognitive impairment was evaluated using area under the receiver operating characteristic curve (AUROC), and multivariate logistic regression was applied to evaluate predictive accuracy of biomarkers on cognitive impairment; 178 subjects (41 PD, 31 VaD and 106 normal controls) were included. In multiple linear regression analysis of PD patients, α-synuclein, anti-α-synuclein, α-synuclein/Aβ40 and anti-α-synuclein/Aβ40 were highly predictive of MMSE score in both full model and parsimonious model (R = 0.838 and 0.835, respectively) compared to non-significant results in VaD group (R = 0.149) and in normal controls (R = 0.056). Α-synuclein and anti-α-synuclein/Aβ40 were positively associated with MMSE score, and anti-α-synuclein, α-synuclein/Aβ40 were negatively associated with the MMSE score among PD patients (all Ps < 0.005). In the AUROC analysis, anti-α-synuclein (AUROC = 0.788) and anti-α-synuclein/Aβ40 (AUROC = 0.749) were significant individual predictors of cognitive impairment. In multivariate logistic regression, full model of combined biomarkers showed high accuracy in predicting cognitive impairment (AUROC = 0.890; 95%CI 0.796–0.984) for PD versus controls, as was parsimonious model (AUROC = 0.866; 95%CI 0.764–0.968). In conclusion, simple combination of biomarkers inclusive of α-synuclein/Aβ40 strongly correlates with MMSE score in PD patients versus controls and is highly predictive of cognitive impairment.
  • Absence of age differences in emotion perception and gaze patterns using a contextually rich film-based assessment

    Age differences in emotion perception are now well documented. However, a key limitation of many studies in this literature is the reliance on highly artificial tasks that lack context and consequently have poor ecological validity. This study reports two separate experiments that investigated age differences in emotion perception abilities using a highly contextualised film-based assessment along with a traditional emotion perception task. Experiment 2 additionally included a middle-aged sample and an assessment of eye-gaze patterns to the emotional films. The inclusion of eye-tracking in Experiment 2 was motivated by the fact that older adults consistently show visual biases to static emotion stimuli, yet it remains unclear whether biases also emerge in response to dynamic contextualised emotion stimuli. Experiment 1 identified age effects recognising displays of anger in the traditional emotion perception task but no age differences emerged on the film-based task. This finding was replicated in Experiment 2 with significant group differences on the traditional emotion perception task but no age differences on the film-based task. Experiment 2 also showed that there were no age differences in gaze patterns to these stimuli, showing for the first time that age-related visual biases to emotion stimuli may be task dependent. These findings highlight the fact that task-related features play a key role in the evaluation of age effects in emotion perception.
  • Visual representations: insights from neural decoding

    Patterns of brain activity contain meaningful information about the perceived world. Recent decades have welcomed a new era in neural analyses, with computational techniques from machine learning applied to neural data to “decode” information represented in the brain. In this article, we review how decoding approaches have advanced our understanding of visual representations, and discuss efforts to characterize both their complexity and behavioral relevance. We outline the current consensus regarding the spatiotemporal structure of visual representations, and review recent findings that suggest visual representations are at once robust to perturbations, yet sensitive to different mental states. Beyond representations of the physical world, recent decoding work has shone a light on how the brain instantiates internally-generated states, for example during imagery and prediction. Going forward, decoding has remarkable potential to assess how visual representations function for behavior, during development and aging, and in various mental disorders.
  • Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer’s disease

    Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer’s disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the cholinergic neurodegeneration was mediated by the accumulation of nuclear hypoxia inducible factor 1 alpha. Furthermore, restoring blood oxygen levels during sleep to prevent hypoxia prevented the pathological changes induced by the SDB. These findings suggest a signaling mechanism whereby SDB induces cholinergic basal forebrain degeneration.
  • SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein

    Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson’s disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson’s disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.
  • Colour vision in stomatopod crustaceans

    The stomatopod crustaceans, or mantis shrimps, are colourful marine invertebrate predators. Their unusual compound eyes have dorsal and ventral regions resembling typical crustacean apposition designs separated by a unique region called the midband that consists of from two to six parallel rows of ommatidia. In species with six-row midbands, the dorsal four rows are themselves uniquely specialized for colour analysis. Rhabdoms of ommatidia in these rows are longitudinally divided into three distinct regions: an apical ultraviolet (UV) receptor, a shorter-wavelength middle tier receptor and a longer-wavelength proximal tier receptor. Each of the total of 12 photoreceptors has a different spectral sensitivity, potentially contributing to a colour-vision system with 12 channels. Mantis shrimps can discriminate both human-visible and UV colours, but with limited precision compared to other colour-vision systems. Here, we review the structure and function of stomatopod colour vision, examining the types of receptors present in a species, the spectral tuning of photoreceptors both within and across species, the neural analysis of colour and the genetics underlying the multiple visual pigments used for colour vision. Even today, after many decades of research into the colour vision of stomatopods, much of its operation and its use in nature remain a mystery. This article is part of the theme issue 'Understanding colour vision: molecular, physiological, neuronal and behavioural studies in arthropods'.
  • Optogenetic stimulation and spatial localization of neurons using a multi-OLED approach

    Mapping neurons in the brain with micron-resolution is important to understand the neuronal circuits involved in cognitive function and their impairment in neurological diseases. Although current optogenetic tools allow fast activation and inhibition of neuronal activity, they require the use of lasers or LEDs optically coupled to large implants, resulting in poor spatial resolution and light delivery occurring in only one plane. Here, we experimentally test and model the radiation patterns of a simple yet thoroughly designed multi-OLED system to predict the location of a single neuron based on its OLED-evoked response amplitude. Highly simplified OLED pixels based on Super Yellow with an emissive area of 1.5 x 3.5 mm(2) were optimized to deliver a light intensity of 38 mu W mm(-2) at the neuron level. Investigated neurons expressing a red-shifted light-sensitive opsin Chrimson showed a robust neural response up to 16.7 pA that was time-locked to the light stimulation. Critically, the applied model to predict the neuron's location based on the electrophysiological response amplitude matched the observed location with an error below 80 mu m. Taken together, this proof-of-principle study demonstrates that a simple OLED system can be used to stimulate and locate neuronal activity, with the prospect to extend this approach to more advanced geometries in vivo.
  • High-fidelity dendritic sodium spike generation in human layer 2/3 neocortical pyramidal neurons

    Dendritic spikes function as cardinal components of rodent neocortical circuit computations. Recently, the biophysical properties of human pyramidal neurons (PNs) have been reported to be divergent, raising the question of whether dendritic spikes have homologous roles in the human neocortex. To directly address this, we made electrical recordings from the soma and apical dendrites of human and rat layer 2/3 PNs of the temporal cortex. In both species, dendritic excitatory input led to the initiation of sodium-channel-mediated dendritic spikes. Dendritic sodium spikes could be generated across a wide input range, exhibited a similar frequency range of activation, and forward-propagated with high-fidelity to implement stereotyped computations in human and rat PNs. However, the physical expansion and complexification of the apical dendritic trees of human PNs allowed the enriched expression of dendritic spike generation. The computational capacity of human PNs is therefore enhanced by the widespread implementation of a conserved dendritic integration mechanism.
  • Investigating brain development using tissue and single-cell gene expression data

  • Measuring empathy across the adult lifespan: a comparison of three assessment types

    Empathy is a core component of social cognition that can be indexed via behavioral, informant-report, or self-report methods of assessment. However, concerns have been raised regarding the lack of convergence between these assessment approaches for cognitive empathy. Here, we provided the first comparison of all three measurement approaches for cognitive and affective empathy in a large adult sample (N = 371) aged 18 to 101 years. We found that poor convergence was more of a problem for cognitive empathy than affective empathy. While none of the cognitive empathy measures correlated with each other, for affective empathy, self-report was significantly associated with both behavioral and informant-report assessments. However, for both cognitive and affective empathy, there was evidence for poor discriminant validity within the measures. Out of the three assessment approaches, only the informant-report measures were consistently associated with indices of social functioning. Importantly, age did not moderate any of the tested relationships, indicating that both the strengths and the limitations of these different types of assessment do not appear to vary as a function of age. These findings highlight the variation that exists among empathy measures and are discussed in relation to their practical implications for the assessment of empathy.
  • The contribution of general medical conditions to the non-fatal burden of mental disorders: register-based cohort study in Denmark

    BackgroundGeneral medical conditions (GMCs) often co-occur with mental and substance use disorders (MSDs).AimsTo explore the contribution of GMCs to the burden of disease in people with MSDs, and investigate how this varied by age.MethodA population-based cohort of 6 988 507 persons living in Denmark during 2000–2015 followed for up to 16 years. Danish health registers were used to identify people with MSDs and GMCs. For each MSD, years lived with disability and health loss proportion (HeLP) were estimated for comorbid MSDs and GMCs, using a multiplicative model for disability weights.ResultsThose with any MSD lost the equivalent of 43% of healthy life (HeLP = 0.43, 95% CI 0.40–0.44) after including information on GMCs, which was an increase from 25% before including GMCs (HeLP = 0.25, 95% CI 0.23–0.27). Schizophrenia was associated with the highest burden of disease (HeLP = 0.77, 95% CI 0.68–0.85). However, within each disorder, the relative contribution of MSDs and GMCs varied. For example, in those diagnosed with schizophrenia, MSDs and GMCs accounted for 86% and 14% of the total health loss; in contrast, in those with anxiety disorders, the same proportions were 59% and 41%. In general, HeLP increased with age, and was mainly associated with increasing rates of pulmonary, musculoskeletal and circulatory diseases.ConclusionsIn those with mental disorders, the relative contribution of comorbid GMCs to the non-fatal burden of disease increases with age. GMCs contribute substantially to the non-fatal burden of disease in those with MSDs.
  • Theta coupling within the medial prefrontal cortex regulates fear extinction and renewal

    Fear learning, and its extinction, are fundamental learning processes that allow for a response adaptation to aversive events and threats in the environment. Thus, it is critical to understand the neural mechanism that underpins fear learning and its relapse following extinction. The neural dynamics within the subregions of the medial prefrontal cortex, including the prelimbic cortex (PL) and the infralimbic (IL) cortex, and functional connectivity between them during fear extinction and its relapse, are not well understood. Using in-vivo electrophysiological recordings in awake behaving rats, we identified increased theta activity in the PL during fear learning and in the IL following extinction. Importantly, the PL-IL theta coupling is significantly enhanced throughout fear learning and extinction, but not in fear relapse. Together, our results provide evidence for the importance of synchronized PL-IL activity to regulate context-dependent retrieval of a fear extinction memory.
  • Are you for real? Decoding realistic AI-generated faces from neural activity

    Can we trust our eyes? Until recently, we rarely had to question whether what we see is indeed what exists, but this is changing. Artificial neural networks can now generate realistic images that challenge our perception of what is real. This new reality can have significant implications for cybersecurity, counterfeiting, fake news, and border security. We investigated how the human brain encodes and interprets realistic artificially generated images using behaviour and brain imaging. We found that we could reliably decode AI generated faces using people's neural activity. However, while at a group level people performed near chance classifying real and realistic fakes, participants tended to interchange the labels, classifying real faces as realistic fakes and vice versa. Understanding this difference between brain and behavioural responses may be key in determining the 'real' in our new reality. Stimuli, code, and data for this study can be found at https://osf.io/n2z73/.
  • Instant tissue field and magnetic susceptibility mapping from MRI raw phase using Laplacian enhanced deep neural networks

    Quantitative susceptibility mapping (QSM) is an MRI post-processing technique that produces spatially resolved magnetic susceptibility maps from phase data. However, the traditional QSM reconstruction pipeline involves multiple non-trivial steps, including phase unwrapping, background field removal, and dipole inversion. These intermediate steps not only increase the reconstruction time but accumulates errors. This study aims to overcome existing limitations by developing a Laplacian-of-Trigonometric-functions (LoT) enhanced deep neural network for near-instant quantitative field and susceptibility mapping (i.e., iQFM and iQSM) from raw MRI phase data. The proposed iQFM and iQSM methods were compared with established reconstruction pipelines on simulated and in vivo datasets. In addition, experiments on patients with intracranial hemorrhage and multiple sclerosis were also performed to test the generalization of the proposed neural networks. The proposed iQFM and iQSM methods in healthy subjects yielded comparable results to those involving the intermediate steps while dramatically improving reconstruction accuracies on intracranial hemorrhages with large susceptibilities. High susceptibility contrast between multiple sclerosis lesions and healthy tissue was also achieved using the proposed methods. Comparative studies indicated that the most significant contributor to iQFM and iQSM over conventional multi-step methods was the elimination of traditional Laplacian unwrapping. The reconstruction time on the order of minutes for traditional approaches was shortened to around 0.1 s using the trained iQFM and iQSM neural networks.
  • A systematic review of fragile X-associated neuropsychiatric disorders

    Fragile X premutation carriers are reported to have increased neuropsychiatric problems, and thus the term fragile X-associated neuropsychiatric disorders (FXAND) has been proposed. Unfortunately, published prevalence estimates of these phenomena are inconsistent. This systematic review clarified this issue by reviewing both fragile X premutation prevalence in patients with neurodevelopmental disorders and psychiatric disorder prevalence in premutation carriers without fragile X-associated tremor/ataxia syndrome (FXTAS). Average prevalence was derived from studies that used semistructured clinical interviews, diagnostic criteria, and validated rating scales.

    Forty-six studies were reviewed. The rate of fragile X premutation in neurodevelopmental disorders was assessed from five studies. Probands with neurodevelopmental disorders were more likely than those in the general population to be premutation carriers. The rate of psychiatric disorders in premutation carriers was assessed from five studies for neurodevelopmental, 13 studies for mood, 12 studies for anxiety, and two studies for psychotic disorders. The phenotype and sex distribution among premutation carriers were similar to those with fragile X syndrome.

    Compared to control group and general population estimates, the most prevalent psychiatric disorders were neurodevelopmental disorders, anxiety disorders, and bipolar II disorder. Psychiatric disorders were also more common in males. Most studies relied only on past medical history to define the prevalence of psychiatric disorders, yielding variability in results.

    Future studies are needed to avoid bias by identifying cohorts from population-based sampling, to describe cohort demographic characteristics to elucidate differences in age and sex, and to prioritize the use of validated psychiatric assessment methods.
  • Slow‐oscillatory tACS does not modulate human motor cortical response to repeated plasticity paradigms

    Previous history of activity and learning modulates synaptic plasticity and can lead to saturation of synaptic connections. According to the synaptic homeostasis hypothesis, neural oscillations during slow-wave sleep play an important role in restoring plasticity within a functional range. However, it is not known whether slow-wave oscillations—without the concomitant requirement of sleep—play a causal role in human synaptic homeostasis. Here, we aimed to answer this question using transcranial alternating current stimulation (tACS) to induce slow-oscillatory activity in awake human participants. tACS was interleaved between two plasticity-inducing interventions: motor learning, and paired associative stimulation (PAS). The hypothesis tested was that slow-oscillatory tACS would prevent homeostatic interference between motor learning and PAS, and facilitate plasticity from these successive interventions. Thirty-six participants received sham and active fronto-motor tACS in two separate sessions, along with electroencephalography (EEG) recordings, while a further 38 participants received tACS through a control montage. Motor evoked potentials (MEPs) were recorded throughout the session to quantify plasticity changes after the different interventions, and the data were analysed with Bayesian statistics. As expected, there was converging evidence that motor training led to excitatory plasticity. Importantly, we found moderate evidence against an effect of active tACS in restoring PAS plasticity, and no evidence of lasting entrainment of slow oscillations in the EEG. This suggests that, under the conditions tested here, slow-oscillatory tACS does not modulate synaptic homeostasis in the motor system of awake humans.
  • Genome-wide association studies in schizophrenia

    Schizophrenia is a chronic disabling neurodevelopmental disorder characterized by psychotic symptoms, cognitive impairment, dramatically increased mortality rates and severe morbidity. Though details are uncertain, causative factors include a highly polygenic predisposition and environmental exposures. The last decade has seen rapid progress in identifying an expanding number of genetic variants with the application of ever-larger genome-wide association studies (GWAS). Most recently, the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) GWAS revealed 287 genomic loci strongly associated with disease. In a companion paper, the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) consortium discovered ultra-rare coding variants in 10 genes. These latest data, together with previous copy number variant data provide convincing evidence that schizophrenia is primarily a disorder of neuronal structure and function, especially the synapse. For the first time, genes and variants likely to be causal have been identified, thereby delivering a vital resource for mechanistic studies.
  • Prospects of integrated multi-omics-driven biomarkers for efficient hair loss therapy from systems biology perspective

    The term “alopecia” is used for abnormal hair loss and it is a chronic dermatological condition observed in both genders and all races. Androgenetic alopecia (AGA) or male pattern baldness is the most common type of alopecia; however, it may be observed in females. Alopecia areata (AA) is the second most common non-scarring alopecia or hair loss around the world. Beyond the fact that alopecia is a disease itself, sometimes it might be one of the major side effects of many drugs including chemotherapeutics. Since healthy hair has been a symbol of well-being, youth, and vitality for centuries, the treatment of alopecia has essential importance to increasing life quality of the individuals that have faced hair loss. Regarding the progressively generated high-throughput data at various omics levels, systems biology has gained importance to better understand biologic processes by utilizing high-throughput data from multiple sources to develop models of biologic processes In this review, we overviewed AGA and AA via systems biology with the aid of omics technologies point of view to highlight not only the molecular mechanisms of the hair loss phenomenon but also potential preventive and therapeutic avenues. We discussed the findings in light of the multi-omics data integration that converges the future of uncovering personalized therapeutic options targeting hair loss.
  • Developmental exposure to vitamin D deficiency and subsequent risk of schizophrenia

    Over the last half century, a body of convergent evidence has accumulated linking disruption of early brain development with an increased risk of mental disorders, including schizophrenia. The orderly cascade of brain development may be disrupted by exposure to suboptimal concentrations of a range of biological substrates and micronutrients. We hypothesized that those exposed to vitamin D deficiency during early life, have an increased risk of neurodevelopmental disorders, including schizophrenia. The hypothesis was based on the link between an increased risk of schizophrenia in (a) those born in winter and spring, when vitamin D deficiency is more prevalent, and (b) the offspring of dark-skinned migrants living in cold climates, who have a markedly increased risk of vitamin D deficiency. In this review, we summarize evidence from analytic epidemiology related to this hypothesis. Two case-control studies based on Danish neonatal dried blood spots have found that neonatal vitamin deficiency is associated with an increased risk of schizophrenia. However, recent genetic analyses have also suggested that common variants linked to schizophrenia may lead to lower vitamin D concentrations (possibly mediated via reduced outdoor activity). We summarize limitations of the current evidence and outline suggestions that can guide future research. Based on currently available data, there is insufficient evidence to support public health recommendations related to this topic. However, we cannot reject the hypothesis that the provision of vitamin D supplementation to pregnant women and/or offspring in groups vulnerable to vitamin D deficiency may subsequently reduce the incidence of schizophrenia in the offspring.
  • Auditory processing in rodent models of autism: a systematic review

    Autism is a complex condition with many traits, including differences in auditory sensitivity. Studies in human autism are plagued by the difficulty of controlling for aetiology, whereas studies in individual rodent models cannot represent the full spectrum of human autism. This systematic review compares results in auditory studies across a wide range of established rodent models of autism to mimic the wide range of aetiologies in the human population. A search was conducted in the PubMed and Web of Science databases to find primary research articles in mouse or rat models of autism which investigate central auditory processing. A total of 88 studies were included. These used non-invasive measures of auditory function, such as auditory brainstem response recordings, cortical event-related potentials, electroencephalography, and behavioural tests, which are translatable to human studies. They also included invasive measures, such as electrophysiology and histology, which shed insight on the origins of the phenotypes found in the non-invasive studies. The most consistent results across these studies were increased latency of the N1 peak of event-related potentials, decreased power and coherence of gamma activity in the auditory cortex, and increased auditory startle responses to high sound levels. Invasive studies indicated loss of subcortical inhibitory neurons, hyperactivity in the lateral superior olive and auditory thalamus, and reduced specificity of responses in the auditory cortex. This review compares the auditory phenotypes across rodent models and highlights those that mimic findings in human studies, providing a framework and avenues for future studies to inform understanding of the auditory system in autism.
  • Hypoxic human proximal tubular epithelial cells undergo ferroptosis and elicit an NLRP3 inflammasome response in CD1c+ dendritic cells

    Inflammasomes are multiprotein platforms responsible for the release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Mouse studies have identified inflammasome activation within dendritic cells (DC) as pivotal for driving tubulointerstitial fibrosis and inflammation, the hallmarks of chronic kidney disease (CKD). However, translation of this work to human CKD remains limited. Here, we examined the complex tubular cell death pathways mediating inflammasome activation in human kidney DC and, thus, CKD progression. Ex vivo patient-derived proximal tubular epithelial cells (PTEC) cultured under hypoxic (1% O) conditions modelling the CKD microenvironment showed characteristics of ferroptotic cell death, including mitochondrial dysfunction, reductions in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and increases in lipid peroxidation by-product 4-hydroxynonenal (4-HNE) compared with normoxic PTEC. The addition of ferroptosis inhibitor, ferrostatin-1, significantly reduced hypoxic PTEC death. Human CD1c DC activated in the presence of hypoxic PTEC displayed significantly increased production of inflammasome-dependent cytokines IL-1β and IL-18. Treatment of co-cultures with VX-765 (caspase-1/4 inhibitor) and MCC950 (NLRP3 inflammasome inhibitor) significantly attenuated IL-1β/IL-18 levels, supporting an NLRP3 inflammasome-dependent DC response. In line with these in vitro findings, in situ immunolabelling of human fibrotic kidney tissue revealed a significant accumulation of tubulointerstitial CD1c DC containing active inflammasome (ASC) specks adjacent to ferroptotic PTEC. These data establish ferroptosis as the primary pattern of PTEC necrosis under the hypoxic conditions of CKD. Moreover, this study identifies NLRP3 inflammasome signalling driven by complex tubulointerstitial PTEC-DC interactions as a key checkpoint for therapeutic targeting in human CKD.
  • The multifaceted role of platelets in mediating brain function

    Platelets, the small, anucleate blood cells that originate from megakaryocytes in the bone marrow, are typically associated with coagulation. However, it is now apparent that platelets are more multifaceted than originally thought, with their function extending beyond their traditional role in hemostasis to acting as important mediators of brain function. In this review, we outline the broad repertoire of platelet function in the central nervous system, focusing on the similarities between platelets and neurons. We also summarize the role that platelets play in the pathophysiology of various neurological diseases, with a particular focus on neuroinflammation and neurodegeneration. Finally, we highlight the exciting prospect of harnessing the unique features of the platelet proteome and extracellular vesicles, which are rich in neurotrophic, antioxidative, and antiinflammatory factors, for the development of novel neuroprotective and neuroregenerative interventions to treat various neurodegenerative and traumatic pathologies.
  • Reaction Time “Mismatch Costs” Change with the Likelihood of Stimulus–Response Compatibility

    Dyadic interactions require dynamic correspondence between one’s own movements and those of the other agent. This mapping is largely viewed as imitative, with the behavioural hallmark being a reaction-time cost for mismatched actions. Yet the complex motor patterns humans enact together extend beyond direct-matching, varying adaptively between imitation, complementary movements, and counter-imitation. Optimal behaviour requires an agent to predict not only what is likely to be observed but also how that observed action will relate to their own motor planning. In 28 healthy adults, we examined imitation and counter-imitation in a task that varied the likelihood of stimulus–response congruence from highly predictable, to moderately predictable, to unpredictable. To gain mechanistic insights into the statistical learning of stimulus–response compatibility, we compared two computational models of behaviour: (1) a classic fxed learning-rate model (Rescorla–Wagner reinforcement [RW]) and (2) a hierarchical model of perceptual-behavioural processes in which the learning rate adapts to the inferred environmental volatility (hierarchical Gaussian flter [HGF]). Though more complex and hence penalized by model selection, the HGF provided a more likely model of the participants’ behaviour. Matching motor responses were only primed (faster) in the most experimentally volatile context. This bias was reversed so that mismatched actions were primed when beliefs about volatility were lower. Inferential statistics indicated that matching responses were only primed in unpredictable contexts when stimuli–response congruence was at 50:50 chance. Outside of these unpredictable blocks the classic stimulus–response compatibility efect was reversed: Incongruent responses were faster than congruent ones. We show that hierarchical Bayesian learning of environmental statistics may underlie response priming during dyadic interactions.
  • Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

    Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
  • Traumatic brain injury alterations in the functional connectome are associated with neuroinflammation but not tau in a P30IL tauopathy mouse model

    Introduction: Traumatic Brain Injury (TBI) is often associated with long-term cognitive deficits and altered brain networks which have been linked with accumulation of neurofibrillary tau tangles and neuroinflammation. In this work, we investigated the changes in the brain post-TBI in an Alzheimer's disease pR5 tauopathy model and evaluated the contribution of tauopathy and neuroinflammation to connectivity alterations using resting-state functional Magnetic Resonance Imaging (rs-fMRI). Method: 26 P301L tau transgenic mice of 8–9 months of age (21–35 g) expressing the human tau isoform carrying the pathogenic P301L mutation were used for the study. Animals were assessed at day 1 and 7 post-injury/craniotomy and were randomly divided into four groups. All animals underwent an MRI scan on a 9.4T Bruker system where rsfMRI was acquired. Following imaging, brains were stained with pSer (396 + 404), glial fibrillary acidic protein (GFAP), and ionised calcium-binding adaptor molecule-1 (Iba-1). Group-information-guided Independent Component Analysis (GIG-ICA) and region-of-interest (ROI)-based network connectivity approaches were applied. Principal Component Regression was applied to predict connectivity network strength from the corresponding ROIs. Results: TBI mice showed decreased functional connectivity in the dentate gyrus, thalamus, and other areas compared to sham animals at day 1 post-injury with the majority of changes resolving at day 7. Principal Component Regression showed only the contralateral CA1 network strength was correlated with the CA1′s astrocyte and microglia cell density and the ipsilateral thalamus network strength was correlated with the ipsilateral thalamus’ astrocyte and microglia cell density. Conclusion: We present the first report on the temporal alterations in functional connectivity in a P30IL mouse model following TBI. Connectivity between key regions known to be affected in Alzheimer's disease were short-term and reversible following injury. Connectivity strength in CA1 and thalamus showed significant correlation with astrocyte and microglial cell density but not tau density.
  • Developmental vitamin D-deficiency increases the expression of microRNAs involved in dopamine neuron development

    Schizophrenia is a neurodevelopmental disorder associated with abnormal dopamine (DA) signalling and disruptions in early brain development. We have shown that developmental vitamin D-deficiency (DVD-deficiency) increases the risk of schizophrenia in offspring and impairs various aspects of brain development in rodents, particularly that of DA neurons, however the molecular basis of these impairments remains unclear. Here, we explore whether small non-coding microRNAs (miRNAs) are involved. miRNAs regulate gene expression post-transcriptionally via translational repression and destabilisation of mRNA. While dysregulation of multiple miRNAs has been reported in post-mortem brain of patients with schizophrenia, the biological pathways affected by these small RNAs are not clear. Here we identified differential expression of 18 miRNAs in DA neurons isolated from DVD-deficient embryos. Three miRNAs were selected for further functional studies of dopaminergic neuron differentiation based on their interactions with transcripts involved in neuronal maturation. In particular, we show upregulation of miR-181c-5p suppresses neurite outgrowth of dopaminergic neurons. These findings provide further evidence that an environmental risk factor for schizophrenia – DVD-deficiency – disrupts the development of DA neurons and suggests increased miRNA expression may be one possible mechanism. This disruption potentially underlies the long-term alterations in DA mediated brain function in DVD-deficient offspring, and by inference in schizophrenia.
  • Hydrocephalus in Nfix−/− mice is underpinned by changes in ependymal cell physiology

    Nuclear factor one X (NFIX) is a transcription factor required for normal ependymal development. Constitutive loss of Nfix in mice (Nfix−/−) is associated with hydrocephalus and sloughing of the dorsal ependyma within the lateral ventricles. Previous studies have implicated NFIX in the transcriptional regulation of genes encoding for factors essential to ependymal development. However, the cellular and molecular mechanisms underpinning hydrocephalus in Nfix−/− mice are unknown. To investigate the role of NFIX in hydrocephalus, we examined ependymal cells in brains from postnatal Nfix−/− and control (Nfix+/+) mice using a combination of confocal and electron microscopy. This revealed that the ependymal cells in Nfix−/− mice exhibited abnormal cilia structure and disrupted localisation of adhesion proteins. Furthermore, we modelled ependymal cell adhesion using epithelial cell culture and revealed changes in extracellular matrix and adherens junction gene expression following knockdown of NFIX. Finally, the ablation of Nfix from ependymal cells in the adult brain using a conditional approach culminated in enlarged ventricles, sloughing of ependymal cells from the lateral ventricles and abnormal localisation of adhesion proteins, which are phenotypes observed during development. Collectively, these data demonstrate a pivotal role for NFIX in the regulation of cell adhesion within ependymal cells of the lateral ventricles.
  • Activity in the dorsomedial striatum underlies serial reversal learning performance under probabilistic uncertainty

    BackgroundCortico-striatal circuits, particularly the dorsomedial striatum (DMS) and lateral orbitofrontal cortex, are critical for navigating reversal learning under probabilistic uncertainty. These same areas are implicated in the reversal learning impairments observed in those with psychosis, as well as their psychotic symptoms, suggesting they may share a common neurobiological substrate. To address this question, we used psychostimulant exposure and specific activation of the DMS during reversal learning in mice to assess corticostriatal activity.MethodsWe used amphetamine treatment to induce psychosis-relevant neurobiology in male mice during reversal learning and to examine pathway specific cortico-striatal activation. To determine the causal role of DMS activity we used chemogenetics to drive midbrain inputs during a range of probabilistic contingencies.ResultsMice treated with amphetamine showed altered punishment learning, which was associated with decreased shifting after losses and increased perseverative errors after reversals. Reversal learning performance and strategies were dependent on increased activity in lateral orbitofrontal cortex to DMS circuits, as well as in the DMS itself. Specific activation of midbrain to DMS circuits also decreased shifting after losses and reversal learning performance. However, these alterations were dependent on the probabilistic contingency.ConclusionsOur work suggests that the DMS plays a multifaceted role in reversal learning. Increasing DMS activity impairs multiple reversal learning processes dependent on the level of uncertainty, confirming its role in the maintenance and selection of incoming cortical inputs. Together, these outcomes suggest that elevated dopamine in the DMS could contribute to decision-making impairments in those with psychosis.
  • Ancestral SARS-CoV-2, but not Omicron, replicates less efficiently in primary pediatric nasal epithelial cells

    Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when compared to adults. There is a strong body of evidence that children are also less susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remain to be determined. Here, we use primary nasal epithelial cells (NECs) from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the NECs of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the NECs of children. Importantly, the Delta variant also replicated to significantly lower titers in the NECs of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.
  • Meal provision in early childhood education and care programs: Association with geographic disadvantage, social disadvantage, cost, and market competition in an Australian population

    Background: Across developed economies, most children attend early childhood education and care (ECEC) programs attending up to 10,000 h prior to school. These programs present significant opportunity for public health nutrition interventions through provision of healthy food. We sought to identify whether this opportunity is being taken through analysis of population data from Queensland, Australia. Specifically, we asked if meal provision occurs in locations where risk of food insecurity is high and how economic functioning of ECEC services is associated with meal provision. Methods: Of ECEC services in Queensland, (N = 1623) administrative data on meal provision (2020) was available for 947 ECEC services (58.4% of cohort). We assessed the association of meal provision in these services with area indices of social disadvantage (geographic location, social disadvantage, proportion of child developmental vulnerability) and ECEC service economic functioning (fee structure, market competition). Findings: ECEC services in remote and rural communities were less likely to provide meals. A similar but weaker trend was evident in socio-economically disadvantaged metropolitan communities. In these locations market competition increased likelihood of meal provision but without fee increase. Interpretation: The competitive market works contrary to the potential for ECEC services to support child nutrition and promote public health. Children living in disadvantaged communities, where food insecurity is inevitably higher, are less likely to have meals provided by their ECEC service. Market competition increases the likelihood of meal provision, yet in disadvantaged communities, parents’ ability to pay constrains fees that can be charged raising concern about food quality and effects on quality of provision more broadly. Systemic public supports to enable high quality food provision without compromising other aspects of quality, particularly in the most disadvantaged communities, should be a public health priority.
  • Investigating the role of GABA in neural development and disease using mice lacking GAD67 or VGAT genes

    Normal development and function of the central nervous system involves a balance between excitatory and inhibitory neurotransmission. Activity of both excitatory and inhibitory neurons is modulated by inhibitory signalling of the GABAergic and glycinergic systems. Mechanisms that regulate formation, maturation, refinement, and maintenance of inhibitory synapses are established in early life. Deviations from ideal excitatory and inhibitory balance, such as down-regulated inhibition, are linked with many neurological diseases, including epilepsy, schizophrenia, anxiety, and autism spectrum disorders. In the mammalian forebrain, GABA is the primary inhibitory neurotransmitter, binding to GABA receptors, opening chloride channels and hyperpolarizing the cell. We review the involvement of down-regulated inhibitory signalling in neurological disorders, possible mechanisms for disease progression, and targets for therapeutic intervention. We conclude that transgenic models of disrupted inhibitory signalling-in GAD67(+/-) and VGAT(-/-) mice-are useful for investigating the effects of down-regulated inhibitory signalling in a range of neurological diseases.
  • Dissecting the role of adult hippocampal neurogenesis towards resilience versus susceptibility to stress-related mood disorders

    Adult hippocampal neurogenesis in the developmental process of generating and integrating new neurons in the hippocampus during adulthood and is a unique form of structural plasticity with enormous potential to modulate neural circuit function and behaviour. Dysregulation of this process is strongly linked to stress-related neuropsychiatric conditions such as anxiety and depression, and efforts have focused on unravelling the contribution of adult-born neurons in regulating stress response and recovery. Chronic stress has been shown to impair this process, whereas treatment with clinical antidepressants was found to enhance the production of new neurons in the hippocampus. However, the precise role of adult hippocampal neurogenesis in mediating the behavioural response to chronic stress is not clear and whether these adult-born neurons buffer or increase susceptibility to stress-induced mood-related maladaptation remains one of the controversial issues. In this review, we appraise evidence probing the causal role of adult hippocampal neurogenesis in the regulation of emotional behaviour in rodents. We find that the relationship between adult-born hippocampal neurons and stress-related mood disorders is not linear, and that simple subtraction or addition of these neurons alone is not sufficient to lead to anxiety/depression or have antidepressant-like effects. We propose that future studies examining how stress affects unique properties of adult-born neurons, such as the excitability and the pattern of connectivity during their critical period of maturation will provide a deeper understanding of the mechanisms by which these neurons contribute to functional outcomes in stress-related mood disorders.
  • Clinical, demographic, and genetic risk factors of treatment‐attributed suicidality in >10,000 Australian adults taking antidepressants

    Emergence of suicidal symptoms has been reported as a potential antidepressant adverse drug reaction. Identifying risk factors associated could increase our understanding of this phenomenon and stratify individuals at higher risk. Logistic regressions were used to identify risk factors of self-reported treatment-attributed suicidal ideation (TASI). We then employed classifiers to test the predictive ability of the variables identified. A TASI GWAS, as well as SNP-based heritability estimation, were performed. GWAS replication was sought from an independent study. Significant associations were found for age and comorbid conditions, including bipolar and personality disorders. Participants reporting TASI from one antidepressant were more likely to report TASI from other antidepressants. No genetic loci associated with TAS I (p < 5e-8) were identified. Of 32 independent variants with suggestive association (p < 1e-5), 27 lead SNPs were available in a replication dataset from the GENDEP study. Only one variant showed a consistent effect and nominal association in the independent replication sample. Classifiers were able to stratify non-TASI from TASI participants (AUC = 0.77) and those reporting treatment-attributed suicide attempts (AUC = 0.85). The pattern of TASI co-occurrence across participants suggest nonspecific factors underlying its etiology. These findings provide insights into the underpinnings of TASI and serve as a proof-of-concept of the use of classifiers for risk stratification.
  • Self‐reported child maltreatment and cardio‐metabolic risk in 30‐year‐old adults

    Childhood maltreatment (CM) is associated with both dietary fat intake and obesity in later life. There is less information on associations with metabolic risk factors and specific types of CM such as physical, sexual and emotional abuse, as well as neglect.

    To assess the association between five types of self-reported CM and a range of obesity and metabolic indicators in a subsample of a birth cohort.

    This was a study of 1689 adults born in a major metropolitan maternity hospital in Australia and followed-up 30 years later. Body Mass Index, bioimpedance and fasting lipid levels/ insulin resistance were measured. Details on self-reported CM were collected using the Child Trauma Questionnaire. We adjusted for birth weight, parental income and relationship at participants' birth, as well as maternal age and alcohol or tobacco use. We also adjusted for participants' smoking, depression, educational level, marital and employment status at follow-up.

    One fifth reported maltreatment (n = 362), most commonly emotional neglect (n = 175), followed by emotional abuse (n = 128), physical neglect (=123), sexual (n = 121) and physical abuse (n = 116). On adjusted analyses, there were significant associations for CM, particularly neglect or emotional abuse, and one or more of the following outcomes: obesity, the total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio and HDL levels.. Results for other outcomes were more equivocal.

    Of child maltreatment types, emotional abuse and neglect show the strongest associations with obesity and several cardio-metabolic risk factors, so highlighting the public health importance of early intervention to reduce childhood adversity. This article is protected by copyright. All rights reserved.
  • A systematic review of frailty education programs for health care professionals

    ObjectivesTo identify and examine the reported effectiveness of education programs for health professionals on frailty.MethodsA systematic review was conducted of articles published up to June 2021, examining the evaluation of frailty training or education programs targeting health professionals/students. The participant demographics, program content and structure, effectiveness assessment methodology and outcomes, as well as participant feedback, were recorded with narrative synthesis of results.ResultsThere were nine programs that have evaluated training of health professionals in frailty. These programs varied with respect to intensity, duration, and delivery modality, and targeted a range of health professionals and students. The programs were well-received and found to be effective in increasing frailty knowledge and self-perceived competence in frailty assessment. Common features of successful programs included having multidisciplinary participants, delivering a clinically tailored program and using flexible teaching modalities. Of note, many programs assessed self-perceived efficacy rather than objective changes in patient outcomes.ConclusionsDespite increasing attention on frailty in clinical practice, this systematic review found that there continues to be limited reporting of frailty training programs.
  • Versatile aza‐BODIPY ‐based low‐bandgap conjugated small molecule for light harvesting and near‐infrared photodetection

    The versatile nature of organic conjugated materials renders their flawless integration into a diverse family of optoelectronic devices with light-harvesting, photodetection, or light-emitting capabilities. Classes of materials that offer the possibilities of two or more distinct optoelectronic functions are particularly attractive as they enable smart applications while providing the benefits of the ease of fabrication using low-cost processes. Here, we develop a novel, multi-purpose conjugated small molecule by combining boron-azadipyrromethene (aza-BODIPY) as electron acceptor with triphenylamine (TPA) as end-capping donor units. The implemented donor–acceptor–donor (D–A–D) configuration, in the form of TPA-azaBODIPY-TPA, preserves ideal charge transfer characteristics with appropriate excitation energy levels, with the additional ability to be used as either a charge transporting interlayer or light-sensing semiconducting layer in optoelectronic devices. To demonstrate its versatility, we first show that TPA-azaBODIPY-TPA can act as an excellent hole transport layer in methylammonium lead triiodide (MAPbI)-based perovskite solar cells with measured power conversion efficiencies exceeding 17%, outperforming control solar cells with PEDOT:PSS by nearly 60%. Furthermore, the optical bandgap of 1.49 eV is shown to provide significant photodetection in the wavelength range of up to 800 nm where TPA-azaBODIPY-TPA functions as donor in near-infrared organic photodetectors (OPDs) composed of fullerene derivatives. Overall, the established versatility of TPA-azaBODIPY-TPA, combined with its robust thermal stability as well as excellent solubility and processability, provides a new guide for developing highly efficient multi-purpose electronic materials for the next-generation of smart optoelectronic devices. (Figure presented.).
  • Frailty and Treatment-Resistant Schizophrenia: A Retrospective Cohort Study

    Frailty, a state of reduced physiological reserve, has not been studied in consumers with treatment-resistant schizophrenia, despite known elevated rates of comorbidity and psychosocial impairment. This study applies a frailty index to the electronic medical records of 78 adults with treatment-resistant schizophrenia, aged 18–64 years, to determine the prevalence and characteristics of frailty (defined as a frailty index score > 0.21). The mean frailty index score was 0.24 (SD = 0.091, range = 0.061–0.54), with 52.6% of the population categorised as frail (40.0% in those aged 18–39 years). Frailty was positively correlated with age and psychiatric illness severity. This study provides novel evidence that individuals with treatment-resistant schizophrenia have a high rate of frailty and become frail at a younger age. Routine frailty assessments could be used to trigger the delivery of appropriate interventions, which have the potential to improve life expectancy and quality of life.
  • Post-stroke apathy: a case series investigation of neuropsychological and lesion characteristics

    Apathy is a multi-dimensional syndrome associated with reduced initiation, executive function and emotion toward goal-directed behaviour. Affecting ∼30% of stroke patients, apathy can negatively impact rehabilitation outcomes and increase caregiver burden. However, relatively little is known about the multi-dimensional nature of post-stroke apathy and whether these dimensions map onto neuropsychological and neuroanatomical correlates. The present study aimed to address this question in a case series of stroke patients with apathy. 65 patients with acute stroke were assessed on a comprehensive battery of neuropsychological tasks and 12 patients were identified as having clinically significant apathy on one or more domains on the Dimensional Apathy Scale. Individual scores were compared to a group of healthy controls and normative data where available. Lesion mapping was completed from clinical CT and MRI scans to characterise the extent and locations of each patient's lesion. All participants performed significantly poorer than controls on one or more tasks. Difficulties with inhibition were observed across all dimensions. Prospective memory deficits were also common, while speed and social cognition were only reduced in initiation and emotional apathy, respectively. Verbal fluency was not impaired in any of the patients, despite previously established relationships with apathy. Lesions were predominantly located in right subcortical regions, with some additional frontal, temporal and cerebellar/brainstem involvement. There was substantial overlap in lesion locations within and between dimensions, such that similar apathy symptoms occurred in patients with very different lesion sites. Overall, our results suggest that neuropsychological and lesion profiles of apathy in stroke patients may be more complex and heterogenous than in neurodegenerative disease, possibly due to functional changes occurring beyond the lesion site.
  • Does a rare mutation in PTPRA contribute to the development of Parkinson's disease in an Australian multi-incident family?

    The genetic study of multi-incident families is a powerful tool to investigate genetic contributions to the development of Parkinson's disease. In this study, we identified the rare PTPRA p.R223W variant as one of three putative genetic factors potentially contributing to disease in an Australian family with incomplete penetrance. Whole exome sequencing identified these mutations in three affected cousins. The rare PTPRA missense variant was predicted to be damaging and was absent from 3,842 alleles from PD cases. Overexpression of the wild-type RPTPα and R223W mutant in HEK293T cells identified that the R223W mutation did not impair RPTPα expression levels or alter its trafficking to the plasma membrane. The R223W mutation did alter proteolytic processing of RPTPα, resulting in the accumulation of a cleavage product. The mutation also resulted in decreased activation of Src family kinases. The functional consequences of this variant, either alone or in concert with the other identified genetic variants, highlights that even minor changes in normal cellular function may increase the risk of developing PD.
  • Correlation between fluorodeoxyglucose positron emission tomography brain hypometabolism and posttraumatic stress disorder symptoms in temporal lobe epilepsy

    The relationship between posttraumatic stress disorder (PTSD) and focal epilepsy is poorly understood. It has been hypothesized that there is a complex and reciprocal potential reinforcement of the symptoms of each condition. In this study, we investigated whether there are PTSD-specific brain changes in temporal lobe epilepsy (TLE). Brain fluorodeoxyglucose positron emission tomography (PET) metabolism was compared between controls and two groups of TLE patients: one group of 15 patients fulfilling the criteria for a potential diagnosis of PTSD (TLE-PTSD+), another group of 24 patients without a diagnosis of PTSD (TLE-PTSD-), and a group of 30 healthy control participants. We compared the differences in brain PET metabolism among these three groups, and we studied their correlations with interictal and peri-ictal scales of PTSD symptoms. TLE-PTSD+ patients showed more significant hypometabolism involving right temporal and right orbitofrontal cortex in comparison to TLE-PTSD- patients and healthy subjects. Moreover, degree of reduced metabolism in these brain areas correlated with interictal and peri-ictal PTSD questionnaire scores. PTSD in temporal epilepsy is associated with specific changes in neural networks, affecting limbic and paralimbic structures. This illustrates the close intertwining of epileptogenic and psychogenic processes in these patients.
  • Cortical axon sub-population maintains density, but not turnover, of en passant boutons in the aged APP/PS1 amyloidosis model

    Synaptic dysfunction is one of the key mechanisms associated with cognitive deficits observed in Alzheimer's disease (AD), yet little is known about the presynaptic axonal boutons in AD. Focusing on cortical en passant boutons (EPBs) along axons located in the motor, sensory and prefrontal regions of the cerebral cortex in the APP/PS1 mouse model of AD, we investigated structural properties of EPBs over the lifespan and in response to a midlife environmental enrichment (EE) intervention. At 3, 12, and 18-22 months and following 6 months of midlife EE, we found that EPBs showed remarkable resilience in preserving overall synaptic output, as evidenced by the maintained density of EPBs along the axon shaft across all experimental conditions. Using cranial window imaging to monitor synaptic changes in real time, we report that despite maintaining a stable synaptic density, the dynamic fraction (gains and losses) of EPBs was significantlyreduced at 10-13 months of age in APP/PS1 axons compared to age matched controls.
  • Lifetime prevalence and correlates of perinatal depression in a case-cohort study of depression

    This study sought to evaluate the prevalence, timing of onset and duration of symptoms of depression in the perinatal period (PND) in women with depression, according to whether they had a history of depression prior to their first perinatal period. We further sought to identify biopsychosocial correlates of perinatal symptoms in women with depression.

    The Australian Genetics of Depression Study is an online case cohort study of the aetiology of depression. For a range of variables, women with depression who report significant perinatal depressive symptoms were compared with women with lifetime depression who did not experience perinatal symptoms.

    In a large sample of parous women with major depressive disorder (n=7182), we identified two subgroups of PND cases with and without prior depression history (n=2261; n=878, respectively).

    The primary outcome measure was a positive screen for PND on the lifetime version of the Edinburgh Postnatal Depression Scale. Descriptive measures reported lifetime prevalence, timing of onset and duration of PND symptoms. There were no secondary outcome measures.

    The prevalence of PND among parous women was 70%. The majority of women reported at least one perinatal episode with symptoms both antenatally and postnatally. Of women who experienced depression prior to first pregnancy, PND cases were significantly more likely to report more episodes of depression (OR=1.15 per additional depression episode, 95% CI 1.13 to 1.17, p<0.001), non-European ancestry (OR 1.5, 95% CI 1.0 to 2.1, p=0.03), severe nausea during pregnancy (OR 1.3, 95% CI 1.1 to 1.6, p=0.006) and emotional abuse (OR 1.4, 95% CI 1.1 to 1.7, p=0.005).

    The majority of parous women with lifetime depression in this study experienced PND, associated with more complex, severe depression. Results highlight the importance of perinatal assessments of depressive symptoms, particularly for women with a history of depression or childhood adverse experiences.
  • Fishing for DNA? Designing baits for population genetics in target enrichment experiments: guidelines, considerations and the new tool supeRbaits

    Targeted sequencing is an increasingly popular Next Generation Sequencing (NGS) approach for studying populations that involves focusing sequencing efforts on specific parts of the genome of a species of interest. Methodologies and tools for designing targeted baits are scarce but in high demand. Here, we present specific guidelines and considerations for designing capture sequencing experiments for population genetics for both neutral genomic regions and regions subject to selection. We describe the bait design process for three diverse fish species: Atlantic salmon, Atlantic cod and tiger shark, which was carried out in our research group, and provide an evaluation of the performance of our approach across both historical and modern samples. The workflow used for designing these three bait sets has been implemented in the R-package supeRbaits, which encompasses our considerations and guidelines for bait design for the benefit of researchers and practitioners. The supeRbaits R-package is user-friendly and versatile. It is written in C++ and implemented in R. supeRbaits and its manual are available from Github: https://github.com/BelenJM/supeRbaits.