QBI research publications

  • 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.
  • 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.
  • 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.
  • 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/.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Transcranial direct current stimulation of three cortical targets is no more effective than placebo as treatment for fibromyalgia: a double-blind sham-controlled clinical trial

    Transcranial Direct Current Stimulation (tDCS) over the primary motor cortex (M1) and the Dorsolateral Prefrontal Cortex (DLPFC) seem to improve pain and other symptoms of fibromyalgia (FM), although the evidence on the effectiveness of tDCS and the optimal stimulation target is not robust enough. Our main objective was to establish the optimal area of stimulation, comparing the two classical targets and a novel pain-related area, the Operculo Insular Cortex (OIC), in a sham-controlled trial. Using a double-blind design, we randomly assigned 130 women with FM to four treatment groups (M1, DLPFC, OIC, Sham), each receiving fifteen 20-minute sessions of 2mA anodal tDCS over the left hemisphere. Our primary outcome was pain intensity. The secondary outcomes were the other core symptoms of FM (fatigue, mood, cognitive and sleep disorders, hyperalgesia measured by pressure pain threshold). We performed the assessment at 3 time points (before, immediately after treatment, and at 6 months follow-up). The linear mixed-model ANOVAs showed significant treatment effects across time for clinical pain and for fatigue, cognitive and sleep disturbances, and experimental pain, irrespective of the group. In mood, the three active tDCS groups showed a significantly larger improvement in anxiety and depression than sham. Our findings provide evidence of a placebo effect, support the use of tDCS for the treatment of affective symptoms, and challenge the effectiveness of tDCS as treatment of FM.
  • Neural development: bicoid not as a morphogen

    Bicoid is famous for its role in early embryo patterning of Drosophila by activating Hunchback expression to establish the anterior–posterior axis. A new study found that in a type of post-mitotic neuron Hunchback conversely activates Bicoid expression to regulate synapse targeting and locomotor behavior.
  • Isolation and culture of pure adult mouse microglia and astrocytes for in vitro characterization and analyses

    Microglia and astrocytes are implicated in aging and age-related diseases. Here, we present a protocol to isolate and culture these glia cells from the murine brain. The protocol consists of two parts: magnetic sorting of adult microglia and mechanical/magnetic sorting of adult microglia and astrocytes. We then describe the characterization of these glial cells by flow cytometry and immunohistochemistry. Microglia isolated from aged mice maintain age-related phenotype during culture. These purified glia cells can be applied in ex vivo studies.
  • Emotional quality of early education programs improves language learning: A within‐child across context design

    Observational studies comparing child outcomes in early care and education classrooms of differing quality are often confounded by between-child differences. A within-child design, tracking children across contexts, can identify the effects of quality with less confounding. An analysis of Australian children (N = 1128, mean age 5 years, 48% female, 2.9% Indigenous, ethnicity data unavailable) tracked across pre-K, K, and year 1 (2010–2012) was conducted to assess how changes in observed quality (Classroom Assessment Scoring System) were associated with changes in cognitive development (Woodcock–Johnson III). Thresholds of quality were also investigated. Increases in Emotional Support were associated with improved language development (β = 0.54, 95% CI [0.1–0.99], approximating 2.6 weeks development). Results highlight that emotional quality is an integral and potent component of early learning.
  • Optimising the classification of feature-based attention in frequency-tagged electroencephalography data

    Brain-computer interfaces (BCIs) are a rapidly expanding field of study and require accurate and reliable real-time decoding of patterns of neural activity. These protocols often exploit selective attention, a neural mechanism that prioritises the sensory processing of task-relevant stimulus features (feature-based attention) or task-relevant spatial locations (spatial attention). Within the visual modality, attentional modulation of neural responses to different inputs is well indexed by steady-state visual evoked potentials (SSVEPs). These signals are reliably present in single-trial electroencephalography (EEG) data, are largely resilient to common EEG artifacts, and allow separation of neural responses to numerous concurrently presented visual stimuli. To date, efforts to use single-trial SSVEPs to classify visual attention for BCI control have largely focused on spatial attention rather than feature-based attention. Here, we present a dataset that allows for the development and benchmarking of algorithms to classify feature-based attention using single-trial EEG data. The dataset includes EEG and behavioural responses from 30 healthy human participants who performed a feature-based motion discrimination task on frequency tagged visual stimuli.
  • Prenatal hypoxia alters the early ontogeny of dopamine neurons

    Dopaminergic (DA) dysfunction is a significant feature in the pathophysiology of schizophrenia. Established developmental risk factors for schizophrenia such as maternal immune activation (MIA) or developmental vitamin D (DVD) deficiency, when modelled in animals, reveal the differentiation of early DA neurons in foetal brains is delayed suggesting this may be a convergent aetiological pathway. Here we have assessed the effects of prenatal hypoxia, another well-known developmental risk factor for schizophrenia, on developing DA systems. Pregnant mice were exposed to a hypoxic environment of 10% oxygen for 48 h from embryonic day 10 (E10) to E12. Embryonic brains were collected and the positioning of mesencephalic cells, expression of DA specification and maturation factors were examined along with the expression of factors that may govern the migration of these neurons. We show that prenatal hypoxia results in a decrease in dopaminergic progenitors retards early DA neuron lateral migration and reduces expression of the receptors known to govern this process. A second time-point, postnatal day 10 (P10) was also examined in order to assess whether prenatal hypoxia alters early presynaptic architecture in the developing striatum. We show reduced expression of tyrosine hydroxylase (TH) in the postnatal striatum along with increases in the density of high-probability DA release sites within TH varicosities. These findings add to the emerging literature showing that multiple epidemiologically validated environmental risk factors for schizophrenia may induce early alterations to develop DA systems. This may represent a possible convergent mechanism in the onset of presynaptic DA dysfunction in patients.
  • Implementation of a Hybrid Teleneuropsychology Method to Assess Middle Aged and Older Adults During the COVID-19 Pandemic

    ObjectiveHybrid teleneuropsychology has emerged as a useful assessment method to manage physical distancing requirements during the COVID-19 pandemic. We describe the development of a hybrid teleneuropsychology clinic and compare results of six neuropsychological tasks across testing modalities, as well as a participant experience survey.MethodHealthy middle-aged and older adults completed a face-to-face assessment two years previously. Participants either completed reassessment face-to-face or via the hybrid setup. Results were compared across time points and delivery modality.ResultsThere were no significant differences in scores at reassessment between face-to-face and a hybrid setup on nonverbal fluid intelligence, verbal memory, visual memory, language, working memory or verbal initiation. Retest reliability was moderate to excellent for verbal and visual memory, attention and naming. Results of an anonymous survey indicated that participants felt comfortable and established good rapport with the examiner.ConclusionsThis hybrid method of teleneuropsychology can be used to obtain high quality and reliable results including on tasks yet to be evaluated for teleneuropsychology, including the Graded Naming Test and the Topographical Recognition Memory Test.
  • Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

    We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
  • Social Inference from Middle to Older Adulthood

    ObjectiveInferring the emotional state or the true meaning of another person’s utterance is a key aspect of social cognition and critical for successful social interactions. In this study, we assess age-related differences in emotion recognition and sincere and sarcastic social exchanges in the context of cognitive and demographic factors.MethodOne hundred and eighty-seven adults ranging from middle to older adulthood completed the Mini-SEA Emotion Recognition test and Part B of The Awareness of Social Inference Test – Short Form (TASIT-S). Fluid intelligence and executive abilities were also assessed. Sex differences and the relationship with education level were also investigated. Regression models were used to assess age-related differences controlling for baseline cognitive and demographic factors.ResultsAge was negatively associated with accuracy for inferring sincere social exchanges. No differences were identified for accuracy for inferring sarcastic exchanges. Likewise, no age differences were identified for emotion recognition (Mini-SEA). Fluid intelligence was associated with accuracy for inferring sincere exchanges, but this was independent of age-related effects. A female advantage was identified for emotion recognition.ConclusionAge is associated with difficulty in inferring sincere exchanges, which is not explained by fluid intelligence, verbal abstract reasoning, or auditory verbal attention. A female advantage in emotion recognition is consistent with findings reported in younger adults. Both age and sex should be considered in clinical assessments using the Mini-SEA and the TASIT-S.
  • Unconscious influences on “free will” movement initiation: slow-wave brain stimulation and the readiness potential

    A central objective in the study of volition has been to identify how changes in neural activity relate to voluntary-"free will"-movement. The readiness potential (RP) is observed in the EEG as a slow-building signal that precedes action onset. Many consider the RP as a marker of an underlying preparatory process for initiating voluntary movement. However, the RP may emerge from ongoing slow-wave brain oscillations that influence the timing of movement initiation in a phase-dependent manner. Transcranial alternating current stimulation (tACS) enables brain oscillations to be entrained at the frequency of stimulation. We delivered tACS at a slow-wave frequency over frontocentral motor areas while participants (n = 30) performed a simple, self-paced button press task. During the active tACS condition, participants showed a tendency to initiate actions in the phase of the tACS cycle that corresponded to increased negative potentials across the frontocentral motor region. Comparisons of premovement EEG activity observed over frontocentral and central scalp electrodes showed earlier onset and increased amplitude of RPs from active stimulation compared with sham stimulation. This suggests that movement-related activity in the brain can be modulated by the delivery of weak, nonconsciously perceptible alternating currents over frontocentral motor regions. We present novel findings that support existing theories, which suggest the timing of voluntary movement is influenced by the phase of slow-changing oscillating brain states.
  • After the acute crisis – engaging people with psychosis in rehabilitation-oriented care

  • Deep neural networks predict the need for CT in pediatric mild traumatic brain injury: a corroboration of the PECARN rule

    PurposeOnly 10% of CT scans unveil positive findings in mild traumatic brain injury, raising concerns of its overuse in this population. A number of clinical rules have been developed to address this issue, but they still suffer limitations in their specificity. Machine learning models have been applied in limited studies to mimic clinical rules; however, further improvement in terms of balanced sensitivity and specificity is still needed. In this work, the authors applied a deep artificial neural networks (DANN) model and an instance hardness threshold algorithm to reproduce the Pediatric emergency Care Applied Research Network (PECARN) clinical rule in a pediatric population collected as a part of the PECARN study between 2004 and 2006.MethodsThe DANN model was applied using 14,983 patients younger than 18 years with Glasgow Coma Scale scores ≥ 14 who had head CT reports. The clinical features of the PECARN rules, PECARN-A (group A, age < 2 years) and PECARN-B (group B, age ≤ 2 years), were used to directly evaluate the model. The average accuracy, sensitivity, precision, and specificity were calculated by comparing the model’s prediction outcome to that reported by the PECARN investigators. The instance hardness threshold and DANN model were applied to predict the need for CT in pediatric patients using fivefold cross-validation.ResultsIn the first phase, the DANN model resulted in 98.6% sensitivity and 99.7% specificity for predicting the need for CT using the predictors of the two PECARN clinical rules combined to train the model. In the second phase, the DANN model was superior to both the PECARN-A and PECARN-B rules using the predictors for each age group separately to train the model. Compared with the clinical rule, for group A, the model achieved average sensitivity (93.7% vs 100%) and specificity (97.5% vs 53.6%); for group B, the average sensitivity of the model was 99.2% versus 98.6%, and specificity was 98.8% versus 58.2%.ConclusionsIn this study, a DANN model achieved comparable sensitivity and outstanding specificity for replicating the PECARN clinical rule and predicting the need for CT in pediatric patients after mild traumatic brain injury compared with the original statistically derived clinical rule.
  • Increased context adjustment is associated with auditory sensitivities but not with autistic traits

    Bayesian models of autism suggest that alterations in context-sensitive prediction error weighting may underpin sensory perceptual alterations, such as hypersensitivities. We used an auditory oddball paradigm with pure tones arising from high or low uncertainty contexts to determine whether autistic individuals display differences in context adjustment relative to neurotypicals. We did not find group differences in early prediction error responses indexed by mismatch negativity. A dimensional approach revealed a positive correlation between context-dependent prediction errors and subjective reports of auditory sensitivities, but not with autistic traits. These findings suggest that autism studies may benefit from accounting for sensory sensitivities in group comparisons. Lay Summary: We aimed to understand if autistic and non-autistic groups showed differences in their electrical brain activity measured by electroencephalography (EEG) when listening to surprising tones infrequently embedded in a statistical pattern. We found no differences between the autistic and the non-autistic group in their EEG response to the surprising sound even if the pattern switched, indicating their ability to learn a pattern. We did find that, as subjective sensory sensitivities (but not autistic traits) increased, there were increasingly large differences between the EEG responses to surprising tones that were embedded in the different statistical patterns of tones. These findings show that perceptual alterations may be a function of sensory sensitivities, but not necessarily autistic traits. We suggest that future EEG studies in autism may benefit from accounting for sensory sensitivities.
  • State-dependent effects of neural stimulation on brain function and cognition

    Invasive and non-invasive brain stimulation methods are widely used in neuroscience to establish causal relationships between distinct brain regions and the sensory, cognitive and motor functions they subserve. When combined with concurrent brain imaging, such stimulation methods can reveal patterns of neuronal activity responsible for regulating simple and complex behaviours at the level of local circuits and across widespread networks. Understanding how fluctuations in physiological states and task demands might influence the effects of brain stimulation on neural activity and behaviour is at the heart of how we use these tools to understand cognition. Here we review the concept of such 'state-dependent' changes in brain activity in response to neural stimulation, and consider examples from research on altered states of consciousness (for example, sleep and anaesthesia) and from task-based manipulations of selective attention and working memory. We relate relevant findings from non-invasive methods used in humans to those obtained from direct electrical and optogenetic stimulation of neuronal ensembles in animal models. Given the widespread use of brain stimulation as a research tool in the laboratory and as a means of augmenting or restoring brain function, consideration of the influence of changing physiological and cognitive states is crucial for increasing the reliability of these interventions.
  • Mechanistic models of COVID-19: insights into disease progression, vaccines, and therapeutics

    The COVID-19 pandemic has severely impacted health systems and economies worldwide. Significant global efforts are therefore ongoing to improve vaccine efficacies, optimize vaccine deployment, and develop new antiviral therapies to combat the pandemic. Mechanistic viral dynamics and quantitative systems pharmacology models of SARS-CoV-2 infection, vaccines, immunomodulatory agents, and antiviral therapeutics have played a key role in advancing our understanding of SARS-CoV-2 pathogenesis and transmission, the interplay between innate and adaptive immunity to influence the outcomes of infection, effectiveness of treatments, mechanisms and performance of COVID-19 vaccines, and the impact of emerging SARS-CoV-2 variants. Here, we review some of the critical insights provided by these models and discuss the challenges ahead.
  • Genome-wide association study suggests the variant rs7551288*A within the DHCR24 gene is associated with poor overall survival in melanoma patients

    Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed over all 23 chromosomes were used for a genome-wide analysis. A suggestive genome-wide significant association of the intronic allele rs7551288*A with diminished melanoma-specific survival was detected (p = 2 × 10−6). The frequency of rs7551288*A was 0.43 and was not associated with melanoma risk, hair and eye colour, tanning and total naevus count. Cox regression multivariate analyses revealed a 5.31-fold increased risk of melanoma-specific death for patients with the rs7551288 A/A genotype, independent of tumour thickness, ulceration and stage of disease at diagnoses. The variant rs7551288 belongs to the DHCR24 gene, which encodes Seladin-1, an enzyme involved in the biosynthesis of cholesterol. Further investigations are needed to confirm this genetic variant as a novel prognostic biomarker and to explore whether specific treatment strategies for melanoma patients might be derived from it.
  • Complement drives circuit modulation in the adult brain

    Once widely considered an immune-privileged organ, the brain is now known to be intimately intertwined with immune-system activation. In particular, the complement system, an enzymatic cascade conferring innate immunity, has crucial functions for several neurodevelopmental and neuromigratory mechanisms. Recent advances have demonstrated the neurological importance of complement activation in the adult brain, whereby phagocytosis of weakened synapses biologically encodes "forgetting" of information through complement activation. Neurophysiologically, complement factors can also influence the brain's computational processes, increasing neuronal calcium influx and neurotransmitter release and altering synaptic strength. The complement system's effects on synaptic connectivity can also be observed in many pathological conditions including epilepsy, schizophrenia, and viral-induced cognitive deficits, where perturbations of complement-stimulated synaptic remodelling lead to severe dysfunction. In this review we provide an overview of current knowledge for complement in neurodevelopment, and examine recent evidence highlighting a critical physiological role of complement in the plasticity of the adult brain. This is especially relevant due to the explosion of complement-targeted therapeutics in clinical trials to treat neurological disorders.
  • HUSH, retrotransposon RNA, you're NEXT to decay

    Garland et al. (2022) discover a physical and functional connection between the HUSH silencing complex and the NEXT nuclear RNA decay complex in mouse embryonic stem cells and conclude HUSH recruits NEXT to degrade prematurely terminated retrotransposon RNAs.
  • The basal forebrain volume reduction detected by MRI does not necessarily link with the cholinergic neuronal loss in the Alzheimer's Disease mouse model

    Degeneration of cholinergic neurons in the basal forebrain (BF) contributes to cognitive impairment in Alzheimer's disease (AD) and other disorders. Atrophy of BF volume measured by structural MRI is thought to represent the loss of cholinergic neurons in this structure. As there are multiple types of neurons in the BF as well as glia and axons, whether this MRI measure actually reflects the change of cholinergic neurons has not been verified. In this study, we assessed BF cholinergic neuron number by histological counts and compared with the volume measurements by in vivo MRI in 3xTg mice, a model of familial AD. Both manual and template-based segmentation revealed atrophy of the medial septum (MS), consistent with a significant reduction in cholinergic neuron number. However, MRI-measured volume reduction did not correlate with the reduced cholinergic neuron number. To directly test whether specific loss of cholinergic neurons results in BF atrophy, we selectively ablated the cholinergic neurons in the MS. However, no detectable change in MRI volume was observed between lesioned and unlesioned mice. The results indicate that although loss of cholinergic neurons within the BF likely contributes to volume loss, this volume change cannot be taken as a direct biomarker of cholinergic neuron number.
  • Transcriptional signature in microglia isolated from an Alzheimer's disease mouse model treated with scanning ultrasound

    Transcranial scanning ultrasound combined with intravenously injected microbubbles (SUS) has been shown to transiently open the blood–brain barrier and reduce the amyloid-β (Aβ) pathology in the APP23 mouse model of Alzheimer's disease (AD). This has been accomplished through the activation of microglial cells; however, their response to the SUS treatment is incompletely understood. Here, wild-type (WT) and APP23 mice were subjected to SUS, using nonsonicated mice as sham controls. After 48 h, the APP23 mice were injected with methoxy-XO4 to label Aβ aggregates, followed by microglial isolation into XO4 and XO4 populations using flow cytometry. Both XO4 and XO4 cells were subjected to RNA sequencing and transcriptome profiling. The analysis of the microglial cells revealed a clear segregation depending on genotype (AD model vs. WT mice) and Aβ internalization (XO4 vs. XO4 microglia), but interestingly, no differences were found between SUS and sham in WT mice. Differential gene expression analysis in APP23 mice detected 278 genes that were significantly changed by SUS in the XO4 cells (248 up/30 down) and 242 in XO cells (225 up/17 down). Pathway analysis highlighted differential expression of genes related to the phagosome pathway and marked upregulation of cell cycle-related transcripts in XO4 and XO4- microglia isolated from SUS-treated APP23 mice. Together, this highlights the complexity of the microglial response to transcranial ultrasound, with potential applications for the treatment of AD.
  • Unconscious Influences on “Free Will” Movement Initiation: Slow-wave Brain Stimulation and the Readiness Potential

    A central objective in the study of volition has been to identify how changes in neural activity relate to voluntary—“free will”—movement. The readiness potential (RP) is observed in the EEG as a slow-building signal that precedes action onset. Many consider the RP as a marker of an underlying preparatory process for initiating voluntary movement. However, the RP may emerge from ongoing slow-wave brain oscillations that influence the timing of movement initiation in a phase-dependent manner. Transcranial alternating current stimulation (tACS) enables brain oscillations to be entrained at the frequency of stimulation. We delivered tACS at a slow-wave frequency over frontocentral motor areas while participants (n = 30) performed a simple, self-paced button press task. During the active tACS condition, participants showed a tendency to initiate actions in the phase of the tACS cycle that corresponded to increased negative potentials across the frontocentral motor region. Comparisons of premovement EEG activity observed over frontocentral and central scalp electrodes showed earlier onset and increased amplitude of RPs from active stimulation compared with sham stimulation. This suggests that movement-related activity in the brain can be modulated by the delivery of weak, nonconsciously perceptible alternating currents over frontocentral motor regions. We present novel findings that support existing theories, which suggest the timing of voluntary movement is influenced by the phase of slow-changing oscillating brain states.
  • The m6A-epitranscriptome in brain plasticity, learning and memory

    Activity-dependent gene expression and protein translation underlie the ability of neurons to dynamically adjust their synaptic strength in response to sensory experience and during learning. The emerging field of epitranscriptomics (RNA modifications) has rapidly shifted our views on the mechanisms that regulate gene expression. Among hundreds of biochemical modifications on RNA, N-methyladenosine (mA) is the most abundant reversible mRNA modification in the brain. Its dynamic nature and ability to regulate all aspects of mRNA processing have positioned mA as an important and versatile regulator of nervous system functions, including neuronal plasticity, learning and memory. In this review, we summarise recent experimental evidence that supports the role of mA signalling in learning and memory, as well as providing an overview of the underlying molecular mechanisms in neurons. We also discuss the consequences of perturbed mA signalling and/or its regulatory networks which are increasingly being linked to various cognitive disorders in humans.
  • Assessing dietary, exercise, and non-pharmacological modalities within psychiatric hospitals

  • Clozapine—balancing the body and the mind

  • Phototransduction in a marine sponge provides insights into the origin of animal vision

    Most organisms respond to light. Here, we investigate the origin of metazoan phototransduction by comparing well-characterized opsin-based photosystems in neural animals with those in the sponge Amphimedon queenslandica. Although sponges lack neurons and opsins, they can respond rapidly to light. In Amphimedon larvae, this is guided by the light-sensing posterior pigment ring. We first use cell-type-specific transcriptomes to reveal that genes that characterize eumetazoan Gt- and Go-mediated photosystems are enriched in the pigment ring. We then apply a suite of signaling pathway agonists and antagonists to swimming larvae exposed to directional light. These experiments implicate metabotropic glutamate receptors, phospholipase-C, protein kinase C, and voltage-gated calcium channels in larval phototaxis; the inhibition of phospholipase-C, a key transducer of the Gq-mediated pathway, completely reverses phototactic behavior. Together, these results are consistent with aneural sponges sharing with neural metazoans an ancestral set of photosignaling pathways.
  • Subacute cytokine changes after a traumatic brain injury predict chronic brain microstructural alterations on advanced diffusion imaging in the male rat

    Introduction: The process of neuroinflammation occurring after traumatic brain injury (TBI) has received significant attention as a potential prognostic indicator and interventional target to improve patients’ outcomes. Indeed, many of the secondary consequences of TBI have been attributed to neuroinflammation and peripheral inflammatory changes. However, inflammatory biomarkers in blood have not yet emerged as a clinical tool for diagnosis of TBI and predicting outcome. The controlled cortical impact model of TBI in the rodent gives reliable readouts of the dynamics of post-TBI neuroinflammation. We now extend this model to include a panel of plasma cytokine biomarkers measured at different time points post-injury, to test the hypothesis that these markers can predict brain microstructural outcome as quantified by advanced diffusion-weighted magnetic resonance imaging (MRI). Methods: Fourteen 8–10-week-old male rats were randomly assigned to sham surgery (n = 6) and TBI (n = 8) treatment with a single moderate-severe controlled cortical impact. We collected blood samples for cytokine analysis at days 1, 3, 7, and 60 post-surgery, and carried out standard structural and advanced diffusion-weighted MRI at day 60. We then utilized principal component regression to build an equation predicting different aspects of microstructural changes from the plasma inflammatory marker concentrations measured at different time points. Results: The TBI group had elevated plasma levels of IL-1β and several neuroprotective cytokines and chemokines (IL-7, CCL3, and GM-CSF) compared to the sham group from days 3 to 60 post-injury. The plasma marker panels obtained at day 7 were significantly associated with the outcome at day 60 of the trans-hemispheric cortical map transfer process that is a frequent finding in unilateral TBI models. Discussion: These results confirm and extend prior studies showing that day 7 post-injury is a critical temporal window for the reorganisation process following TBI. High plasma level of IL-1β and low plasma levels of the neuroprotective IL-7, CCL3, and GM-CSF of TBI animals at day 60 were associated with greater TBI pathology.
  • Do the numbers add up? Questioning measurement that places Australian ECEC teaching as ‘low quality’

    Internationally, standard observational measures of Early Childhood Education and Care (ECEC) are used to assess the quality of provision. They are applied as research tools but, significantly, also guide policy decisions, distribution of resources and public opinion. Considerable faith is placed in such measures, yet their validity, reliability and functioning within context should all be considered in interpreting the findings they generate. We examine the case of the Classroom Assessment Scoring System (CLASS) in the Australian study, Effective Early Education for Children (E4Kids). Using this measure Australian educators were identified as "low quality" in provision of instruction (average 2.1 on a scale of 1-7). When these results became public, they attracted negative press coverage and the potential for harm. We interrogate these findings asking three questions relating to sampling, contextual and empirical evidence that define quality and measurement strategies. We conclude that measurement problems, most notably a floor effect, is the most likely explanation for uniformly low CLASS-Instructional scores among Australian ECEC educators, and indeed across international studies. Using a theoretically and empirically informed rescaling strategy we show that there is a diversity of instructional quality across Australian ECEC, and that rescaling might more effectively guide improvement strategies to target those of lowest quality. Beyond, our findings call for a more critical approach in interpretation of standard measures of ECEC quality and their applications in policy and practice, internationally.
  • Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor Neuron Disease

    A central event in the pathogenesis of motor neuron disease (MND) is the loss of neuromuscular junctions (NMJs), yet the mechanisms that lead to this event in MND remain to be fully elucidated. Maintenance of the NMJ relies upon neural agrin (n-agrin) which, when released from the nerve terminal, activates the postsynaptic Muscle Specific Kinase (MuSK) signaling complex to stabilize clusters of acetylcholine receptors. Here, we report that muscle from MND patients has an increased proportion of slow fibers and muscle fibers with smaller diameter. Muscle cells cultured from MND biopsies failed to form large clusters of acetylcholine receptors in response to either non-MND human motor axons or n-agrin. Furthermore, levels of expression of MuSK, and MuSK-complex components: LRP4, Caveolin-3, and Dok7 differed between muscle cells cultured from MND patients compared to those from non-MND controls. To our knowledge, this is the first time a fault in the n-agrin-LRP4-MuSK signaling pathway has been identified in muscle from MND patients. Our results highlight the n-agrin-LRP4-MuSK signaling pathway as a potential therapeutic target to prolong muscle function in MND.
  • Fixed point attractor theory bridges structure and function in C. elegans neuronal network

    Understanding the structure–function relationship in a neuronal network is one of the major challenges in neuroscience research. Despite increasing researches at circuit connectivity and neural network structure, their structure-based biological interpretability remains unclear. Based on the attractor theory, here we develop an analytical framework that links neural circuit structures and their functions together through fixed point attractor in Caenorhabditis elegans. In this framework, we successfully established the structural condition for the emergence of multiple fixed points in C. elegans connectome. Then we construct a finite state machine to explain how functions related to bistable phenomena at the neural activity and behavioral levels are encoded. By applying the proposed framework to the command circuit in C. elegans, we provide a circuit level interpretation for the forward-reverse switching behaviors. Interestingly, network properties of the command circuit and first layer amphid interneuron circuit can also be inferred from their functions in this framework. Our research indicates the reliability of the fixed point attractor bridging circuit structure and functions, suggesting its potential applicability to more complex neuronal circuits in other species.
  • A graph network model for neural connection prediction and connection strength estimation

    Reconstruction of connectomes at the cellular scale is a prerequisite for understanding the principles of neural circuits. However, due to methodological limits, scientists have reconstructed the connectomes of only a few organisms such as C. elegans, and estimated synaptic strength indirectly according to their size and number.

    Here, we propose a graph network model to predict synaptic connections and estimate synaptic strength by using the calcium activity data from C. elegans.

    The results show that this model can reliably predict synaptic connections in the neural circuits of C. elegans, and estimate their synaptic strength, which is an intricate and comprehensive reflection of multiple factors such as synaptic type and size, neurotransmitter and receptor type, and even activity dependence. In addition, the excitability or inhibition of synapses can be identified by this model. We also found that chemical synaptic strength is almost linearly positively correlated to electrical synaptic strength, and the influence of one neuron on another is non-linearly correlated with the number between them. This reflects the intrinsic interaction between electrical and chemical synapses.

    Our model is expected to provide a more accessible quantitative and data-driven approach for the reconstruction of connectomes in more complex nervous systems, as well as a promising method for accurately estimating synaptic strength.
  • Color discrimination thresholds vary throughout color space in a reef fish (Rhinecanthus aculeatus)

    Animal use color vision in a range of behaviours. Visual performance is limited by thresholds, which are set by noise in photoreceptors and subsequent neural processing. The receptor noise limited (RNL) model of color discrimination is widely used for modelling color vision and accounts well for experimental data from many species. In one of the most comprehensive tests yet of color discrimination in a non-human species, we using Ishihara-style stimulus patterns to examine thresholds for 21 directions at five locations in color space for the fish Rhineacanthus aculeatus. Thresholds matched RNL model predictions most closely for stimuli near to the the achromatic point, but exceeded predictions (indicating a decline in sensitivity) with distance from this point. Thresholds were also usually higher for saturation than for hue differences. These changes in color threshold with color space location and direction may give insight into photoreceptor non-linearities and post-receptoral mechanisms of color vision in fish. Our results highlight the need for a cautious interpretation of the RNL model - especially for modelling colours that differ from one another in saturation (rather than hue), and especially for highly saturated colours distant from the achromatic point in colour space.
  • The DUB club: deubiquitinating enzymes and neurodevelopmental disorders

    Protein ubiquitination is a widespread, multifunctional, posttranslational protein modification, best known for its ability to direct protein degradation via the ubiquitin proteasome system (UPS). Ubiquitination is also reversible, and the human genome encodes over 90 deubiquitinating enzymes (DUBs), many of which appear to target specific subsets of ubiquitinated proteins. This review focuses on the roles of DUBs in neurodevelopmental disorders (NDDs). We present the current genetic evidence connecting 12 DUBs to a range of NDDs and the functional studies implicating at least 19 additional DUBs as candidate NDD genes. We highlight how the study of DUBs in NDDs offers critical insights into the role of protein degradation during brain development. Because one of the major known functions of a DUB is to antagonize the UPS, loss of function of DUB genes has been shown to culminate in loss of abundance of its protein substrates. The identification and study of NDD DUB substrates in the developing brain is revealing that they regulate networks of proteins that themselves are encoded by NDD genes. We describe the new technologies that are enabling the full resolution of DUB protein networks in the developing brain, with the view that this knowledge can direct the development of new therapeutic paradigms. The fact that the abundance of many NDD proteins is regulated by the UPS presents an exciting opportunity to combat NDDs caused by haploinsufficiency, because the loss of abundance of NDD proteins can be potentially rectified by antagonizing their UPS-based degradation.
  • Genetic variants associated with longitudinal changes in brain structure across the lifespan

    Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.
  • Neurochemical and functional interactions for improved perceptual decisions through training

    Learning and experience are known to improve our ability to make perceptual decisions. Yet, our understanding of the brain mechanisms that support improved perceptual decisions through training remains limited. Here, we test the neurochemical and functional interactions that support learning for perceptual decisions in the context of an orientation identification task. Using magnetic resonance spectroscopy (MRS), we measure neurotransmitters (i.e., glutamate, GABA) that are known to be involved in visual processing and learning in sensory [early visual cortex (EV)] and decision-related [dorsolateral prefrontal cortex (DLPFC)] brain regions. Using resting-state functional magnetic resonance imaging (rs-fMRI), we test for functional interactions between these regions that relate to decision processes. We demonstrate that training improves perceptual judgments (i.e., orientation identification), as indicated by faster rates of evidence accumulation after training. These learning-dependent changes in decision processes relate to lower EV glutamate levels and EV-DLPFC connectivity, suggesting that glutamatergic excitation and functional interactions between visual and dorsolateral prefrontal cortex facilitate perceptual decisions. Further, anodal transcranial direct current stimulation (tDCS) in EV impairs learning, suggesting a direct link between visual cortex excitation and perceptual decisions. Our findings advance our understanding of the role of learning in perceptual decision making, suggesting that glutamatergic excitation for efficient sensory processing and functional interactions between sensory and decision-related regions support improved perceptual decisions.NEW & NOTEWORTHY Combining multimodal brain imaging [magnetic resonance spectroscopy (MRS), functional connectivity] with interventions [transcranial direct current stimulation (tDCS)], we demonstrate that glutamatergic excitation and functional interactions between sensory (visual) and decision-related (dorsolateral prefrontal cortex) areas support our ability to optimize perceptual decisions through training.
  • The human mediodorsal thalamus: organization, connectivity, and function

    The human mediodorsal thalamic nucleus (MD) is crucial for higher cognitive functions, while the fine anatomical organization of the MD and the function of each subregion remain elusive. In this study, using high-resolution data provided by the Human Connectome Project, an anatomical connectivity-based method was adopted to unveil the topographic organization of the MD. Four fine-grained subregions were identified in each hemisphere, including the medial (MDm), central (MDc), dorsal (MDd), and lateral (MDl), which recapitulated previous cytoarchitectonic boundaries from histological studies. The subsequent connectivity analysis of the subregions also demonstrated distinct anatomical and functional connectivity patterns, especially with the prefrontal cortex. To further evaluate the function of MD subregions, partial least squares analysis was performed to examine the relationship between different prefrontal-subregion connectivity and behavioral measures in 1012 subjects. The results showed subregion-specific involvement in a range of cognitive functions. Specifically, the MDm predominantly subserved emotional-cognition domains, while the MDl was involved in multiple cognitive functions especially cognitive flexibility and inhibition. The MDc and MDd were correlated with fluid intelligence, processing speed, and emotional cognition. In conclusion, our work provides new insights into the anatomical and functional organization of the MD and highlights the various roles of the prefrontal-thalamic circuitry in human cognition.
  • Monoclonal antibodies targeting surface-exposed epitopes of Candida albicans cell wall proteins confer in vivo protection in an infection model

    Monoclonal antibody (mAb)-based immunotherapies targeting systemic and deep-seated fungal infections are still in their early stages of development, with no licensed antifungal mAbs currently being available for patients at risk. The cell wall glycoproteins of Candida albicans are of particular interest as potential targets for therapeutic antibody generation due to their extracellular location and key involvement in fungal pathogenesis. Here, we describe the generation of recombinant human antibodies specifically targeting two key cell wall proteins (CWPs) in C. albicans: Utr2 and Pga31. These antibodies were isolated from a phage display antibody library using peptide antigens representing the surface-exposed regions of CWPs expressed at elevated levels during in vivo infection. Reformatted humanmouse chimeric mAbs preferentially recognized C. albicans hyphal forms compared to yeast cells, and increased binding was observed when the cells were grown in the presence of the antifungal agent caspofungin. In J774.1 macrophage interaction assays, mAb pretreatment resulted in the faster engulfment of C. albicans cells, suggesting a role of the CWP antibodies as opsonizing agents during phagocyte recruitment. Finally, in a series of clinically predictive mouse models of systemic candidiasis, our lead mAb achieved improved survival (83%) and a several-log reduction of the fungal burden in the kidneys, similar to the levels achieved for the fungicidal drug caspofungin and superior to the therapeutic efficacy of any anti-Candida mAb reported to date.
  • Investigating the role of future thinking in highly superior autobiographical memory

    Highly superior autobiographical memory (HSAM) is characterised by a profound ability to recall personal experiences from long-term memory with extremely high detail and accuracy. Since the first documented case of HSAM in 2006, studies have demonstrated the apparent automatic and effortless retrieval of autobiographical memories, despite their Average performance on laboratory and neuropsychological tests of episodic memory. It remains unclear, however, if their ability to imagine future-oriented scenarios is also superior, a process that is known to rely heavily on our capacity to remember the past. Here we investigate autobiographical memory and future thinking in a case of HSAM. We report RS who endorses re-experiencing a constant influx of memories from almost every day of her life since early adolescence. RS’s performance on tasks of autobiographical memory, episodic future thinking, and future-oriented scene construction was contrasted with six age- and sex-matched healthy control participants. Recollections of past autobiographical events were episodically richer in RS, but only when personal relevance of the event was highly constrained (i.e., cued by a single word and within a time limit). In addition, while imagination of plausible future events was significantly richer in episodic detail, construction of future-oriented narrative scenes was unremarkable. Our study is the first to investigate future thinking in HSAM. These individuals may engage in superior imagination of future scenarios, but only when these scenarios can be easily tied to their own personal narrative.
  • Comorbidity between eating disorders and psychiatric disorders

    Objective: Previous literature has established an increased risk of eating disorders among individuals with other psychiatric disorders and vice versa. However, often studies have focused on eating disorders as a single diagnostic entity and/or investigated selected psychiatric comorbidities. We conducted a comprehensive study, exploring bidirectional associations between different types of eating disorders and broad groups of all other psychiatric disorders, to identify patterns of comorbidity. Method: We included all people born in Denmark 1963–2010. We collected information on eating disorders and considered the risk of subsequent psychiatric disorders using Cox-proportional hazards regression. Absolute risks were calculated using competing risks survival analyses. We also considered prior psychiatric disorders and subsequent eating disorders. Results: An increased risk was seen for almost all disorder pairs of diagnoses evaluated. Following an anorexia nervosa (AN) diagnosis, the median hazard ratio for the different subsequent psychiatric disorders was 3.80 (range 2.48–6.15); following an other eating disorder (OED) diagnosis, it was 3.16 (range 2.05–5.14). After different psychiatric disorder diagnoses, the median hazard ratio was 2.66 for later AN (range 1.21–5.31), and 2.51 for later OED (range 1.25–4.10). Absolute risk of eating disorders was also higher among those with other psychiatric disorders than those without. Discussion: In this broad examination, we identified bidirectional increases in risk of comorbidity for those with both eating disorder diagnoses and psychiatric disorder diagnoses. Although our findings indicate different patterns of comorbidity between eating disorders, these variations were generally small.