A principle-based framework for disclosing a psychosis risk diagnosis.

In recent decades, researchers have attempted to prospectively identify individuals at high risk of developing psychosis in the hope of delaying or preventing psychosis onset. These psychosis risk individuals are identified as being in an 'At-Risk Mental State' (ARMS) through a standardised psychometric interview. However, disclosure of ARMS status has attracted criticism due to concerns about the risk-benefit ratio of disclosure to patients. Only approximately one quarter of ARMS patients develop psychosis after three years, raising concerns about the unnecessary harm associated with such 'false-positive' results. These harms are especially pertinent when identifying psychosis risk individuals due to potential stigma and discrimination in a young clinical population. A dearth of high-quality evidence supporting interventions for ARMS patients raises further doubts about the benefit accompanying an ARMS disclosure. Despite ongoing discussion in the bioethical literature, these concerns over the ethical justification of disclosure to ARMS patients are not directly addressed in clinical guidelines. In this paper, we aim to provide a unified disclosure strategy grounded in principle-based analysis for ARMS clinicians. After considering the ethical values at stake in ARMS disclosure, and their normative significance, we argue that full disclosure of the ARMS label is favoured in the vast majority of clinical situations due to the strong normative significance of enhancing patients' understanding. We then compare our framework with other approaches to ARMS disclosure and outline its limitations.

ZNF423 patient variants, truncations, and in-frame deletions in mice define an allele-dependent range of midline brain abnormalities.

Interpreting rare variants remains a challenge in personal genomics, especially for disorders with several causal genes and for genes that cause multiple disorders. ZNF423 encodes a transcriptional regulatory protein that intersects several developmental pathways. ZNF423 has been implicated in rare neurodevelopmental disorders, consistent with midline brain defects in Zfp423-mutant mice, but pathogenic potential of most patient variants remains uncertain. We engineered ~50 patient-derived and small deletion variants into the highly-conserved mouse ortholog and examined neuroanatomical measures for 791 littermate pairs. Three substitutions previously asserted pathogenic appeared benign, while a fourth was effectively null. Heterozygous premature termination codon (PTC) variants showed mild haploabnormality, consistent with loss-of-function intolerance inferred from human population data. In-frame deletions of specific zinc fingers showed mild to moderate abnormalities, as did low-expression variants. These results affirm the need for functional validation of rare variants in biological context and demonstrate cost-effective modeling of neuroanatomical abnormalities in mice.

Perm1 promotes cardiomyocyte mitochondrial biogenesis and protects against hypoxia/reoxygenation-induced damage in mice.

Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.

Role of N-methyl-d-aspartate receptor subunits GluN2A and GluN2B in auditory thalamocortical long-term potentiation in adult mice.

Cortical neurons undergo continuous remodelling throughout development and into adulthood, associated with long-term changes in the synaptic transmission of thalamocortical pathways, i.e., long-term potentiation (LTP); such plasticity is input-specific, reflected in the frequency-specificity of the auditory system. It is well established that thalamocortical LTP is dependent on the activation of N-methyl-d-aspartate (NMDA) receptors. In this study, the roles of NMDA receptor subunits GluN2A and GluN2B in LTP induction were examined in thalamocortical pathways of the auditory system using subunit-selective pharmacological inhibition and in vivo tetanic stimulation of the auditory thalamus, while recording neural response in the primary auditory cortex. Long-term enhancement of thalamocortical field excitatory postsynaptic potentials (i.e., thalamocortical LTP) were induced by high frequency tetanic stimulation of the ventral division of the medial geniculate body. Such enhancement in thalamocortical fEPSPs was decreased when a GluN2A blocker (NVP-M077) was applied to the recording site in the primary auditory cortex and was increased when a GluN2B blocker (Ro25-6981) was applied. Our data suggest that the induction of thalamocortical LTP is dependent on the differential expression of the GluN2A and GluN2B subunits of NMDA receptors in thalamocortical circuits.

Explainability Metrics of Deep Convolutional Networks for Photoplethysmography Quality Assessment.

Photoplethysmography (PPG) is a noninvasive way to monitor various aspects of the circulatory system, and is becoming more and more widespread in biomedical processing. Recently, deep learning methods for analyzing PPG have also become prevalent, achieving state of the art results on heart rate estimation, atrial fibrillation detection, and motion artifact identification. Consequently, a need for interpretable deep learning has arisen within the field of biomedical signal processing. In this paper, we pioneer novel explanatory metrics which leverage domain-expert knowledge to validate a deep learning model. We visualize model attention over a whole testset using saliency methods and compare it to human expert annotations. Congruence, our first metric, measures the proportion of model attention within expert-annotated regions. Our second metric, Annotation Classification, measures how much of the expert annotations our deep learning model pays attention to. Finally, we apply our metrics to compare between a signal based model and an image based model for PPG signal quality classification. Both models are deep convolutional networks based on the ResNet architectures. We show that our signal-based one dimensional model acts in a more explainable manner than our image based model; on average 50.78% of the one dimensional model's attention are within expert annotations, whereas 36.03% of the two dimensional model's attention are within expert annotations. Similarly, when thresholding the one dimensional model attention, one can more accurately predict if each pixel of the PPG is annotated as artifactual by an expert. Through this testcase, we demonstrate how our metrics can provide a quantitative and dataset-wide analysis of how explainable the model is.

Stress gates an astrocytic energy reservoir to impair synaptic plasticity.

Astrocytes support the energy demands of synaptic transmission and plasticity. Enduring changes in synaptic efficacy are highly sensitive to stress, yet whether changes to astrocyte bioenergetic control of synapses contributes to stress-impaired plasticity is unclear. Here we show in mice that stress constrains the shuttling of glucose and lactate through astrocyte networks, creating a barrier for neuronal access to an astrocytic energy reservoir in the hippocampus and neocortex, compromising long-term potentiation. Impairing astrocytic delivery of energy substrates by reducing astrocyte gap junction coupling with dominant negative connexin 43 or by disrupting lactate efflux was sufficient to mimic the effects of stress on long-term potentiation. Furthermore, direct restoration of the astrocyte lactate supply alone rescued stress-impaired synaptic plasticity, which was blocked by inhibiting neural lactate uptake. This gating of synaptic plasticity in stress by astrocytic metabolic networks indicates a broader role of astrocyte bioenergetics in determining how experience-dependent information is controlled.

Author Correction: Stress gates an astrocytic energy reservoir to impair synaptic plasticity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The onset and post-onset auditory responses of cochlear nucleus neurons are modulated differently by cortical activation.

Auditory cortex exhibit a capacity of modulating the functions of subcortical auditory nuclei and even inner ear through descending pathways. The cochlear nucleus (CN), which acts as the gateway from the auditory periphery to the central auditory system, is also subjected to corticofugal modulation. Cortical modulation of subcortical nuclei is highly specific to the frequency tunings of cortical and subcortical neurons. It is unclear whether the high frequency-specificity of the cortical modulation of CN frequency tuning is implemented in the CN, in the auditory periphery, or in both. We analyzed the corticofugal effects on the frequency tuning, constructed from both onset (OS) and post-onset (pOS) response components of CN neurons in C57 mice. We found that the focal electrical stimulation of the primary auditory cortex (ESAI) induced remarkable changes in the response magnitude, response latency and the frequency response curves of CN neurons. The changes in the pOS components were highly specific to the difference in BFs between the stimulated AI neurons and recorded CN neurons. The changes in the OS component mostly involved the augmentation of the auditory responses of CN neurons, while exhibiting far poorer frequency-specificity. Considering the large differences in the temporal response patterns and the tuning shapes between the auditory nerve (AN) and the CN, our data suggest that the CN intrinsic neural circuitry plays a critical role in the frequency specificity of corticofugal modulation. Cortical modulation of the inner ear mostly contributes to the augmentation of the AN inputs to the CN, around the BFs of stimulated AI neurons.

Corticofugal Augmentation of the Auditory Brainstem Response With Respect to Cortical Preference.

Physiological studies documented highly specific corticofugal modulations making subcortical centers focus processing on sounds that the auditory cortex (AC) has experienced to be important. Here, we show the effects of focal conditioning (FC) of the primary auditory cortex (FCAI) on auditory brainstem response (ABR) amplitudes and latencies in house mice. FCAI significantly increased ABR peak amplitudes (peaks I-V), decreased thresholds, and shortened peak latencies in responses to the frequency tuned by conditioned cortical neurons. The amounts of peak amplitude increases and latency decreases were specific for each processing level up to the auditory midbrain. The data provide new insights into possible corticofugal modulation of inner hair cell synapses and new corticofugal effects as neuronal enhancement of processing in the superior olivary complex (SOC) and lateral lemniscus (LL). Thus, our comprehensive ABR approach confirms the role of the AC as instructor of lower auditory levels and extends this role specifically to the cochlea, SOC, and LL. The whole pathway from the cochlea to the inferior colliculus appears, in a common mode, instructed in a very similar way.

Analyzing Oxygen Consumption Rate in Primary Cultured Mouse Neonatal Cardiomyocytes Using an Extracellular Flux Analyzer.

Mitochondria and oxidative metabolism are critical for maintaining cardiac muscle function. Research has shown that mitochondrial dysfunction is an important contributing factor to impaired cardiac function found in heart failure. By contrast, restoring defective mitochondrial function may have beneficial effects to improve cardiac function in the failing heart. Therefore, studying the regulatory mechanisms and identifying novel regulators for mitochondrial function could provide insight which could be used to develop new therapeutic targets for treating heart disease. Here, cardiac myocyte mitochondrial respiration is analyzed using a unique cell culture system. First, a protocol has been optimized to rapidly isolate and culture high viability neonatal mouse cardiomyocytes. Then, a 96-well format extracellular flux analyzer is used to assess the oxygen consumption rate of these cardiomyocytes. For this protocol, we optimized seeding conditions and demonstrated that neonatal mouse cardiomyocytes oxygen consumption rate can be easily assessed in an extracellular flux analyzer. Finally, we note that our protocol can be applied to a larger culture size and other studies, such as intracellular signaling and contractile function analysis.

Horizontal ladder task-specific re-training in adult rats with contusive thoracic spinal cord injury.

PURPOSE: Using the horizontal ladder task, we examined some issues that need to be resolved before task-specific rehabilitative training can be employed clinically for the frequent contusive spinal cord injury (SCI). We hypothesized that improving recovery in task performance after contusive thoracic SCI requires frequent re-training and initiating the re-training early during spontaneous recovery. METHODS: Contusive SCI was produced at the adult female Sprague Dawley rat T10 vertebra. Task re-training was initiated one week later when occasional weight-supported plantar steps were taken overground (n = 8). It consisted of 2 repetitions each day, 5 days each week, for 3 weeks. Task performance and overground locomotion were assessed weekly. Neurotransmission through the SCI ventrolateral funiculus was examined. SCI morphometry was determined. RESULTS: Re-training did not improve task performance recovery compared to untrained Controls (n = 7). Untrained overground locomotion and neurotransmission through the SCI did not change. Lesion area at the injury epicenter as a percentage of the total spinal cord area as well as total tissue, lesion, and spared tissue, white matter, or gray matter volumes did not differ. CONCLUSIONS: For the horizontal ladder task after contusive thoracic SCI, earlier re-training sessions with more repetitions and critical neural circuitry may be necessary to engender a rehabilitation effect.