Nature Neuroscience Research Articles

Identifying novel chemical-related susceptibility genes for five psychiatric disorders through integrating genome-wide association study and tissue-specific 3'aQTL annotation datasets.

The establishment of 3'aQTLs comprehensive database provides an opportunity to help explore the functional interpretation from the genome-wide association study (GWAS) data of psychiatric disorders. In this study, we aim to search novel susceptibility genes, pathways, and related chemicals of five psychiatric disorders via GWAS and 3'aQTLs datasets. The GWAS datasets of five psychiatric disorders were collected from the open platform of Psychiatric Genomics Consortium (PGC, https://www.med.unc.edu/pgc/ ) and iPSYCH ( https://ipsych.dk/ ) (Demontis et al. in Nat Genet 51(1):63-75, 2019; Grove et al. in Nat Genet 51:431-444, 2019; Genomic Dissection of Bipolar Disorder and Schizophrenia in Cell 173: 1705-1715.e1716, 2018; Mullins et al. in Nat Genet 53: 817-829; Howard et al. in Nat Neurosci 22: 343-352, 2019). The 3'untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) summary datasets of 12 brain regions were obtained from another public platform ( https://wlcb.oit.uci.edu/3aQTLatlas/ ) (Cui et al. in Nucleic Acids Res 50: D39-D45, 2022). First, we aligned the GWAS-associated SNPs of psychiatric disorders and datasets of 3'aQTLs, and then, the GWAS-associated 3'aQTLs were identified from the overlap. Second, gene ontology (GO) and pathway analysis was applied to investigate the potential biological functions of matching genes based on the methods provided by MAGMA. Finally, chemical-related gene-set analysis (GSA) was also conducted by MAGMA to explore the potential interaction of GWAS-associated 3'aQTLs and multiple chemicals in the mechanism of psychiatric disorders. A number of susceptibility genes with 3'aQTLs were found to be associated with psychiatric disorders and some of them had brain-region specificity. For schizophrenia (SCZ), HLA-A showed associated with psychiatric disorders in all 12 brain regions, such as cerebellar hemisphere (P = 1.58 × 10-36) and cortex (P = 1.58 × 10-36). GO and pathway analysis identified several associated pathways, such as Phenylpropanoid Metabolic Process (GO:0009698, P = 6.24 × 10-7 for SCZ). Chemical-related GSA detected several chemical-related gene sets associated with psychiatric disorders. For example, gene sets of Ferulic Acid (P = 6.24 × 10-7), Morin (P = 4.47 × 10-2) and Vanillic Acid (P = 6.24 × 10-7) were found to be associated with SCZ. By integrating the functional information from 3'aQTLs, we identified several susceptibility genes and associated pathways especially chemical-related gene sets for five psychiatric disorders. Our results provided new insights to understand the etiology and mechanism of psychiatric disorders.

Amyloid β Induces Lipid Droplet‐Mediated Microglial Dysfunction in Alzheimer’s Disease

AbstractBackgroundSeveral microglia‐expressed genes have emerged as top risk variants for Alzheimer’s disease (AD) that are involved in lipid droplet (LD) formation and processing. Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD‐risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. LD accumulation in aging (Nat Neurosci. 23(2),194‐208, 2020) appears to increase microglial inflammatory responses, while inflammatory challenges increase LD formation, thereby potentially setting up a feed‐forward injury that could contribute to the relentless progression in AD.MethodLD formation is dependent upon age and disease progression, and is more prominent in the hippocampus in brains from human patients and the AD mouse model 5xFAD. Despite variability in LD load between microglia from male versus female animals and between cells from different brain regions, LD‐laden microglia exhibited a deficit in amyloid‐beta (Aβ) phagocytosis evaluated using AβpH ‐ a human Aβ1‐42 analog that exhibits fluorescence upon lysosomal internalization (Chem Sci. 12, 10901‐10918, 2021). Extensive unbiased lipidomic and metabolomic profiling in microglia identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation.ResultWe show that microglia form LDs upon exposure to Aβ, and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. Mechanistically, Aβ alone is sufficient to induce LD formation in microglia and that this conversion requires a specific metabolic conversion of FFAs to TAGs (the building blocks of LDs). This conversion is likely protective for the brain and microglia, as we recently showed that long‐chain saturated FFAs can be neurotoxic (Nature 599,102‐107, 2021), but it is not without cost for microglial phagocytic abilities. We demonstrate that a key enzyme for the conversion of FFAs to TAGs, promotes microglial LD formation, is increased in microglia from 5xFAD and human AD brains, and that inhibiting it improved microglial uptake of Aβ.ConclusionThese findings identify a new lipid‐mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.

Unraveling the lymphatic system in the spinal cord meninges: a critical element in protecting the central nervous system.

The lymphatic vasculature plays a crucial role in fluid clearance and immune responses in peripheral organs by connecting them to distal lymph nodes. Recently, attention has been drawn to the lymphatic vessel network surrounding the brain's border tissue (Aspelund et al. in J Exp Med 212:991-999, 2015. https://doi.org/10.1084/jem.20142290 ; Louveau et al. in Nat Neurosci 21:1380-1391, 2018. https://doi.org/10.1038/s41593-018-0227-9 ), which guides immune cells in mediating protection against tumors (Song et al. in Nature 577:689-694, 2020. https://doi.org/10.1038/s41586-019-1912-x ) and pathogens Li et al. (Nat Neurosci 25:577-587, 2022. https://doi.org/10.1038/s41593-022-01063-z ) while also contributing to autoimmunity (Louveau et al. 2018) and neurodegeneration (Da Mesquita et al. in Nature 560:185-191, 2018. https://doi.org/10.1038/s41586-018-0368-8 ). New studies have highlighted the integral involvement of meningeal lymphatic vessels in neuropathology. However, our limited understanding of spinal cord meningeal lymphatics and immunity hinders efforts to protect and heal the spinal cord from infections, injury, and other immune-mediated diseases. This review aims to provide a comprehensive overview of the state of spinal cord meningeal immunity, highlighting its unique immunologically relevant anatomy, discussing immune cells and lymphatic vasculature, and exploring the potential impact of injuries and inflammatory disorders on this intricate environment.

A comparative review on neuroethical issues in neuroscientific and neuroethical journals.

This study is a pilot literature review that compares the interest of neuroethicists and neuroscientists. It aims to determine whether there is a significant gap between the neuroethical issues addressed in philosophical neuroethics journals and neuroscience journals. We retrieved 614 articles from two specialist neuroethics journals (Neuroethics and AJOB Neuroscience) and 82 neuroethics-focused articles from three specialist neuroscience journals (Neuron, Nature Neuroscience, and Nature Reviews Neuroscience). We classified these articles in light of the neuroethical issue in question before we compared the neuroethical issues addressed in philosophical neuroethics with those addressed by neuroscientists. A notable result is a parallelism between them as a general tendency. Neuroscientific articles cover most neuroethical issues discussed by philosophical ethicists and vice versa. Subsequently, there are notable discrepancies between the two bodies of neuroethics literature. For instance, theoretical questions, such as the ethics of moral enhancement and the philosophical implications of neuroscientific findings on our conception of personhood, are more intensely discussed in philosophical-neuroethical articles. Conversely, neuroscientific articles tend to emphasize practical questions, such as how to successfully integrate ethical perspectives into scientific research projects and justifiable practices of animal-involving neuroscientific research. These observations will help us settle the common starting point of the attempt at "ethics integration" in emerging neuroscience, contributing to better governance design and neuroethical practice.

Awake Hippocampal-Cortical Co-reactivation Is Associated with Forgetting.

Systems consolidation theories posit that consolidation occurs primarily through a coordinated communication between hippocampus and neocortex [Moscovitch, M., & Gilboa, A. Systems consolidation, transformation and reorganization: Multiple trace theory, trace transformation theory and their competitors. PsyArXiv, 2021; Kumaran, D., Hassabis, D., & McClelland, J. L. What learning systems do intelligent agents need? Complementary learning systems theory updated. Trends in Cognitive Sciences, 20, 512-534, 2016; McClelland, J. L., & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419-457, 1995]. Recent sleep studies in rodents have shown that hippocampus and visual cortex replay the same information at temporal proximity ("co-replay"; Lansink, C. S., Goltstein, P. M., Lankelma, J. V., McNaughton, B. L., & Pennartz, C. M. A. Hippocampus leads ventral striatum in replay of place-reward information. PLoS Biology, 7, e1000173, 2009; Peyrache, A., Khamassi, M., Benchenane, K., Wiener, S. I., & Battaglia, F. P. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nature Neuroscience, 12, 919-926, 2009; Wierzynski, C. M., Lubenov, E. V., Gu, M., & Siapas, A. G. State-dependent spike-timing relationships between hippocampal and prefrontal circuits during sleep. Neuron, 61, 587-596, 2009; Ji, D., & Wilson, M. A. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nature Neuroscience, 10, 100-107, 2007). We developed a novel repetition time (TR)-based co-reactivation analysis method to study hippocampal-cortical co-replays in humans using fMRI. Thirty-six young adults completed an image (face or scene) and location paired associate encoding task in the scanner, which were preceded and followed by resting state scans. We identified post-encoding rest TRs (± 1) that showed neural reactivation of each image-location trials in both hippocampus (HPC) and category-selective cortex (fusiform face area [FFA]). This allowed us to characterize temporally proximal coordinated reactivations ("co-reactivations") between HPC and FFA. Moreover, we found that increased HPC-FFA co-reactivations were associated with incorrectly recognized trials after a 1-week delay (p = .004). Finally, we found that these HPC-FFA co-reactivations were also associated with trials that were initially correctly recognized immediately after encoding but were later forgotten in 1-day (p = .043) and 1-week delay period (p = .031). We discuss these results from a trace transformation perspective [Sekeres, M. J., Winocur, G., & Moscovitch, M. The hippocampus and related neocortical structures in memory transformation. Neuroscience Letters, 680, 39-53, 2018; Winocur, G., & Moscovitch, M. Memory transformation and systems consolidation. Journal of the International Neuropsychological Society, 17, 766-780, 2011] and speculate that HPC-FFA co-reactivations may be integrating related events, at the expense of disrupting event-specific details, hence leading to forgetting.

Memory capacity and prioritization in female mice

Our brain’s capacity for memory storage may be vast but is still finite. Given that we cannot remember the entirety of our experiences, how does our brain select what to remember and what to forget? Much like the triage of a hospital’s emergency room, where urgent cases are prioritized and less critical patients receive delayed or even no care, the brain is believed to go through a similar process of memory triage. Recent salient memories are prioritized for consolidation, which helps create stable, long-term representations in the brain; less salient memories receive a lower priority, and are eventually forgotten if not sufficiently consolidated (Stickgold and Walker in Nat Neurosci 16(2):139–145, 2013). While rodents are a primary model for studying memory consolidation, common behavioral tests typically rely on a limited number of items or contexts, well within the memory capacity of the subject. A memory test allowing us to exceed an animal’s memory capacity is key to investigating how memories are selectively strengthened or forgotten. Here we report a new serial novel object recognition task designed to measure memory capacity and prioritization, which we test and validate using female mice.

Methods in Prioritizing Pathways and Targets from Expression Data

AbstractBackgroundExpression datasets, such as those from RNAseq and mass‐spec platforms, have been growing at an everincreasing rate and are relevant to a wide variety of diseases, however, it remains challenging to yield interpretable and actionable results. In this poster, we present novel computational methods that attempt to resolve this issues and demonstrate their use in several Alzheimer’s Disease datasets.MethodTwo publicaly available datasets were used for this analysis: a post‐mortem single‐nucleus RNAseq dataset from the entorhinal cortex of Alzheimer’s Disease and non‐demented donors (Leng et al., 2021, Nature Neuroscience) and a post‐mortem single‐soma RNAseq dataset from the prefrontal cortex of Alzheimer’s Disease donors where tangle‐bearing neurons were sorted prior to sequencing (Otero‐Garcia et al., 2020, bioRxiv). In brief, our method, which we have named GeneFunnel, firstly optimizes filtering steps and statistical correctness (such as pseudobulking) to yield robust gene set enrichment results. Gene set enrichment is then used to guide prioritization of differentially expressed genes using hierarchial clustering and graph theory, focusing especially on the overlap of genes between gene sets.ResultUsing several forms of visualization, we demonstrate how GeneFunnel can create a clear and succint overview of the processes involved in Alzheimer’s Disease. As the name implies, the results are made intuitively explorable, effectively facilitating a “funnel” that allows inspection at broad and narrow levels of depth.ConclusionWe show a novel approach to tackling large and complex expression datasets, demonstrating its utility in summarizing key molecular changes that take place in Alzheimer’s Disease.

Reflections from the former Chief Editors of Nature Neuroscience.

To mark the 25th anniversary of Nature Neuroscience, Shari Wiseman spoke with each of the past Chief Editors of the journal: Charles Jennings (1998–2003), Sandra Aamodt (2003–2008), Kalyani Narasimhan (2008–2014), Meredith LeMasurier (2014–2016), and Kevin Da Silva (2016–2021). They shared their memories and insights about the journal’s early days, scientific publishing, and the field of neuroscience.

Twenty-five years of Nature Neuroscience

Twenty-five years of Nature Neuroscience

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

Participation of Na+ Channels in Epilepsy: A Bibliometric Analysis of the Scientific Production in the World

Background: Bibliometric analysis can be used to measure and evaluate scientific activities in certain areas, so we know where to focus our efforts. Epilepsies are mostly idiopathic and genetic, as in Dravet’s syndrome, linked to sodium channels. With this in mind, this paper delves into the published articles related to the involvement of sodium (Na+) channels in epilepsy, to get a better perspective of this specific area. Methods: The analysis was carried out by means of the scientific follow-up of epilepsy and the study of Na+ channels in the SCOPUS databases. The information was extracted from original articles between 2000 and 2022, using epilepsy, seizure, epileptic, Na, sodium, channel, channelopathy, and channelopathies, as keywords. From the articles obtained, these were filtered and categorized (mechanisms, drugs, genetics, clinical cases, tumors, diagnosis and models), to analyze the data. Results: 290 original works were produced from 2000 to 2022. The largest contribution comes from the United States specializing in mechanisms, followed by the United Kingdom with a greater interest in antiepileptic drugs, as well as the Netherlands. Overall, the most researched areas are mechanisms and antiepileptic drugs. Additionally, the type 1 sodium channel is the most studied, with unnamed drugs accounting for 50% of this output. On the other hand, we found that Nature Neuroscience is the top-cited journal with only one article, while Epilepsia Journal has 23 articles and 170 citations. Finally, the authors' number per article ranges from one to sixty-four and 90% of publications belong to the experimental type. Conclusion: Epilepsy is a disease that significantly affects developing countries. The poorest countries have the highest rates of suffering from this neurological condition, which is in stark contrast to their scientific production in this field. This is probably due to technology, or the absence in SCOPUS database the articles.

Participation of Na+ Channels in Epilepsy: A Bibliometric Analysis of the Scientific Production in the World

Background: Bibliometric analysis can be used to measure and evaluate scientific activities in certain areas, so we know where to focus our efforts. Epilepsies are mostly idiopathic and genetic, as in Dravet’s syndrome, linked to sodium channels. With this in mind, this paper delves into the published articles related to the involvement of sodium (Na+) channels in epilepsy, to get a better perspective of this specific area. Methods: The analysis was carried out by means of the scientific follow-up of epilepsy and the study of Na+ channels in the SCOPUS databases. The information was extracted from original articles between 2000 and 2022, using epilepsy, seizure, epileptic, Na, sodium, channel, channelopathy, and channelopathies, as keywords. From the articles obtained, these were filtered and categorized (mechanisms, drugs, genetics, clinical cases, tumors, diagnosis and models), to analyze the data. Results: 290 original works were produced from 2000 to 2022. The largest contribution comes from the United States specializing in mechanisms, followed by the United Kingdom with a greater interest in antiepileptic drugs, as well as the Netherlands. Overall, the most researched areas are mechanisms and antiepileptic drugs. Additionally, the type 1 sodium channel is the most studied, with unnamed drugs accounting for 50% of this output. On the other hand, we found that Nature Neuroscience is the top-cited journal with only one article, while Epilepsia Journal has 23 articles and 170 citations. Finally, the authors' number per article ranges from one to sixty-four and 90% of publications belong to the experimental type. Conclusion: Epilepsy is a disease that significantly affects developing countries. The poorest countries have the highest rates of suffering from this neurological condition, which is in stark contrast to their scientific production in this field. This is probably due to technology, or the absence in SCOPUS database the articles.

Dealing with uncertainty in sensorimotor control in sports: A systematic review

Introduction
 In complex sensorimotor behavior, uncertainty arises from ambiguity in the sensory inputs of the environment (e.g. Kersten et al., 2004) as well as from noise in sensory detection and motor execution (e.g. Todorov & Jordan, 2002). Moreover, the observable sensory inputs are delayed and there are typically multiple solutions to solve a motor task (e.g. Franklin & Wolpert, 2011). In sports, where human capacity reaches its limit with these challenges, dealing with uncertainty is crucial. Thus, the question arises how humans are able to deal with uncertainty in sensorimotor control in naturalistic situations such as sports.
 Methods
 A systematic search for original articles was conducted in six scientific databases with the following terms: (uncertainty OR noise) AND (sensor* OR motor) AND control AND sport AND movement. After independently screening 4,309 articles and additional reference lists by two raters, 70 articles remained for the review.
 Results
 There is clear evidence that prior knowledge (or similar contextual information) and multiple sensory information affect perception, action and performance. Moreover, there is considerable evidence that prior knowledge and multiple sensory information get integrated according to their reliability in order to reduce uncertainty. Furthermore, it has been reported that gaze behavior is close to the optimal compared to an optimal Bayesian observer in an expected and unexpected uncertain environment. There is also considerable evidence that not all variables have to be controlled and rather uncertainty is accepted in variables that do not impair overall performance. Some findings show that inherent noise is taken into account when planning motor execution so that the potential costs and rewards of the movement outcome are optimized. Finally, some findings show that unforeseen perturbation can be absorbed by means of higher muscle stiffness resulting from muscular co-contraction.
 Discussion
 The strategies to deal with uncertainty mentioned in the results section can be summarized under the umbrella of Bayesian decision theory (Franklin & Wolpert, 2011). Only a few alternative models were referenced that, however, were conceptually quite similar to Bayesian models. Therefore, Bayesian decision theory seems to offer a promising framework for future research on uncertainty in sensorimotor control in sport science.
 References
 Franklin, D. W., & Wolpert, D. M. (2011). Computational mechanisms of sensorimotor control. Neuron, 72(3), 425-442. https://doi.org/10.1016/j.neuron.2011.10.006
 Kersten, D., Mamassian, P., & Yuille, A. (2004). Object perception as Bayesian inference. Annual Review of Psychology, 55, 271-304. https://doi.org/10.1146/annurev.psych.55.090902.142005
 Todorov, E., & Jordan, M. I. (2002). Optimal feedback control as a theory of motor coordination. Nature Neuroscience, 5(11), 1226-1235. https://doi.org/10.1038/nn963

O‐GlcNAcylation modulates GLUT1 levels at the blood‐brain barrier

AbstractBackgroundGlucose transporter 1 (GLUT1) at the blood‐brain barrier (BBB) is essential for glucose uptake into the brain. Previous studies have shown that GLUT1 levels are reduced at the BBB in Alzheimer’s disease (AD) post‐mortem brain, and perhaps explains the decreased glucose utilization observed in AD (Sweeney et al., Nat Rev Neurol, 2018). Individuals with a genetic reduction of GLUT1, known as GLUT1‐deficiency syndrome, were treated with increased blood glucose with no long‐lasting increase in brain glucose. Diabetes is a risk factor for AD and AD is sometimes referred to as Type‐3 diabetes due to elevated blood glucose levels. Taken together, these ideas provoked us to investigate connections between glucose and GLUT1 levels. Here, we tested if the glucose‐dependent post‐translational modification, O‐linked‐N‐acetylglucosaminylation (O‐GlcNAcylation), is the missing link. We hypothesized that increasing glucose concentrations will elevate O‐GlcNAcylation and decrease GLUT1 levels at the BBB. Furthermore, previous studies have shown that decreased GLUT1 levels result in reduced levels of the low‐density lipoprotein receptor‐related protein‐1 (LRP‐1) (Winkler, Nat Neurosci, 2015). Thus, we also are determining if altering glucose levels not only changes GLUT1 levels, but also other key BBB receptors implicated in AD.MethodsMouse brain endothelial (bEnd.3) cells were treated with vehicle (glucose 5.6 mmol), DMSO, the O‐GlcNAcase inhibitor Thiamet‐G (TMG, 1 µM), or the O‐GlcNAc transferase inhibitor OSMI‐1 (20 µM), for 24 and 48 hours. Next, the protein expression of O‐GlcNAc and GLUT1 were measured by western blot.ResultsAs previously reported, TMG increased and OSMI‐1 decreased O‐GlcNAcylation at both 24 and 48 h, compared to vehicle. Notably, TMG treatment significantly reduced and OSMI‐1 increased GLUT1 expression at both time points.ConclusionGLUT1 levels are modulated through O‐GlcNAcylation at BBB. When blood glucose levels are high, O‐GlcNAcylation will be high, thereby reducing GLUT1 at the BBB and brain glucose uptake. This is likely a homeostatic mechanism to prevent spikes in brain glucose levels when blood sugar levels are elevated.

Open science and conflict of interest policies of medical and health sciences journals before and during the COVID-19 pandemic: A repeat cross-sectional study

To audit the transparent and open science standards of health and medical sciences journal policies and explore the impact of the COVID-19 pandemic. Repeat cross-sectional study. 19 journals listed in Google Scholar's Top Publications for health and medical sciences. Blood, Cell, Circulation, European Heart Journal, Gastroenterology, Journal of Clinical Oncology, Journal of the American College of Cardiology, Nature Genetics, Nature Medicine, Nature Neuroscience, Neuron, PLoS ONE, Proceedings of the National Academy of Sciences, Science Translational Medicine, The British Medical Journal, The Journal of the American Medical Association, The Lancet, The Lancet Oncology, and The New England Journal of Medicine. We used the Transparency and Openness Promotion (TOP) guideline and the International Committee of Medical Journal Editors (ICMJE) requirements for disclosing conflicts of interest (COIs) to evaluate journals standards. TOP scores slightly improved during the COVID-19 pandemic, from a median of 5 (IQR: 2-12.5) out of a possible 24 points in February 2020 to 7 (IQR: 4-12) in May 2021, but overall, scores were very low at both time points. Journal policies scored highest for their adherence to data transparency and scored lowest for preregistration of study protocols and analysis plans and the submission of replication studies. Most journals fulfilled all ICMJE provisions for reporting COIs before (84%; n = 16) and during (95%; n = 18) the COVID-19 pandemic. The COVID-19 pandemic has highlighted the importance of practising open science. However, requirements for open science practices in audited policies were overall low, which may impede progress in health and medical research. As key stakeholders in disseminating research, journals should promote a research culture of greater transparency and more robust open science practices.

Structural Analysis of SOD1 Fibrils with Mass Spectrometry, Limited Proteolysis, and Atomic Force Microscopy (AFM).

This protocol describes a method to purify SOD1 in Saccharomyces cerevisiae to characterize using ICP-MS and AFM, to agitate and fibrillate for aggregation of SOD1. The human SOD1 (hSOD1) is a 32-kDa homodimer, with one copper- and one zinc-binding site per 153-amino acid subunit. Misfolded protein aggregates are often correlated with diseases known as amyloidosis, including ALS, Alzheimer's, Parkinson's, and prion disease (Valentine and Hart, Proc Natl Acad Sci USA 100: 3617-3622, 2003; Tanzi and Bertram, Cell 120: 545-555, 2005; Soto and Pritzkow, Nat Neurosci 21:1332-1340, 2018; Sarafian et al., J Neurosci Res 95:1871-1887, 2017). Proteinaceous aggregates containing hSOD1 have frequently been found in the spinal cords of ALS patients.

Not Only Gene Discovery: Genome-wide Association Studies and Polygenic Risk Scores as Tools to Dissect the Heterogeneity of Major Depressive Disorder

Large-scale genome-wide association studies (GWASs) based on biobanks and meta-analyses of many cohorts have revolutionized our ability to investigate the polygenic architecture of psychiatric disorders and traits. This has been possible because of national and international collaborations such as the Psychiatric Genomics Consortium (PGC) ( 1 Sullivan P.F. Agrawal A. Bulik C.M. Andreassen O.A. Borglum A.D. Breen G. et al. Psychiatric genomics: An update and an agenda. Am J Psychiatry. 2018; 175: 15-27 Crossref PubMed Scopus (292) Google Scholar ). While combining cohorts with different characteristics and various phenotypic assessments led to uncovering hundreds of loci associated with major depressive disorder (MDD) ( 2 Levey D.F. Stein M.B. Wendt F.R. Pathak G.A. Zhou H. Aslan M. et al. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nat Neurosci. 2021; 24: 954-963 Crossref PubMed Scopus (47) Google Scholar ), this has limited our ability to investigate the genetic heterogeneity of MDD. Owing to the massive sample sizes required to identify the small individual effects of single risk loci, it is not useful to directly compare gene discovery of GWASs of different MDD subtypes because the sample size available for each subtype is a primary driver of a GWAS’s statistical power. Indeed, although minimal phenotyping may reduce the specificity of MDD loci identified by GWASs ( 3 Cai N. Revez J.A. Adams M.J. Andlauer T.F.M. Breen G. Byrne E.M. et al. Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nat Genet. 2020; 52: 437-447 Crossref PubMed Scopus (92) Google Scholar ), sample size still trumps phenotyping when focusing only on gene discovery. SEE CORRESPONDING ARTICLE ON PAGE 227 The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between SubtypesBiological PsychiatryVol. 92Issue 3PreviewMajor depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery—often achieved with a trade-off in the depth of phenotyping. Full-Text PDF

Establishing Institutional Scores With the Rigor and Transparency Index: Large-scale Analysis of Scientific Reporting Quality.

BackgroundImproving rigor and transparency measures should lead to improvements in reproducibility across the scientific literature; however, the assessment of measures of transparency tends to be very difficult if performed manually.ObjectiveThis study addresses the enhancement of the Rigor and Transparency Index (RTI, version 2.0), which attempts to automatically assess the rigor and transparency of journals, institutions, and countries using manuscripts scored on criteria found in reproducibility guidelines (eg, Materials Design, Analysis, and Reporting checklist criteria).MethodsThe RTI tracks 27 entity types using natural language processing techniques such as Bidirectional Long Short-term Memory Conditional Random Field–based models and regular expressions; this allowed us to assess over 2 million papers accessed through PubMed Central.ResultsBetween 1997 and 2020 (where data were readily available in our data set), rigor and transparency measures showed general improvement (RTI 2.29 to 4.13), suggesting that authors are taking the need for improved reporting seriously. The top-scoring journals in 2020 were the Journal of Neurochemistry (6.23), British Journal of Pharmacology (6.07), and Nature Neuroscience (5.93). We extracted the institution and country of origin from the author affiliations to expand our analysis beyond journals. Among institutions publishing >1000 papers in 2020 (in the PubMed Central open access set), Capital Medical University (4.75), Yonsei University (4.58), and University of Copenhagen (4.53) were the top performers in terms of RTI. In country-level performance, we found that Ethiopia and Norway consistently topped the RTI charts of countries with 100 or more papers per year. In addition, we tested our assumption that the RTI may serve as a reliable proxy for scientific replicability (ie, a high RTI represents papers containing sufficient information for replication efforts). Using work by the Reproducibility Project: Cancer Biology, we determined that replication papers (RTI 7.61, SD 0.78) scored significantly higher (P<.001) than the original papers (RTI 3.39, SD 1.12), which according to the project required additional information from authors to begin replication efforts.ConclusionsThese results align with our view that RTI may serve as a reliable proxy for scientific replicability. Unfortunately, RTI measures for journals, institutions, and countries fall short of the replicated paper average. If we consider the RTI of these replication studies as a target for future manuscripts, more work will be needed to ensure that the average manuscript contains sufficient information for replication attempts.

Time to go green?

Time to go green?

HP11: Periodic and aperiodic properties of globus pallidus during head movements in patients with cervical dystonia: a case study

The aim of the study was to analyze the pallidal activity during voluntary head movements in 3 cervical dystonia patients with torticollis and jerky movements, sinusoidal tremor, and retrocollis without tremor. Cervical dystonia (CD) is the most common form of focal dystonia, and it is typically characterized by abnormal postures of the head, which can be associated with jerky or sinusoidal head oscillations. Surgical treatment of refractory to medical management CD with deep brain stimulation (DBS) of globus pallidus has been successful. We analyzed local field potentials recorded from globus pallidus on the second day after DBS surgeries during voluntary head movements simultaneously with EMG of neck muscles. We used a method of parameterizing neuronal power spectra into periodic and aperiodic (1/f) components [1]. In a patient with torticollis, we showed that head movement to the direction opposite torticollis caused significantly higher aperiodic spectra component (1/f) in contrast to a straight position and head movement in an ipsilateral direction, which caused significantly higher beta and gamma oscillations. We didn’t find any differences in both aperiodic and periodic components for a retrocollis patient without tremor. Head movement in both directions was characterized by significantly lower theta and alpha oscillations in comparison with the straight position in a patient with sinusoidal tremor. Our preliminary data showed the differences in motor control of head movement in globus pallidus of CD patients with different manifestations. [1] Donoghue, T., et al. Parameterizing neural power spectra into periodic and aperiodic components. Nat Neurosci 23, 1655–1665 (2020).