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Rethinking phase 2 trials in amyotrophic lateral sclerosis.
There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on Phase 2 data, which then fail in Phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected. Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to Phase 2 go/no-go decisions. Over-interpretation of Phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritisation for the investment needed for definitive Phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to Phase 2 design and implementation.
Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation.
To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centers (GCs). Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)-155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase, Kdm2a, whose expression increases in response to hypoxia. The miR-155-Kdm2a interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.
A distributed subcortical circuit linked to instrumental information-seeking about threat.
Daily life for humans and other animals requires switching between periods of threat- and reward-oriented behavior. We investigated neural activity associated with spontaneous switching, in a naturalistic task, between foraging for rewards and seeking information about potential threats with 7T fMRI in healthy humans. Switching was driven by estimates of likelihood of threat and reward. Both tracking of threat and switching to a vigilant mode in which people sought more information about potential threats were associated with specific but distributed patterns of activity spanning habenula, dorsal raphe nucleus (DRN), anterior cingulate cortex, and anterior insula cortex. Different aspects of the distributed activity patterns were linked to monitoring the threat level, seeking information about the threat, and actual threat detection. A distinct pattern of activity in the same circuit and elsewhere occurred during returns to reward-oriented behavior. Individual variation in DRN activity reflected individual variation in the seeking of information about threats.
Asymmetric projection of introspection reveals a behavioural and neural mechanism for interindividual social coordination.
When we collaborate with others to tackle novel problems, we anticipate how they will perform their part of the task to coordinate behavior effectively. We might estimate how well someone else will perform by extrapolating from estimates of how well we ourselves would perform. This account predicts that our metacognitive model should make accurate predictions when projected onto people as good as, or worse than, us but not on those whose abilities exceed our own. We demonstrate just such a pattern and that it leads to worse coordination when working with people more skilled than ourselves. Metacognitive projection is associated with a specific activity pattern in anterior lateral prefrontal cortex (alPFC47). Manipulation of alPFC47 activity altered metacognitive projection and impaired interpersonal social coordination. By contrast, monitoring of other individuals' observable performance and outcomes is associated with a distinct pattern of activity in the posterior temporal parietal junction (TPJp).
The missing pieces: an investigation into the parallels between Charles Bonnet, phantom limb and tinnitus syndromes.
Charles Bonnet syndrome (CBS) is a condition characterised by visual hallucinations of varying complexity on a background of vision loss. CBS research has gained popularity only in recent decades, despite evidence dating back to 1760. Knowledge of CBS among both the patient and professional populations unfortunately remains poor, and little is known of its underlying pathophysiology. CBS parallels two other better-known conditions that occur as a result of sensory loss: phantom limb syndrome (PLS) (aberrant sensation of the presence of a missing limb) and tinnitus (aberrant sensation of sound). As 'phantom' conditions, CBS, PLS and tinnitus share sensory loss as a precipitating factor, and, as subjective perceptual phenomena, face similar challenges to investigations. Thus far, these conditions have been studied separately from each other. This review aims to bridge the conceptual gap between CBS, PLS and tinnitus and seek common lessons between them. It considers the current knowledge base of CBS and explores the extent to which an understanding of PLS and tinnitus could provide valuable insights into the pathology of CBS (including the roles of cortical reorganisation, emotional and cognitive factors), and towards identifying effective potential management for CBS.
Disruption of macroscale functional network organisation in patients with frontotemporal dementia.
Neurodegenerative dementias have a profound impact on higher-order cognitive and behavioural functions. Investigating macroscale functional networks through cortical gradients provides valuable insights into the neurodegenerative dementia process and overall brain function. This approach allows for the exploration of unimodal-multimodal differentiation and the intricate interplay between functional brain networks. We applied cortical gradients mapping to resting-state functional MRI data of patients with frontotemporal dementia (FTD) (behavioural-bvFTD, non-fluent and semantic) and healthy controls. In healthy controls, the principal gradient maximally distinguished sensorimotor from default-mode network (DMN) and the secondary gradient visual from salience network (SN). In all FTD variants, the principal gradient's unimodal-multimodal differentiation was disrupted. The secondary gradient, however, showed widespread disruptions impacting the interactions among all networks specifically in bvFTD, while semantic and non-fluent variants exhibited more focal alterations in limbic and sensorimotor networks. Additionally, the visual network showed responsive and/or compensatory changes in all patients. Importantly, these disruptions extended beyond atrophy distribution and related to symptomatology in patients with bvFTD. In conclusion, optimal brain function requires networks to operate in a segregated yet collaborative manner. In FTD, our findings indicate a collapse and loss of differentiation between networks not solely explained by atrophy. These specific cortical gradients' fingerprints could serve as a functional signature for identifying early changes in neurodegenerative diseases or potential compensatory processes.
Associations between sex and lifestyle activities with cognitive reserve in mid-life adults with genetic risk for Alzheimer's disease.
BACKGROUND: Females have a higher age-adjusted incidence of Alzheimer's Disease (AD) than males, even when accounting for longer lifespan and, therefore, stand to benefit the most from dementia prevention efforts. As exposure to many modifiable risk factors for dementia begins in mid-life, interventions must be implemented from middle-age. Building cognitive reserve, particularly through stimulating avocational activities and occupational attainment presents a crucial, underexplored, dementia prevention approach for mid-life. It is currently unknown, however, whether modifiable lifestyle factors can protect against AD processes, from mid-life, differentially for females and males who carry inherited risk for late-life dementia. To address this gap, this study investigated the impact of biological sex and APOE4 carrier status on the relationship between stimulating activities, occupational attainment, and cognition in mid-life. METHODS: We leveraged the PREVENT-Dementia program, the world's largest study investigating the origins and early diagnosis of dementia in mid-life at-risk individuals (N = 700; 40-59 years). Cognitive performance was measured using the Cognito Battery and the Visual Short Term Memory Binding task. Mid-life specific reserve contributors were assessed via the Lifetime of Experiences Questionnaire. RESULTS: Females had significantly better episodic and relational memory (p
Patterns of Brain Maturation in Autism and Their Molecular Associations.
IMPORTANCE: In the neurotypical brain, regions develop in coordinated patterns, providing a fundamental scaffold for brain function and behavior. Whether altered patterns contribute to clinical profiles in neurodevelopmental conditions, including autism, remains unclear. OBJECTIVES: To examine if, in autism, brain regions develop differently in relation to each other and how these differences are associated with molecular/genomic mechanisms and symptomatology. DESIGN, SETTING, AND PARTICIPANTS: This study was an analysis of one the largest deep-phenotyped, case-control, longitudinal (2 assessments separated by approximately 12-24 months) structural magnetic resonance imaging and cognitive-behavioral autism datasets (EU-AIMS Longitudinal European Autism Project [LEAP]; study dates, February 2014-November 2017) and an out-of-sample validation in the Brain Development Imaging Study (BrainMapASD) independent cohort. Analyses were performed during the 2022 to 2023 period. This multicenter study included autistic and neurotypical children, adolescents, and adults. Autistic participants were included if they had an existing autism diagnosis (DSM-IV/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision or DSM-5 criteria). Autistic participants with co-occurring psychiatric conditions (except psychosis/bipolar disorder) and those taking regular medications were included. EXPOSURES: Neuroanatomy of neurotypical and autistic participants. MAIN OUTCOMES AND MEASURES: Intraindividual changes in surface area and cortical thickness over time, analyzed via surface-based morphometrics. RESULTS: A total of 386 individuals in the LEAP cohort (6-31 years at first visit; 214 autistic individuals, mean [SD] age, 17.3 [5.4] years; 154 male [72.0%] and 172 neurotypical individuals, mean [SD] age, 16.35 [5.7] years; 108 male [62.8%]) and 146 individuals in the BrainMapASD cohort (11-18 years at first visit; 49 autistic individuals, mean [SD] age, 14.31 [2.4] years; 42 male [85.7%] and 97 neurotypical individuals, mean [SD] age, 14.10 [2.5] years; 58 male [59.8%]). Maturational between-group differences in cortical thickness and surface area were established that were mostly driven by sensorimotor regions (eg, across features, absolute loadings for early visual cortex ranged from 0.07 to 0.11, whereas absolute loadings for dorsolateral prefrontal cortex ranged from 0.005 to 0.06). Neurodevelopmental differences were transcriptomically enriched for genes expressed in several cell types and during various neurodevelopmental stages, and autism candidate genes (eg, downregulated genes in autism, including those regulating synaptic transmission; enrichment odds ratio =3.7; P =2.6 × -10). A more neurotypical, less autismlike maturational profile was associated with fewer social difficulties and more typical sensory processing (false discovery rate P
Real-world effects of antidepressants for depressive disorder in primary care: population-based cohort study.
BACKGROUND: Antidepressants' effects are established in randomised controlled trials (RCTs), but not in the real world. AIMS: To investigate real-world comparative effects of antidepressants for depression and compare them with RCTs. METHOD: We performed a cohort study based on the QResearch database. We included people with a newly recorded diagnosis of depression, exposed to licensed antidepressants in the UK. We assessed all-cause dropouts (acceptability), dropouts for adverse events (tolerability), occurrence of at least one adverse event (safety), and response and remission on the Patient Health Questionnaire (PHQ)-9 (effectiveness) at 2 and 12 months. Logistic regressions were used to compute adjusted-odds ratio (aOR) with 99% CIs, assessing the associations between exposure to each antidepressant against fluoxetine (comparator) and outcomes of interest. We compared estimates from the real world with RCTs using ratio-of-odds ratio (ROR) with 95% CI. RESULTS: A total of 673 177 depressed people were studied: females 57.1%, mean age 42.8 (s.d. 17.7) years, mean baseline PHQ-9 17.1 (s.d. 5.0) (moderately severe depression). At 2 months, antidepressant acceptability was 61.4%, tolerability 94.4%, safety 54.5%, PHQ-9 decreased to 12.3 (s.d. 6.5). At 12 months, acceptability was 12.3%, tolerability 87.5%, safety 28.8%, PHQ-9 12.9 (s.d. 6.8). In the short and long term, tricyclics, mirtazapine and trazodone were worse than fluoxetine for most outcomes; citalopram had better acceptability than fluoxetine (aOR 0.95; 99% CI 0.92, 0.97), sertraline had lower tolerability (aOR 1.12; 99% CI 1.06, 1.18), and both citalopram and sertraline had lower safety (aOR 1.17 and 1.25, respectively). In the long term, citalopram had better acceptability (aOR 0.78; 99% CI 0.76, 0.81) and effectiveness (aOR 1.12 for both response and remission), but worse tolerability (aOR 1.09; 99% CI 1.06, 1.13) and safety (aOR 1.12; 99% CI 1.08, 1.16). Observational and randomised data were similar for citalopram and sertraline, while there was some difference for drugs less prescribed in the real world. CONCLUSIONS: Antidepressants showed low acceptability, moderate-to-high tolerability and safety, and small-to-moderate effectiveness in the real world. Real-world and RCT estimates showed similar findings only when the analyses were carried out using large datasets; otherwise, the results diverged.
Comparing the impact of contextual associations and statistical regularities in visual search and attention orienting.
During visual search, we quickly learn to attend to an object's likely location. Research has shown that this process can be guided by learning target locations based on consistent spatial contextual associations or other statistical regularities. Here, we tested how different types of associations guide learning and the utilisation of established memories for different purposes. Participants learned contextual associations or rule-like statistical regularities that predicted target locations within different scenes. The consequences of this learning for subsequent performance were then evaluated on attention-orienting and memory-recall tasks. Participants demonstrated facilitated attention-orienting and recall performance based on both contextual associations and statistical regularities. Contextual associations facilitated attention orienting with a different time course compared to statistical regularities. Benefits to memory-recall performance depended on the alignment between the learned association or regularity and the recall demands. The distinct patterns of behavioural facilitation by contextual associations and statistical regularities show how different forms of long-term memory may influence neural information processing through different modulatory mechanisms.
Reward Bases: A simple mechanism for adaptive acquisition of multiple reward types.
Animals can adapt their preferences for different types of reward according to physiological state, such as hunger or thirst. To explain this ability, we employ a simple multi-objective reinforcement learning model that learns multiple values according to different reward dimensions such as food or water. We show that by weighting these learned values according to the current needs, behaviour may be flexibly adapted to present preferences. This model predicts that individual dopamine neurons should encode the errors associated with some reward dimensions more than with others. To provide a preliminary test of this prediction, we reanalysed a small dataset obtained from a single primate in an experiment which to our knowledge is the only published study where the responses of dopamine neurons to stimuli predicting distinct types of rewards were recorded. We observed that in addition to subjective economic value, dopamine neurons encode a gradient of reward dimensions; some neurons respond most to stimuli predicting food rewards while the others respond more to stimuli predicting fluids. We also proposed a possible implementation of the model in the basal ganglia network, and demonstrated how the striatal system can learn values in multiple dimensions, even when dopamine neurons encode mixtures of prediction error from different dimensions. Additionally, the model reproduces the instant generalisation to new physiological states seen in dopamine responses and in behaviour. Our results demonstrate how a simple neural circuit can flexibly guide behaviour according to animals' needs.
12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study
Background: While semaglutide, approved for type-2 diabetes mellitus (T2DM), is being investigated as a treatment for brain disorders, concerns over adverse neuropsychiatric events have emerged. More data are therefore needed to assess the effects of semaglutide on brain health. This study provides robust estimates of the risk of neurological and psychiatric outcomes following semaglutide use compared to three other antidiabetic medications. Methods: This retrospective cohort study used electronic health records from TriNetX US Collaborative Network, covering >100 million patients in the USA. Due to the exploratory nature of this study, we did not use a pre-registered protocol or statistical analysis plan. Three cohorts with T2DM prescribed semaglutide between 1st December 2017 and 31st May 2021 were propensity-score matched (1:1 using a greedy nearest-neighbour algorithm with calliper distance of 0.1) with cohorts receiving sitagliptin, empagliflozin, and glipizide. Using Cox regression analysis, we compared the risks of 22 neurological and psychiatric outcomes within one year since the index prescription: encephalitis, parkinsonism, cognitive deficit, dementia, epilepsy/seizure, migraine, insomnia, nerve disorder, myoneural junction/muscle disease, intracranial haemorrhage, ischaemic stroke, alcohol misuse, opioid misuse, cannabis misuse, stimulants misuse, nicotine misuse, psychosis, bipolar disorder, depression, anxiety, obsessive-compulsive disorder, and suicidality. Negative control outcomes (NCOs) were used to assess unmeasured confounding. Findings: Each matched cohort included 23,386 (semaglutide vs sitagliptin), 22,584 (vs empagliflozin), and 19,206 (vs glipizide) patients. Semaglutide was not associated with an increased risk of neurological and psychiatric outcomes. Instead, after multiple-testing correction, semaglutide was associated with reduced risk for several such outcomes, notably cognitive deficit compared to sitagliptin (HR 0.72, 95% CI 0.64–0.80) and glipizide (HR 0.72, 95% CI 0.63–0.81), dementia compared to sitagliptin (HR 0.52, 95% CI 0.40–0.68), and nicotine misuse across most comparisons (HR 0.72, 95% CI 0.61–0.85 against glipizide; HR 0.77, 95% CI 0.65–0.90 against empagliflozin; HR 0.82, 95% CI 0.70–0.95 against sitagliptin, though the latter was no longer statistically significant after adjustment for multiple comparisons). Empagliflozin showed fewest differences from semaglutide. No differences in NCOs were observed between cohorts. Interpretation: Semaglutide is not associated with higher 12-month risk of adverse neuropsychiatric outcomes compared to other antidiabetic medications. Potential beneficial associations with some outcomes, especially cognitive deficit and nicotine misuse, should stimulate validation in clinical trials. Funding: National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre, Medical Research Council.