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BackgroundMajor depressive disorder (MDD) is a highly prevalent psychiatric condition associated with significant disability, mortality and economic burden. A large proportion of MDD patients are treated in primary health care in the local community. Attentional Bias Modification (ABM) training in combination with antidepressants could be an effective treatment. Here we test the hypothesis that adding an ABM procedure to regular treatment with antidepressants in primary health care will result in further improvement of symptoms compared to treatment with antidepressants alone (treatment as usual, TAU) and as compared to an active comparison condition.MethodsA total of 246 patients with a diagnosis of MDD will be included in this study. The study is a three-armed pragmatic randomized controlled trial comparing the efficacy of ABM as add-on to treatment with antidepressants in primary care (ABM condition) compared to standard antidepressant treatment (TAU condition). In a third group participants will complete the same schedule of intermediate assessments as the ABM condition in addition to TAU, but no ABM, thus controlling for the non-training-specific aspects of the ABM condition (Antidepressant active comparison group).DiscussionThe clinical outcome of this study may help develop easily accessible, low-cost treatment of depression in primary health care. Moreover, the study aims to broaden our knowledge of optimal treatment for patients with a MDD by providing adjunct treatment to facilitate recovery and long-term gain.
\n \n\n \n \nRATIONALE: Therapeutic administration of psychedelics has shown significant potential in historical accounts and recent clinical trials in the treatment of depression and other mood disorders. A recent randomized double-blind phase-IIb study demonstrated the safety and efficacy of COMP360, COMPASS Pathways' proprietary synthetic formulation of psilocybin, in participants with treatment-resistant depression. OBJECTIVE: While the phase-IIb results are promising, the treatment works for a portion of the population and early prediction of outcome is a key objective as it would allow early identification of those likely to require alternative treatment. METHODS: Transcripts were made from audio recordings of the psychological support session between participant and therapist 1 day post COMP360 administration. A zero-shot machine learning classifier based on the BART large language model was used to compute two-dimensional sentiment (valence and arousal) for the participant and therapist from the transcript. These scores, combined with the Emotional Breakthrough Index (EBI) and treatment arm were used to predict treatment outcome as measured by MADRS scores. (Code and data are available at https://github.com/compasspathways/Sentiment2D .) RESULTS: Two multinomial logistic regression models were fit to predict responder status at week 3 and through week 12. Cross-validation of these models resulted in 85% and 88% accuracy and AUC values of 88% and 85%. CONCLUSIONS: A machine learning algorithm using NLP and EBI accurately predicts long-term patient response, allowing rapid prognostication of personalized response to psilocybin treatment and insight into therapeutic model optimization. Further research is required to understand if language data from earlier stages in the therapeutic process hold similar predictive power.
\n \n\n \n \nPURPOSE: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. METHODS: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. RESULTS: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12\u2009mL/100\u2009g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59\u2009mL/100\u2009g/min) compared to submitted results. CONCLUSIONS: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization.
\n \n\n \n \nBACKGROUND: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH. METHODS: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged \u226518 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation. RESULTS: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years. CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.
\n \n\n \n \nOBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5\u2009\u00b1\u20096.3\u2009years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6\u2009\u00b1\u20097.1\u2009years, 78.4% males) and 160 controls (68.2\u2009\u00b1\u20097.2\u2009years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024.
\n \n\n \n \nElectroencephalogram (EEG) and behavioural data (joystick) was collected from 15 healthy participants who completed a modified version of a Go/No-go task. This dataset consists of raw data, pre-processed EEG and behavioural data, along with impulsivity scores in a .csv file. The pre-processed data is in MATLAB .mat format. \n\nRaw Data \n\nThe EEG and behavioural data (Joystick) along with trigger data was collected using a TMSi Porti amplifier with a sampling rate of 2,048Hz and is in .een format. The raw EEG files contain brain activity recorded in the first 16 channels and last 2 channels (channels 17 and 18) correspond to Joystick and Trigger information (used to identify the type of event \u2013 Go/Conflict/NoGo) respectively. \n\nThe Raw data is segregated into 2 folders- Active and Sham which is further divided into baseline and after stimulation conditions. \n\nThe main behavioural outcome is the change in NoGo errors (pre-processed folder- Figure 1C in from the article \u2018Tuning the brakes \u2013 Modulatory role of transcranial random noise stimulation on inhibition,\u2019 Brain Stimulation, 2024), comparing baseline and after-stimulation in sham and active conditions. Metadata corresponding to impulsivity scores and the change in NoGo behaviour are provided in \u2018UPPS_nogo.csv\u2019 (used for Figure 1D). The EEG data was recorded while the participants completed the task during baseline and after stimulation, and was used to calculate the spectral power (Figure 1E). The study also presents intermittent bursts from the EEG data, comparing the average burst durations at baseline and after-stimulation (Figure 1F) in sham and active stimulation conditions. \n\n \n\nCode \n\nAll data were analysed in MATLAB (2018b) using a combination of EEGLAB, ERP LAB and FieldTrip packages. \n\nInstallation guides can be found on \nhttps://sccn.ucsd.edu/eeglab/index.php \nhttps://matlab.mathworks.com/ \nhttps://erpinfo.org/erplab\u202f \nhttps://www.fieldtriptoolbox.org/download/\n\nThe behavioural data plots use the software IOSR toolbox :\nhttps://github.com/IoSR-Surrey/MatlabToolbox \n\nCode_figure_IC.m: This script plots the NoGo error rates in baseline and after stimulation in sham and active conditions. This script uses the mat file \u2018Nogo_behav_pre_post.mat\u2019 \n\nCode_figure_1E.m: This script plots the spectral power and grand average of the after-stimulation EEG data with clusters obtained from a non-parametric analysis. This script uses the mat file \u2018data_psd_trns_pre_post.mat\u2019. \n\nCode_figure_1F.m: This script plots the intermittent burst durations during sham and active conditions and uses the file \u2018Nogo_bursts_pre_post.mat\u2019
\n \n\n \n \nExisting neurostimulation systems implanted for the treatment of neurodegenerative disorders generally deliver invariable therapy parameters, regardless of phase of the sleep/wake cycle. However, there is considerable evidence that brain activity in these conditions varies according to this cycle, with discrete patterns of dysfunction linked to loss of circadian rhythmicity, worse clinical outcomes and impaired patient quality of life. We present a targeted concept of circadian neuromodulation using a novel device platform. This system utilises stimulation of circuits important in sleep and wake regulation, delivering bioelectronic cues (Zeitgebers) aimed at entraining rhythms to more physiological patterns in a personalised and fully configurable manner. Preliminary evidence from its first use in a clinical trial setting, with brainstem arousal circuits as a surgical target, further supports its promising impact on sleep/wake pathology. Data included in this paper highlight its versatility and effectiveness on two different patient phenotypes. In addition to exploring acute and long-term electrophysiological and behavioural effects, we also discuss current caveats and future feature improvements of our proposed system, as well as its potential applicability in modifying disease progression in future therapies.
\n \n\n \n \nBACKGROUND: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) show a high prevalence and rapid progression of dysphagia, which is associated with reduced survival. Despite this, the evidence base for gastrostomy is poor, and the optimal frequency and outcomes of this intervention are not known. We aimed to characterise the prevalence and outcomes of gastrostomy in patients with these three atypical parkinsonian disorders. METHOD: We analysed data from the natural history and longitudinal cohorts of the PROSPECT-M-UK study with up to 60\u2009months of follow-up from baseline. Survival post-gastrostomy was analysed using Kaplan-Meier survival curves. RESULTS: In a total of 339 patients (mean age at symptom onset 63.3\u2009years, mean symptom duration at baseline 4.6\u2009years), dysphagia was present in >50% across all disease groups at baseline and showed rapid progression during follow-up. Gastrostomy was recorded as recommended in 44 (13%) and performed in 21 (6.2%; MSA 7, PSP 11, CBS 3) of the total study population. Median survival post-gastrostomy was 24\u2009months compared with 12\u2009months where gastrostomy was recommended but not done (p\u2009=\u20090.008). However, this was not significant when correcting for age and duration of symptoms at the time of procedure or recommendation. CONCLUSIONS: Gastrostomy was performed relatively infrequently in this cohort despite the high prevalence of dysphagia. Survival post-gastrostomy was longer than previously reported, but further data on other outcomes and clinician and patient perspectives would help to guide use of this intervention in MSA, PSP and CBS.
\n \n\n \n \nPURPOSE: Fatigue is a common and debilitating problem in patients recovering from critical illness. To address a lack of evidence-based interventions for people with fatigue after critical illness, we co-produced a self-management intervention based on self-regulation theory. This article reports the development and initial user testing of the co-produced intervention. METHODS: We conducted three workshops with people experiencing fatigue after critical illness, family members, and healthcare professionals to develop a first draft of the FACT intervention, designed in web and electronic document formats. User testing and interviews were conducted with four people with fatigue after critical illness. Modifications were made based on the findings. RESULTS: Participants found FACT acceptable and easy to use, and the content provided useful strategies to manage fatigue. The final draft intervention includes four key topics: (1) about fatigue which discusses the common characteristics of fatigue after critical illness; (2) managing your energy with the 5 Ps (priorities, pacing, planning, permission, position); (3) strategies for everyday life (covering physical activity; home life; leisure and relationships; work, study, and finances; thoughts and feelings; sleep and eating); and (4) goal setting and making plans. All material is presented as written text, videos, and supplementary infographics. FACT includes calls with a facilitator but can also be used independently. CONCLUSIONS: FACT is a theory driven intervention co-produced by patient, carer and clinical stakeholders and is based on contemporary available evidence. Its development illustrates the benefits of stakeholder involvement to ensure interventions are informed by user needs. Further testing is needed to establish the feasibility and acceptability of FACT. IMPLICATIONS FOR CLINICAL PRACTICE: The FACT intervention shows promise as a self-management tool for people with fatigue after critical illness. It has the potential to provide education and strategies to patients at the point of discharge and follow-up.
\n \n\n \n \nWhat drives our curiosity remains an elusive and hotly debated issue, with multiple hypotheses proposed but a cohesive account yet to be established. This review discusses traditional and emergent theories that frame curiosity as a desire to know and a drive to learn, respectively. We adopt a model-based approach that maps the temporal dynamics of various factors underlying curiosity-based exploration, such as uncertainty, information gain, and learning progress. In so doing, we identify the limitations of past theories and posit an integrated account that harnesses their strengths in describing curiosity as a tool for optimal environmental exploration. In our unified account, curiosity serves as a 'common currency' for exploration, which must be balanced with other drives such as safety and hunger to achieve efficient action.
\n \n\n \n \nBACKGROUND: Cognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized. Whether objectively measurable cognitive deficits exist and how long they persist are unclear. METHODS: We invited 800,000 adults in a study in England to complete an online assessment of cognitive function. We estimated a global cognitive score across eight tasks. We hypothesized that participants with persistent symptoms (lasting \u226512 weeks) after infection onset would have objectively measurable global cognitive deficits and that impairments in executive functioning and memory would be observed in such participants, especially in those who reported recent poor memory or difficulty thinking or concentrating (\"brain fog\"). RESULTS: Of the 141,583 participants who started the online cognitive assessment, 112,964 completed it. In a multiple regression analysis, participants who had recovered from Covid-19 in whom symptoms had resolved in less than 4 weeks or at least 12 weeks had similar small deficits in global cognition as compared with those in the no-Covid-19 group, who had not been infected with SARS-CoV-2 or had unconfirmed infection (-0.23 SD [95% confidence interval {CI}, -0.33 to -0.13] and -0.24 SD [95% CI, -0.36 to -0.12], respectively); larger deficits as compared with the no-Covid-19 group were seen in participants with unresolved persistent symptoms (-0.42 SD; 95% CI, -0.53 to -0.31). Larger deficits were seen in participants who had SARS-CoV-2 infection during periods in which the original virus or the B.1.1.7 variant was predominant than in those infected with later variants (e.g., -0.17 SD for the B.1.1.7 variant vs. the B.1.1.529 variant; 95% CI, -0.20 to -0.13) and in participants who had been hospitalized than in those who had not been hospitalized (e.g., intensive care unit admission, -0.35 SD; 95% CI, -0.49 to -0.20). Results of the analyses were similar to those of propensity-score-matching analyses. In a comparison of the group that had unresolved persistent symptoms with the no-Covid-19 group, memory, reasoning, and executive function tasks were associated with the largest deficits (-0.33 to -0.20 SD); these tasks correlated weakly with recent symptoms, including poor memory and brain fog. No adverse events were reported. CONCLUSIONS: Participants with resolved persistent symptoms after Covid-19 had objectively measured cognitive function similar to that in participants with shorter-duration symptoms, although short-duration Covid-19 was still associated with small cognitive deficits after recovery. Longer-term persistence of cognitive deficits and any clinical implications remain uncertain. (Funded by the National Institute for Health and Care Research and others.).
\n \n\n \n \nBrain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased \u03b2-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.
\n \n\n \n \nTDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as \"TDP-43 proteinopathies\". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ~50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3\u202fmonths of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6\u202fmonths of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3\u202fmonths of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12\u202fmonths of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.
\n \n\n \n \nBACKGROUND: Gender clinic and single-item questionnaire-based data report increased co-occurrence of gender diversity and neurodevelopmental conditions. The nuances of these associations are under-studied. We used a transdiagnostic approach, combining categorical and dimensional characterization of neurodiversity, to further the understanding of its associations with gender diversity in identity and expression in children. METHODS: Data from 291 children (Autism N\u2009=\u2009104, ADHD N\u2009=\u2009104, Autism\u2009+\u2009ADHD N\u2009=\u200917, neurotypical N\u2009=\u200966) aged 4-12\u2009years enrolled in the Province of Ontario Neurodevelopmental Network were analyzed. Gender diversity was measured multi-dimensionally using a well-validated parent-report instrument, the Gender Identity Questionnaire for Children (GIQC). We used gamma regression models to determine the significant correlates of gender diversity among age, puberty, sex-assigned-at-birth, categorical neurodevelopmental diagnoses, and dimensional neurodivergent traits (using the Social Communication Questionnaire and the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scales). Internalizing and externalizing problems were included as covariates. RESULTS: Neither a categorical diagnosis of autism nor ADHD significantly correlated with current GIQC-derived scores. Instead, higher early-childhood dimensional autistic social-communication traits correlated with higher current overall gender incongruence (as defined by GIQC-14 score). This correlation was potentially moderated by sex-assigned-at-birth: greater early-childhood autistic social-communication traits were associated with higher current overall gender incongruence in assigned-males-at-birth, but not assigned-females-at-birth. For fine-grained gender diversity domains, greater autistic restricted-repetitive behavior traits were associated with greater diversity in gender identity across sexes-assigned-at-birth; greater autistic social-communication traits were associated with lower stereotypical male expression across sexes-assigned-at-birth. CONCLUSIONS: Dimensional autistic traits, rather than ADHD traits or categorical neurodevelopmental diagnoses, were associated with gender diversity domains across neurodivergent and neurotypical children. The association between early-childhood autistic social-communication traits and overall current gender diversity was most evident in assigned-males-at-birth. Nuanced interrelationships between neurodivergence and gender diversity should be better understood to clarify developmental links and to offer tailored support for neurodivergent and gender-diverse populations.
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