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People born without one hand, who are still able to use both limbs well in otherwise two-handed tasks, are likely to show brain activity which resembles that of people with two hands.
AbstractWhile it is well established that dopamine transmission is integral in mediating the influence of reward expectations on reward-seeking actions, the precise causal role of dopamine transmission in moment-to-moment cue-driven behavioural control remains contentious. This is a particular issue in situations where it is necessary to refrain from responding to achieve a beneficial outcome. To examine this, we manipulated dopamine transmission pharmacologically as rats performed a Go/No-Go task that required them to either make or withhold action to gain either a small or large reward. Stimulation of D1Rs, both globally and locally in the nucleus accumbens core (NAcC) region consistently disrupted No-Go performance, potentiating inappropriate responses that clustered strongly just after cue presentation. D1R blockade did not, however, improve rats’ ability to withhold responses, but instead primarily disrupted performance on Go trials. While global D1R blockade caused a general reduction of invigoration of reward seeking actions, intra-NAcC administration of the D1R antagonist by contrast increased the likelihood that Go trial performance was in an “unfocused” state. Such a state was characterised, both on and off drug, by a reduction in the precision and speed of responding even though the appropriate action sequence was often executed. These findings suggests that the balance of activity at NAcC D1Rs plays a key role in enabling the rapid activation of a focused, reward-seeking state to enable animals to efficiently and accurately achieve their goal.
Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons
Abstractα-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.
Educational Initiatives and Implementation of Electroencephalography into the Acute Care Environment: a protocol of a Systematic Review
Abstract Background: Use of electroencephalography (EEG) is currently recommended by the American Clinical Neurophysiology Society for a wide range of indications, including diagnosis of nonconvulsive status epilepticus and evaluation of unexplained disorders of consciousness. Data interpretation usually occurs by expert personnel (e.g. epileptologists, neurophysiologists), with information relayed to the primary care team. However, data cannot always be read in time-sensitive fashion, leading to potential delays in EEG interpretation and patient management. Multiple training programs have recently been described to enable non-experts to rapidly interpret EEG at the bedside. A comprehensive review of these training programs, including the tools used, outcomes obtained, and potential pitfalls, is currently lacking. Therefore, the optimum training program and implementation strategy remain unknown. Methods: We will conduct a systematic review of descriptive studies, case series, cohort studies and randomized controlled trials assessing training programs for EEG interpretation by non-experts. Our primary objective is to comprehensively review educational programs in this domain and report their structure, patterns of implementation, limitations, and trainee feedback. Our secondary objective will be to compare the performance of non-experts for EEG interpretation with a gold standard (e.g. interpretation by a certified electroencephalographers). Studies will be limited to those performed in acute care settings in both adult and paediatric populations (intensive care unit, emergency department, or post-anesthesia care units). Comprehensive search strategies will be developed for MEDLINE, EMBASE, WoS, CINAHL, and CENTRAL to identify studies for review. The gray literature will be scanned for further eligible studies. Two reviewers will independently screen the search results to identify studies for inclusion. A standardized data extraction form will be used to collect important data from each study. If possible, we will attempt to meta-analyse the quantitative data. If heterogeneity between studies is too high, we will present meaningful quantitative comparisons of secondary outcomes as per the synthesis without meta-analysis (SWiM) reporting guidelines. Discussion: We will aim to summarize the current literature in this domain to understand the structure, patterns, and pitfalls of EEG training programs for non-experts. This review is undertaken with a view to inform future education designs, potentially enabling rapid detection of EEG abnormalities and timely intervention by the treating physician. PROSPERO registration: Submitted and undergoing review (URL currently unavailable).
Almost any injury to the brain may initiate disturbances in local and systemic coagulation. This statement is particularly true for subarachnoid hemorrhage, traumatic brain injuries, and cranial and spinal dural arteriovenous fistulae. The pathogenesis of coagulative disorders is highlighted from both a genetic and a structural biology perspective, along with a discussion of predictive biomarkers and clinical risk factors to guide the selection of eligible patients for primary prevention. This comprehensive review allows a better understanding of the coagulative disorders affecting patients harboring CNS diseases and accordingly offers new insights into their pharmacological and surgical treatment.
In critically ill patients, the activation of blood coagulation occurs in parallel with the release of inflammatory mediators, which characterizes systemic inflammatory response syndrome and sepsis and sepsis-related conditions such as severe sepsis and septic shock. As a consequence, the overall hemostatic balance is shifted toward the activation of the coagulation, due to either the activation of the clotting system or the downregulation of the anticoagulant pathways. Systemic inflammation during sepsis leads to the generation of proinflammatory cytokines that, among other things, orchestrate coagulation and fibrinolytic activation. Abundant intravascular fibrin formation leads to microvascular thrombosis, which causes widespread ischemic organ damage up to organ necrosis and clinically impresses as widespread skin necrosis and multiple organ dysfunction syndrome. On the basis of the pathophysiologic concepts and the striking anticoagulant and anti-inflammatory properties of coagulation inhibitors in models for severe sepsis, administration of these inhibitors has been considered an attractive therapeutic approach for human sepsis.
Hypothermia describes a state in which the body's mechanism for temperature regulation is overwhelmed in the face of a cold stressor. Hypothermia is classified as accidental or intentional, primary or secondary, and according to its severity.
As seen in the previous section, nanotechnology holds the promise to redesign the realm of medicine as we know it nowadays, because it basically provides new dramatic tools to prevent diseases, promote health, and alleviate human sufiering, which are surely among our strongest mandate. Having this huge impact, a potential for both great good or even great harm, the nanofuture certainly represents the latest stage toward which ethics is called to focus. Physicist Freeman Dyson once stated, “Progress of science is destined to bring enormous confusion andmisery tomankind unless it is accompanied by progress in ethics” . Ethics, in fact, has always provided a rational approach to moral dilemmas, and bioethics has expanded rapidly in recent decades to specifically address them in life sciences. Dilemmas in innovation technology are common, and no big surprise if they are also gradually arising as part of the initial difiusion of nanotechnology-driven solutions to healthcare needs . Aiming to better analyze and understand those dilemmas, while moving our scientific research at the maximum speed for the sake of its benefits, in this section of the book we will cover the themes of risk assessment, risk management, risk communication, and research and development regulations, and finally we will discuss the concerns associated with human enhancement.
Genes and environment in multiple sclerosis: Impact of temporal changes in the sex ratio on recurrence risks.
OBJECTIVE: To evaluate the impact of temporal increase of female to male (F:M) sex ratio for persons with multiple sclerosis (MS) on the familial risk (empiric recurrence risks or RRs) for biological relatives of affected individuals. METHODS: Detailed family histories were systematically obtained from people with MS attending the University of British Columbia Hospital MS Clinic. The study cohort was born in 1970 or more recently. Data were collected from 1 September 2015 to 31 January 2019. The study was designed to allow only one proband per family. Age-corrected RRs for biological relatives of probands were calculated based on a modification of the maximum-likelihood approach. RESULTS: Data analyses were possible for 746 unique probands (531 females; 215 males) and 19,585 of their biological relatives. RRs were temporally impacted. CONCLUSION: Both genetic sharing and environmental factors are important in determining RRs. It appears that there is an increase in MS risk due to environmental factors in later life (i.e. not shared family environment). Environmental exposures in genetically predisposed individuals might be driving the MS risk. The increase in F:M ratio of RRs for sisters/brothers of female probands over time is likely due to environmental differences.
Adjuvant External Beam Radiotherapy Following Enucleation of Eyes With Extraocular Extension From Uveal Melanoma.
PURPOSE: To report local disease control and all-cause mortality in patients with extraocular extension (EOE) of uveal melanoma undergoing enucleation followed by observation or external beam radiotherapy (EBRT). METHODS: Charts of patients enucleated between January 1, 1997 and December 31, 2019, with histopathological evidence of EOE of uveal melanoma were reviewed. RESULTS: The cohort comprised 51 patients with a mean age of 67 ± 15 years, 22 (43%) of whom underwent adjuvant postenucleation EBRT. Risk factors for metastasis included presence of epithelioid cells (29/45; 88%), closed loops (20/43; 47%), monosomy 3 (16/25; 64%), and gain of 8q (20/22; 91%). Patients undergoing EBRT had more extensive EOE (median: 5.1 mm vs. 2.6 mm, p = 0.008) and surgical excision was less likely to be histologically complete (2/20; 10% vs. 14/25; 56%, p = 0.002). Local side effects following EBRT were seen in 64% (14/22). At latest follow up, 59% of patients (30/51) were alive, with a median follow up of 1.8 years (interquartile range: 2.9; range: 0.1-6.5]. By Kaplan-Meier survival analysis, the 5- and 10-year overall survival rates were 56% and 12%, respectively. There was no difference in all-cause mortality between those receiving adjuvant EBRT and those who were observed (log rank, p = 0.273). No cases of orbital recurrence were documented. CONCLUSIONS: Orbital EBRT causes significant morbidity. Cases with relatively small EOE undergoing enucleation can be safely observed, without adjuvant EBRT. Multicenter studies are required to better assess the role of EBRT when EOE is more extensive.
Background New-onset atrial fibrillation (NOAF) is common during critical illness and is associated with poor outcomes. Many risk factors for NOAF during critical illness have been identified, overlapping with risk factors for atrial fibrillation in patients in community settings. To develop interventions to prevent NOAF during critical illness, modifiable risk factors must be identified. These have not been studied in detail and it is not clear which variables warrant further study. Methods We undertook an international three-round Delphi process using an expert panel to identify important predictors of NOAF risk during critical illness. Results Of 22 experts invited, 12 agreed to participate. Participants were located in Europe, North America and South America and shared 110 publications on the subject of atrial fibrillation. All 12 completed the three Delphi rounds. Potentially modifiable risk factors identified include 15 intervention-related variables. Conclusions We present the results of the first Delphi process to identify important predictors of NOAF risk during critical illness. These results support further research into modifiable risk factors including optimal plasma electrolyte concentrations, rates of change of these electrolytes, fluid balance, choice of vasoactive medications and the use of preventative medications in high-risk patients. We also hope our findings will aid the development of predictive models for NOAF.
Brain structure is linked to the association between family environment and behavioral problems in children in the ABCD study
AbstractChildren’s behavioral problems have been associated with their family environments. Here, we investigate whether specific features of brain structures could relate to this link. Using structural magnetic resonance imaging of 8756 children aged 9-11 from the Adolescent Brain Cognitive Developmental study, we show that high family conflict and low parental monitoring scores are associated with children’s behavioral problems, as well as with smaller cortical areas of the orbitofrontal cortex, anterior cingulate cortex, and middle temporal gyrus. A longitudinal analysis indicates that psychiatric problems scores are associated with increased family conflict and decreased parental monitoring 1 year later, and mediate associations between the reduced cortical areas and family conflict, and parental monitoring scores. These results emphasize the relationships between the brain structure of children, their family environments, and their behavioral problems.
Sensory, somatomotor and internal mentation networks emerge dynamically in the resting brain with internal mentation predominating in older age.
Age-related changes in the brain are associated with a decline in functional flexibility. Intrinsic functional flexibility is evident in the brain's dynamic ability to switch between alternative spatiotemporal states during resting state. However, the relationship between brain connectivity states, associated psychological functions during resting state, and the changes in normal aging remain poorly understood. In this study, we analyzed resting-state functional magnetic resonance imaging (rsfMRI) data from the Human Connectome Project (HCP; N=812) and the UK Biobank (UKB; N=6,716). Using signed community clustering to identify distinct states of dynamic functional connectivity, and text-mining of a large existing literature for functional annotation of each state, our findings from the HCP dataset indicated that the resting brain spontaneously transitions between three functionally specialized states: sensory, somatomotor, and internal mentation networks. The occurrence, transition-rate, and persistence-time parameters for each state were correlated with behavioural scores using canonical correlation analysis. We estimated the same brain states and parameters in the UKB dataset, subdivided into three distinct age ranges: 50-55, 56-67, and 68-78 years. We found that the internal mentation network was more frequently expressed in people aged 71 and older, whereas people younger than 55 more frequently expressed sensory and somatomotor networks. Furthermore, analysis of the functional entropy - a measure of uncertainty of functional connectivity - also supported this finding across the three age ranges. Our study demonstrates that dynamic functional connectivity analysis can expose the time-varying patterns of transition between functionally specialized brain states, which are strongly tied to increasing age.
Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson's disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The 'Exenatide-PD3' study.
INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure. METHODS AND ANALYSIS: This is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences. ETHICS AND DISSEMINATION: This trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format. TRIAL REGISTRATION NUMBERS: NCT04232969, ISRCTN14552789.
Quantifying activities of daily living impairment in Parkinson's disease using the Functional Activities Questionnaire.
OBJECTIVE: Cognitive-driven activity of daily living (ADL) impairment in Parkinson's disease (PD) is increasingly discussed as prodromal marker for dementia. Diagnostic properties of assessments for this specific ADL impairment are sparsely investigated in PD. The ability of the Functional Activities Questionnaire (FAQ) for differentiating between PD patients with normal cognition and with mild cognitive impairment (PD-MCI), according to informant and self-reports, was examined. Global cognitive function in groups with and without mild ADL impairment was compared according to different cut-offs. METHODS: Multicenter data of 589 patients of an international cohort (CENTRE-PD) were analyzed. Analyses were run separately for informant-rated and self-rated FAQ. Receiver operating characteristic (ROC) analysis was conducted to define the optimal FAQ cut-off for PD-MCI (≥ 1), and groups were additionally split according to reported FAQ cut-offs for PD-MCI in the literature (≥ 3, ≥ 5). Binary logistic regressions examined the effect of the Montreal Cognitive Assessment (MoCA) score in PD patients with and without mild ADL impairment. RESULTS: Two hundred and twenty-five (38.2%) patients were classified as PD-MCI. For all three cut-off values, sensitivity was moderate to low ( 0.54) with a tendency of higher values for self-reported deficits. For the self-report, the cut-off ≥ 3 showed a significant effect of the MoCA (B = - 0.31, p = 0.003), where FAQ ≥ 3 patients had worse cognition. No effect for group differences based on informant ratings was detected. CONCLUSION: Our data argue that self-reported ADL impairments assessed by the FAQ show a relation to the severity of cognitive impairment in PD.
Optimising a Simple Fully Convolutional Network for Accurate Brain Age Prediction in the PAC 2019 Challenge.
Brain age prediction from brain MRI scans not only helps improve brain ageing modelling generally, but also provides benchmarks for predictive analysis methods. Brain-age delta, which is the difference between a subject's predicted age and true age, has become a meaningful biomarker for the health of the brain. Here, we report the details of our brain age prediction models and results in the Predictive Analysis Challenge 2019. The aim of the challenge was to use T1-weighted brain MRIs to predict a subject's age in multicentre datasets. We apply a lightweight deep convolutional neural network architecture, Simple Fully Convolutional Neural Network (SFCN), and combined several techniques including data augmentation, transfer learning, model ensemble, and bias correction for brain age prediction. The model achieved first place in both of the two objectives in the PAC 2019 brain age prediction challenge: Mean absolute error (MAE) = 2.90 years without bias removal (Second Place = 3.09 yrs; Third Place = 3.33 yrs), and MAE = 2.95 years with bias removal, leading by a large margin (Second Place = 3.80 yrs; Third Place = 3.92 yrs).
BACKGROUND: Sex-based neurobiological heterogeneity in autism is poorly understood. Research is disproportionately biased to males, leading to an unwarranted presumption that autism neurobiology is the same across sexes. Previous neuroimaging studies using amalgamated multi-center datasets to increase autistic female samples are characterized by large statistical noise. METHODS: We used a better-powered dataset of 1,183 scans of 839 individuals-299 (467 scans) autistic males, 74 (102 scans) autistic females, 240 (334 scans) control males and 226 (280 scans) control females-to test two whole-brain models of overall/global sex-modulations on autism neuroanatomy, by summary measures computed across the brain: local magnitude model, where the same brain regions/circuitries are involved across sexes but effect sizes are larger in females, indicating quantitative sex-modulation; and spatial dissimilarity model, where the neuroanatomy differs spatially between sexes, indicating qualitative sex-modulation. The male and female autism groups were matched on age, IQ and autism symptoms. Autism brain features were defined by comparisons to same-sex controls. RESULTS: Across five metrics (cortical thickness, surface area, volume, mean absolute curvature, and subcortical volume), we found no evidence supporting the local magnitude model. We found indicators supporting the spatial dissimilarity model on cortical mean absolute curvature and subcortical volume, but not other metrics. CONCLUSIONS: The overall/global autism neuroanatomy in females and males does not simply differ quantitatively in the same brain regions/circuitries. They may differ qualitatively in spatial involvement in cortical curvature and subcortical volume. The neuroanatomy of autism may be partly sex-specific. Sex-stratification to inform autism preclinical/clinical research is needed to identify sex-informed neurodevelopmental targets.
Dopaminergic organization of striatum is linked to cortical activity and brain expression of genes associated with psychiatric illness.
Dopamine signaling is constrained to discrete tracts yet has brain-wide effects on neural activity. The nature of this relationship between local dopamine signaling and brain-wide neuronal activity is not clearly defined and has relevance for neuropsychiatric illnesses where abnormalities of cortical activity and dopamine signaling coexist. Using simultaneous PET-MRI in healthy volunteers, we find strong evidence that patterns of striatal dopamine signaling and cortical blood flow (an index of local neural activity) contain shared information. This shared information links amphetamine-induced changes in gradients of striatal dopamine receptor availability to changes in brain-wide blood flow and is informed by spatial patterns of gene expression enriched for genes implicated in schizophrenia, bipolar disorder, and autism spectrum disorder. These results advance our knowledge of the relationship between cortical function and striatal dopamine, with relevance for understanding pathophysiology and treatment of diseases in which simultaneous aberrations of these systems exist.