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Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases
Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti–PD-1 antibody that bound membrane-proximally excluded CD45, triggered SHP2 phosphatase recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti–PD-1 blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer.
Acute to long-term characteristics of impedance recordings during neurostimulation in humans.
Objective:This study aims to characterize the time course of impedance, a crucial electrophysiological proper-ty of brain tissue, in the human thalamus (THL), amygdala-hippocampus (AMG-HPC), and poste-rior hippocampus (post-HPC) over an extended period.Approach:Impedance was periodically sampled every 5-15 minutes over several months in five subjects with drug-resistant epilepsy using an experimental neuromodulation device. Initially, we employed de-scriptive piecewise and continuous mathematical models to characterize the impedance response for approximately three weeks post-electrode implantation. We then explored the temporal dynamics of impedance during periods when electrical stimulation was temporarily halted, observing a mono-tonic increase (rebound) in impedance before it stabilized at a higher value. Lastly, we assessed the stability of amplitude and phase over the 24-hour impedance cycle throughout the multi-month re-cording.Main results:IImmediately post-implantation, the impedance decreased, reaching a minimum value in all brain regions within approximately two days, and then increased monotonically over about 14 days to a stable value. The models accounted for the variance in short-term impedance changes. Notably, the minimum impedance of the THL in the most epileptogenic hemisphere was significantly lower than in other regions. During the gaps in electrical stimulation, the impedance rebound decreased over time and stabilized around 200 days post-implant, likely indicative of the foreign body re-sponse and fibrous tissue encapsulation around the electrodes. The amplitude and phase of the 24-hour impedance oscillation remained stable throughout the multi-month recording, with circadian variation in impedance dominating the long-term measures.Significance:Our findings illustrate the complex temporal dynamics of impedance in implanted electrodes and the impact of electrical stimulation. The data suggest that the temporal dynamics of impedance are dependent on the anatomical location and tissue epileptogenicity. These insights may offer additional guidance for the delivery of therapeutic stimulation at various time points post-implantation for neuromodulation therapy.
Concurrent spinal and brain imaging with optically pumped magnetometers
Background: The spinal cord and its interactions with the brain are fundamental for movement control and somatosensation. However, brain and spinal electrophysiology in humans have largely been treated as distinct enterprises, in part due to the relative inaccessibility of the spinal cord. Consequently, there is a dearth of knowledge on human spinal electrophysiology, including the multiple pathologies that affect the spinal cord as well as the brain. New method: Here we exploit recent advances in the development of wearable optically pumped magnetometers (OPMs) which can be flexibly arranged to provide coverage of both the spinal cord and the brain in relatively unconstrained environments. This system for magnetospinoencephalography (MSEG) measures both spinal and cortical signals simultaneously by employing custom-made scanning casts. Results: We evidence the utility of such a system by recording spinal and cortical evoked responses to median nerve stimulation at the wrist. MSEG revealed early (10 – 15 ms) and late (>20 ms) responses at the spinal cord, in addition to typical cortical evoked responses (i.e., N20). Comparison with existing methods: Early spinal evoked responses detected were in line with conventional somatosensory evoked potential recordings. Conclusion: This MSEG system demonstrates the novel ability for concurrent non-invasive millisecond imaging of brain and spinal cord.
Long-Term Impact of Urgent Secondary Prevention After Transient Ischemic Attack and Minor Stroke: Ten-Year Follow-Up of the EXPRESS Study.
BACKGROUND AND PURPOSE: Urgent assessment aimed at reducing stroke risk after transient ischemic attack or minor stroke is cost-effective over the short-term. However, it is unclear if the short-term impact is lost on long-term follow-up, with recurrent events being delayed rather than prevented. By 10-year follow-up of the EXPRESS study (Early Use of Existing Preventive Strategies for Stroke), previously showing urgent assessment reduced 90-day stroke risk by 80%, we determined whether that early benefit was still evident long-term for stroke risk, disability, and costs. METHODS: EXPRESS was a prospective population-based before (phase 1: April 2002-September 2004; n=310) versus after (phase 2: October 2004-March 2007; n=281) study of the effect of early assessment and treatment of transient ischemic attack/minor stroke on early recurrent stroke risk, with an external control. This report assesses the effect on 10-year recurrent stroke risk, functional outcomes, quality-of-life, and costs. RESULTS: A reduction in stroke risk in phase 2 was still evident at 10 years (55/23.3% versus 82/31.6%; hazard ratio=0.68 [95% CI, 0.48-0.95]; P=0.024), as was the impact on risk of disabling or fatal stroke (17/7.7% versus 32/13.1%; hazard ratio=0.54 [0.30-0.97]; P=0.036). These effects were due to maintenance of the early reduction in stroke risk, with neither additional benefit nor rebound catch-up after 90 days (post-90 days hazard ratio=0.88 [0.65-1.44], P=0.88; and hazard ratio=0.83 [0.42-1.65], P=0.59, respectively). Disability-free life expectancy was 0.59 (0.03-1.15; P=0.043) years higher in patients in phase 2, as was quality-adjusted life expectancy (0.49 [0.03-0.95]; P=0.036). Overall, 10-year costs were nonsignificantly higher in patients attending the phase 2 clinic ($1022 [-3865-5907]; P=0.66). The additional cost per quality-adjusted life year gained in phase 2 versus phase 1 was $2103, well below current cost-effectiveness thresholds. CONCLUSIONS: Urgent assessment and treatment of patients with transient ischemic attack or minor stroke resulted in a long-term reduction in recurrent strokes and improved outcomes, with little atrophy of the early benefit over time, representing good value for money even with a 10-year time horizon. Our results suggest that other effective acute treatments in transient ischemic attack/minor stroke in the short-term will also have the potential to have long-term benefit.
PET-measured human dopamine synthesis capacity and receptor availability predict trading rewards and time-costs during foraging.
Foraging behavior requires weighing costs of time to decide when to leave one reward patch to search for another. Computational and animal studies suggest that striatal dopamine is key to this process; however, the specific role of dopamine in foraging behavior in humans is not well characterized. We use positron emission tomography (PET) imaging to directly measure dopamine synthesis capacity and D1 and D2/3 receptor availability in 57 healthy adults who complete a computerized foraging task. Using voxelwise data and principal component analysis to identify patterns of variation across PET measures, we show that striatal D1 and D2/3 receptor availability and a pattern of mesolimbic and anterior cingulate cortex dopamine function are important for adjusting the threshold for leaving a patch to explore, with specific sensitivity to changes in travel time. These findings suggest a key role for dopamine in trading reward benefits against temporal costs to modulate behavioral adaptions to changes in the reward environment critical for foraging.
The first year of a new era.
What happened when eLife decided to eliminate accept/reject decisions after peer review?
Generative replay underlies compositional inference in the hippocampal-prefrontal circuit.
Human reasoning depends on reusing pieces of information by putting them together in new ways. However, very little is known about how compositional computation is implemented in the brain. Here, we ask participants to solve a series of problems that each require constructing a whole from a set of elements. With fMRI, we find that representations of novel constructed objects in the frontal cortex and hippocampus are relational and compositional. With MEG, we find that replay assembles elements into compounds, with each replay sequence constituting a hypothesis about a possible configuration of elements. The content of sequences evolves as participants solve each puzzle, progressing from predictable to uncertain elements and gradually converging on the correct configuration. Together, these results suggest a computational bridge between apparently distinct functions of hippocampal-prefrontal circuitry and a role for generative replay in compositional inference and hypothesis testing.
A cognitive map for value-guided choice in ventromedial prefrontal cortex
AbstractThe prefrontal cortex is crucial for economic decision-making and representing the value of options. However, how such representations facilitate flexible decisions remains unknown. We reframe economic decision-making in prefrontal cortex in line with representations of structure within the medial temporal lobe because such cognitive map representations are known to facilitate flexible behaviour. Specifically, we framed choice between different options as a navigation process in value space. Here we show that choices in a 2D value space defined by reward magnitude and probability were represented with a grid-like code, analogous to that found in spatial navigation. The grid-like code was present in ventromedial prefrontal cortex (vmPFC) local field potential theta frequency and the result replicated in an independent dataset. Neurons in vmPFC similarly contained a grid-like code, in addition to encoding the linear value of the chosen option. Importantly, both signals were modulated by theta frequency – occurring at theta troughs but on separate theta cycles. Furthermore, we found sharp-wave ripples – a key neural signature of planning and flexible behaviour – in vmPFC, which were modulated by accuracy and reward. These results demonstrate that multiple cognitive map-like computations are deployed in vmPFC during economic decision-making, suggesting a new framework for the implementation of choice in prefrontal cortex.
brainlife.io: a decentralized and open-source cloud platform to support neuroscience research.
Neuroscience is advancing standardization and tool development to support rigor and transparency. Consequently, data pipeline complexity has increased, hindering FAIR (findable, accessible, interoperable and reusable) access. brainlife.io was developed to democratize neuroimaging research. The platform provides data standardization, management, visualization and processing and automatically tracks the provenance history of thousands of data objects. Here, brainlife.io is described and evaluated for validity, reliability, reproducibility, replicability and scientific utility using four data modalities and 3,200 participants.
Behaviour-correlated profiles of cerebellar-cerebral functional connectivity observed in independent neurodevelopmental disorder cohorts.
The cerebellum, through its connectivity with the cerebral cortex, plays an integral role in regulating cognitive and affective processes, and its dysregulation can result in neurodevelopmental disorder (NDD)-related behavioural deficits. Identifying cerebellar-cerebral functional connectivity (FC) profiles in children with NDDs can provide insight into common connectivity profiles and their correlation to NDD-related behaviours. 479 participants from the Province of Ontario Neurodevelopmental Disorders (POND) network (typically developing = 93, Autism Spectrum Disorder = 172, Attention Deficit/Hyperactivity Disorder = 161, Obsessive-Compulsive Disorder = 53, mean age = 12.2) underwent resting-state functional magnetic resonance imaging and behaviour testing (Social Communication Questionnaire, Toronto Obsessive-Compulsive Scale, and Child Behaviour Checklist - Attentional Problems Subscale). FC components maximally correlated to behaviour were identified using canonical correlation analysis. Results were then validated by repeating the investigation in 556 participants from an independent NDD cohort provided from a separate consortium (Healthy Brain Network (HBN)). Replication of canonical components was quantified by correlating the feature vectors between the two cohorts. The two cerebellar-cerebral FC components that replicated to the greatest extent were correlated to, respectively, obsessive-compulsive behaviour (behaviour feature vectors, rPOND-HBN = -0.97; FC feature vectors, rPOND-HBN = -0.68) and social communication deficit contrasted against attention deficit behaviour (behaviour feature vectors, rPOND-HBN = -0.99; FC feature vectors, rPOND-HBN = -0.78). The statistically stable (|z| > 1.96) features of the FC feature vectors, measured via bootstrap re-sampling, predominantly comprised of correlations between cerebellar attentional and control network regions and cerebral attentional, default mode, and control network regions. In both cohorts, spectral clustering on FC loading values resulted in subject clusters mixed across diagnostic categories, but no cluster was significantly enriched for any given diagnosis as measured via chi-squared test (p > 0.05). Overall, two behaviour-correlated components of cerebellar-cerebral functional connectivity were observed in two independent cohorts. This suggests the existence of generalizable cerebellar network differences that span across NDD diagnostic boundaries.
Rebound activation of 5-HT neurons following SSRI discontinuation.
Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas brain tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased c-Fos expression in midbrain 5-HT (TPH2 positive) neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT1A autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study reports evidence that, across a range of experiments, SSRI discontinuation triggers a rebound activation of 5-HT neurons. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.
Impaired Kidney Function, Cerebral Small Vessel Disease and Cognitive Disorders: The Framingham Heart Study.
BACKGROUND AND HYPOTHESIS: It remains unclear if the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD) and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants. METHODS: We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain MRI late in life (exam cycles 7-9), cognitive outcome data and available interim hypertension and blood pressure assessments. We related CKD (estimated glomerular filtration rate
Motor Complications in Parkinson's Disease: Results from 3343 Patients Followed for up to 12 Years.
BACKGROUND: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. OBJECTIVES: To quantify the presence, severity, impact and associated factors for motor complications in PD. METHODS: Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. RESULTS: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). CONCLUSIONS: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications.
Sleep effort and its measurement: A scoping review.
Insomnia disorder is characterized by disruption in sleep continuity and an overall dissatisfaction with sleep. A relevant feature of insomnia is sleep effort, which refers to both cognitive and behavioural conscious attempts to initiate sleep. The Glasgow Sleep Effort Scale is a self-report tool developed to assess this construct. The objective of the current scoping review was to map how sleep effort has been discussed in the literature and operationalized through its respective measure. Medline/PubMed, Scopus, Web of Science and PsycInfo databases were used to search for potential studies. The search query used in databases was the specific name of the self-reported tool itself (Glasgow Sleep Effort Scale) and "sleep effort" term. This scoping review followed JBI guidelines. To be included, records pertaining to any type of study that mentioned the Glasgow Sleep Effort Scale were considered. No language constraint was used. At the end, 166 initial records were retrieved. From those, 46 records met eligibility criteria and were analysed. Among the main findings, it was observed that the Glasgow Sleep Effort Scale has been increasingly used in recent years, with a notable observed upward trend, especially in the last 2 years. In addition to the original measure, only three published adapted versions of the instrument were identified. This suggests that there is limited research on adapting the scale for different populations or contexts. Sleep effort has been increasingly studied in the last few years. Nonetheless, more research on the Glasgow Sleep Effort Scale tool is recommended, including cross-cultural adaptations.
Development of an enhanced scoring system to predict ICU readmission or in-hospital death within 24 hours using routine patient data from two NHS Foundation Trusts.
RATIONALE: Intensive care units (ICUs) admit the most severely ill patients. Once these patients are discharged from the ICU to a step-down ward, they continue to have their vital signs monitored by nursing staff, with Early Warning Score (EWS) systems being used to identify those at risk of deterioration. OBJECTIVES: We report the development and validation of an enhanced continuous scoring system for predicting adverse events, which combines vital signs measured routinely on acute care wards (as used by most EWS systems) with a risk score of a future adverse event calculated on discharge from the ICU. DESIGN: A modified Delphi process identified candidate variables commonly available in electronic records as the basis for a 'static' score of the patient's condition immediately after discharge from the ICU. L1-regularised logistic regression was used to estimate the in-hospital risk of future adverse event. We then constructed a model of physiological normality using vital sign data from the day of hospital discharge. This is combined with the static score and used continuously to quantify and update the patient's risk of deterioration throughout their hospital stay. SETTING: Data from two National Health Service Foundation Trusts (UK) were used to develop and (externally) validate the model. PARTICIPANTS: A total of 12 394 vital sign measurements were acquired from 273 patients after ICU discharge for the development set, and 4831 from 136 patients in the validation cohort. RESULTS: Outcome validation of our model yielded an area under the receiver operating characteristic curve of 0.724 for predicting ICU readmission or in-hospital death within 24 hours. It showed an improved performance with respect to other competitive risk scoring systems, including the National EWS (0.653). CONCLUSIONS: We showed that a scoring system incorporating data from a patient's stay in the ICU has better performance than commonly used EWS systems based on vital signs alone. TRIAL REGISTRATION NUMBER: ISRCTN32008295.