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Decision cost hypersensitivity underlies Huntington's disease apathy.
The neuropsychiatric syndrome of apathy is now recognized to be a common and disabling condition in Huntington's disease. However, the mechanisms underlying it are poorly understood. One way to investigate apathy is to use a theoretical framework of normal motivated behaviour, to determine where breakdown has occurred in people with this behavioural disruption. A fundamental computation underlying motivated, goal-directed behaviour across species is weighing up the costs and rewards associated with actions. Here, we asked whether people with apathy are more sensitive to costs of actions (physical effort and time delay), less sensitive to rewarding outcomes, or both. Based on the unique anatomical substrates associated with Huntington's disease pathology, we hypothesized that a general hypersensitivity to costs would underpin Huntington's disease apathy. Genetically confirmed carriers of the expanded Huntingtin gene (premanifest to mild motor manifest disease, n = 53) were compared to healthy controls (n = 38). Participants performed a physical effort-based decision-making task (Apple Gathering Task) and a delay discounting task (Money Choice Questionnaire). Choice data was analysed using linear regression and drift diffusion models that also accounted for the time taken to make decisions. Apathetic people with Huntington's disease accepted fewer offers overall on the Apple Gathering Task, specifically driven by increased sensitivity to physical effort costs, and not explained by motor severity, mood, cognition or medication. Drift diffusion modelling provided further evidence of effort hypersensitivity, with apathy associated with a faster drift rate towards rejecting offers as a function of varying effort. Increased delay sensitivity was also associated with apathy, both when analysing raw choice and drift rate, where there was moderate evidence of Huntington's disease apathy drifting faster towards the immediately available (low-cost) option. Furthermore, the effort and delay sensitivity parameters from these tasks were positively correlated. The results demonstrate a clear mechanism for apathy in Huntington's disease, cost hypersensitivity, which manifests in both the effort and time costs associated with actions towards rewarding goals. This suggests that Huntington's disease pathology may cause a domain-general disruption of cost processing, which is distinct from apathy occurrence in other brain disorders and may require different therapeutic approaches.
The role of N-glycans in regulatory T cells in autoimmunity.
Regulatory T cells (Tregs) have a key role in the maintenance of immune tolerance and in the prevention of autoimmunity. Recent studies have shown an association between decreased Treg frequency and a deficient suppressive activity with the development of many autoimmune diseases. Although glycosylation, which consists in the addition of glycans to proteins and lipids on the cell surface, is recognized as a critical modification for T cell development and function, the relevance of glycans in Treg biology and activity, as well as their impact in the immunopathogenesis of autoimmune diseases, deserves more attention, as it is far from being fully understood. This review discusses the biological impact of N-glycans in Treg biology, highlighting their potential to uncover novel pathogenic mechanisms in autoimmunity and new targets for promising therapeutic approaches with clinical applications in autoimmune disease patients.
Characterising human disparity tuning properties using population receptive field mapping.
Our visual percept of small differences in depth is largely informed by binocular stereopsis, the ability to decode depth from the horizontal offset between the retinal images in each eye. While multiple cortical areas are associated with stereoscopic processing, it is unclear how tuning to specific binocular disparities is organised across human visual cortex. We used 3T functional magnetic resonance imaging to generate population receptive fields in response to modulation of binocular disparity to characterise the neural tuning to disparity. We also used psychophysics to measure stereoacuity thresholds compared to backgrounds at different depths (pedestal disparity). Ten human participants (7 female) observed correlated or anticorrelated random-dot stereograms with disparity ranging from -0.3° to 0.3°, and responses were modelled as 1-dimensional tuning curves along the depth dimension. First, we demonstrate that lateral and dorsal visual areas show the greatest proportion of vertices selective for binocular disparity. Second, with binocularly correlated stimuli, we show a polynomial relationship between preferred disparity and tuning curve width, with sharply tuned disparity responses at near-zero disparities, and broader disparity tuning profiles at near or far disparities. This relationship held across visual areas and was not present for anticorrelated stimuli. Finally, the individual thresholds for psychophysical stereoacuity at the 3 different pedestal disparities were broadly related to population receptive field tuning width in area V1, suggesting a possible limit for fine stereopsis at the earliest level of cortical processing. Together, these findings point to heterogeneity of disparity processing across human visual areas, comparable to non-human primates.Significance Statement Binocular disparity arises from the horizonal separation of the two eyes and provides information for determining depth and 3D structure. We used functional magnetic resonance imaging and population receptive field mapping to measure tuning of multiple visual areas to binocular disparity in the human visual cortex. We additionally measured psychophysical thresholds for detecting binocular disparity and correlated these with the neural measures. The width of the disparity tuning was related to the preferred disparity across all visual areas. Disparity tuning widths in V1 were also related to psychophysical thresholds. These findings in the human are broadly comparable to non-human primates.
Proceedings of the 12th annual deep brain stimulation think tank: cutting edge technology meets novel applications.
The Deep Brain Stimulation (DBS) Think Tank XII was held on August 21st to 23rd. This year we showcased groundbreaking advancements in neuromodulation technology, focusing heavily on the novel uses of existing technology as well as next-generation technology. Our keynote speaker shared the vision of using neuro artificial intelligence to predict depression using brain electrophysiology. Innovative applications are currently being explored in stroke, disorders of consciousness, and sleep, while established treatments for movement disorders like Parkinson's disease are being refined with adaptive stimulation. Neuromodulation is solidifying its role in treating psychiatric disorders such as depression and obsessive-compulsive disorder, particularly for patients with treatment-resistant symptoms. We estimate that 300,000 leads have been implanted to date for neurologic and neuropsychiatric indications. Magnetoencephalography has provided insights into the post-DBS physiological changes. The field is also critically examining the ethical implications of implants, considering the long-term impacts on clinicians, patients, and manufacturers.
Binding-Site Purification of Actives (B-SPA) Enables Efficient Large-Scale Progression of Fragment Hits by Combining Multi-Step Array Synthesis With HT Crystallography.
Fragment approaches are long-established in target-based ligand discovery, yet their full transformative potential lies dormant because progressing the initial weakly binding hits to potency remains a formidable challenge. The only credible progression paradigm involves multiple cycles of costly conventional design-make-test-analyse medicinal chemistry. We propose an alternative approach to fragment elaboration, namely performing large numbers of parallel and diverse automated multiple step reactions, and evaluating the binding of the crude reaction products by high-throughput protein X-ray crystallography. We show it is effective and low-cost to perform, in parallel, large numbers of non-uniform multi-step reactions, because, even without compound purification, crystallography provides a high-quality readout of binding. This can detect low-level binding of weakly active compounds, which the target binding site extracts directly from crude reaction mixtures. In this proof-of-concept study, we have expanded a fragment hit, from a crystal-based screen of the second bromodomain of pleckstrin homology domain-interacting protein (PHIP(2)), using array synthesis on low-cost robotics. We were able to implement 6 independent multi-step reaction routes of up to 5 steps, attempting the synthesis of 1876 diverse expansions, designs entirely driven by synthetic tractability. The expected product was present in 1108 (59%) crude reaction mixtures, detected by liquid chromatography mass spectrometry (LCMS). 22 individual products were resolved in the crystal structures of crude reaction mixtures added to crystals, providing an initial structure activity relationship map. 19 of these showed binding pose stability, while, through binding instability in the remaining 3 products, we could resolve a stereochemical preference for mixtures containing racemic compounds. One compound showed biochemical potency (IC50=34 μM) and affinity (Kd=50 μM) after resynthesis. This approach therefore lends itself to routine fragment progression, if coupled with algorithmically guided compound and reaction design and new formalisms for data analysis.
CaV2.1 mediates presynaptic dysfunction induced by amyloid β oligomers.
Synaptic dysfunction is an early pathological phenotype of Alzheimer's disease (AD) that is initiated by oligomers of amyloid β peptide (Aβos). Treatments aimed at correcting synaptic dysfunction could be beneficial in preventing disease progression, but mechanisms underlying Aβo-induced synaptic defects remain incompletely understood. Here, we uncover an epithelial sodium channel (ENaC) - CaV2.3 - protein kinase C (PKC) - glycogen synthase kinase-3β (GSK-3β) signal transduction pathway that is engaged by Aβos to enhance presynaptic CaV2.1 voltage-gated Ca2+ channel activity, resulting in pathological potentiation of action-potential-evoked synaptic vesicle exocytosis. We present evidence that the pathway is active in human APP transgenic mice in vivo and in human AD brains, and we show that either pharmacological CaV2.1 inhibition or genetic CaV2.1 haploinsufficiency is sufficient to restore normal neurotransmitter release. These findings reveal a previously unrecognized mechanism driving synaptic dysfunction in AD and identify multiple potentially tractable therapeutic targets.
Recent developments in gene therapy for Parkinson's disease.
Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no cure. Gene therapy has emerged as a novel approach offering renewed hope for the development of treatments that meaningfully alter the course of the disease. In this review we explore various gene therapy strategies currently being developed targeting key aspects of PD pathogenesis: the restoration of the dopamine system by delivering genes involved in dopamine biosynthesis; reinforcing the inhibitory signalling pathways through glutamic acid decarboxylase (GAD) delivery to increase GABA production; enhancing neuronal survival and development by introducing various neurotrophic factors; delivery of genes to complement recessive familial PD mutations to correct mitochondrial dysfunction; restoring lysosomal function through delivery of GBA1 to increase glucocerebrosidase (GCase) activity; and reducing alpha-synuclein levels by reducing or silencing SNCA expression. Despite promising early work, challenges remain in developing safe, effective, and long-lasting gene therapies. Key considerations include optimizing viral vectors for targeted delivery, achieving controlled and sustained gene expression using different promoters, minimizing immune responses and increasing transgene delivery capacity. Future prospects may involve combinatory strategies targeting multiple pathways, such as multi-gene constructs delivered via high-capacity viral systems.
Human-centered design and maternity care: is this a possible interplay?-a systematic review.
This paper argues that putting women at the center of care requires the right balance between adequate clinical care and human-centered design (HCD) approaches. Enhancing their experience during the maternity journey would make it possible to address societal challenges and effectively achieve the humanization of maternity care. Thus, the aim is to investigate the interplay between human-centered design and maternity care through a literature review. MEDLINE (Pubmed), CINAHL (EBSCO), Web of Science, and Scopus databases were searched, and twenty-one papers were selected as primary studies according to predefined inclusion criteria and as per agreement of the authors, either from design/social sciences or clinical backgrounds. Studies from eight countries targeting prenatal, childbirth, and/or postnatal care were reviewed, including healthcare professionals and pregnant women as participants. A systematic approach was followed for the papers, and specific attention was paid to socioeconomic and racial issues. The last phase included prototype testing, which involved digital resources development. Creating solutions for the mainstay problems throughout HCD is a helpful tool in surpassing systems' problems and disadvantages, allowing for identifying and accurately targeting healthcare system gaps and maternity care opportunities to achieve a positive and humanized journey.
Investigating the complex cortical dynamics of an advanced concentrative absorption meditation called jhanas (ACAM-J): a geometric eigenmode analysis.
Advanced meditation has been associated with long- and short-term psychological changes such as bliss, profound insight, and transformation of well-being. However, most advanced meditation neuroimaging analyses have implemented primarily spatially-localized approaches, focusing on discrete regional changes in activity rather than distributed dynamics. The present study uses a geometric eigenmode decomposition of ultrahigh field-strength 7T functional magnetic resonance imaging (fMRI) data from an intensely sampled case study to investigate the complex, distributed cortical dynamics associated with advanced concentrative absorption meditation. Geometric eigenmode decomposition of advanced concentrative absorption meditation and non-meditative control task fMRI data revealed elevated global brain state power and energy patterns of specific advanced concentrative absorption meditation states compared to controls, with mid-frequency spectrum brain state power and energy following a non-random, cubic trajectory through the advanced concentrative absorption meditation sequence. Further, these brain state differences were meaningfully associated with subjective phenomenological reports of attention, intensity of advanced concentrative absorption meditation quality, and sensations. This study unites precise methodological design, a novel fMRI decomposition framework, and rigorous phenomenology to provide valuable insights into the distributed neural signatures of highly refined conscious states. These results underscore similarities and differences between advanced concentrative absorption meditation and other altered states of consciousness like those induced by psychedelics-offering insights into refined conscious states and their implications for health and well-being.
Hypertension and Atrial Fibrillation: A Frontier Review From the AF-SCREEN International Collaboration.
Hypertension is the leading modifiable risk factor for atrial fibrillation (AF) and is estimated to be present in >70% of AF patients. This Frontiers Review was prepared by 29 expert members of the AF-SCREEN International Collaboration to summarize existing evidence and knowledge gaps on links between hypertension, AF, and their cardiovascular sequelae; simultaneous screening for hypertension and AF; and the prevention of AF through antihypertensive therapy. Hypertension and AF are inextricably connected. Both are easily diagnosed, often silent, and frequently treated inadequately. Together, they additively increase the risk of ischemic stroke, heart failure, and many types of dementia, resulting in greater all-cause mortality, considerable disease burden, and increased health care expenditures. Automated upper arm cuff blood pressure devices with implemented technology can be used to simultaneously detect both hypertension and AF. However, positive screening for AF with an oscillometric blood pressure monitor still requires ECG confirmation. The current evidence suggests that high-risk individuals aged ≥65 years or with treatment-resistant hypertension could benefit from AF screening. Since antihypertensive therapy effectively lowers AF risk, particularly in individuals with left ventricular dysfunction, hypertension should be the key target for AF prediction and prevention rather than merely a comorbidity of AF. Nevertheless, several important gaps in knowledge need to be filled over the next years, including the ideal method and selection of patients for simultaneous screening of hypertension and AF and the optimal antihypertensive drug class and blood pressure targets for AF prevention.
Sleep and circadian difficulties in schizophrenia: presentations, understanding, and treatment.
It is common in mental health care to ask about people's days but comparatively rare to ask about their nights. Most patients diagnosed with schizophrenia struggle at nighttime. The next-day effects can include a worsening of psychotic experiences, affective disturbances, and inactivity, which in turn affect the next night's sleep. Objective and subjective cognitive abilities may be affected too. Patients commonly experience a mix of sleep difficulties in a night and across a week. These difficulties include trouble falling asleep, staying asleep, or sleeping at all; nightmares and other awakenings; poor-quality sleep; oversleeping; tiredness; sleeping at the wrong times; and problems establishing a regular sleep pattern. The patient group is also more vulnerable to obstructive sleep apnea and restless legs syndrome. We describe in this article how the complex presentation of non-respiratory sleep difficulties arises from variation across five factors: timing, mental state, need for sleep, self-care, and environment. We set out 10 illustrative patterns of such difficulties experienced by patients with non-affective psychosis. These sleep problems are eminently treatable with intensive psychological therapy delivered over approximately eight sessions. We describe key techniques and their typical order of implementation by presentation. Sleep problems are an important issue for patients. Giving them the therapeutic attention patients often desire brings both real clinical benefits and improves views of services. Treatment is also very likely to lessen psychotic experiences and mood disturbances while improving daytime functioning and quality of life. Tackling sleep difficulties can be a route toward the successful treatment of psychosis.
Sleep pressure accumulates in a voltage-gated lipid peroxidation memory.
Voltage-gated potassium (KV) channels contain cytoplasmically exposed β-subunits1-5 whose aldo-keto reductase activity6-8 is required for the homeostatic regulation of sleep9. Here we show that Hyperkinetic, the β-subunit of the KV1 channel Shaker in Drosophila7, forms a dynamic lipid peroxidation memory. Information is stored in the oxidation state of Hyperkinetic's nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, which changes when lipid-derived carbonyls10-13, such as 4-oxo-2-nonenal or an endogenous analogue generated by illuminating a membrane-bound photosensitizer9,14, abstract an electron pair. NADP+ remains locked in the active site of KVβ until membrane depolarization permits its release and replacement with NADPH. Sleep-inducing neurons15-17 use this voltage-gated oxidoreductase cycle to encode their recent lipid peroxidation history in the collective binary states of their KVβ subunits; this biochemical memory influences-and is erased by-spike discharges driving sleep. The presence of a lipid peroxidation sensor at the core of homeostatic sleep control16,17 suggests that sleep protects neuronal membranes against oxidative damage. Indeed, brain phospholipids are depleted of vulnerable polyunsaturated fatty acyl chains after enforced waking, and slowing the removal of their carbonylic breakdown products increases the demand for sleep.
Transient photocurrents in a subthreshold evidence accumulator accelerate perceptual decisions.
Perceptual decisions are complete when a continuously updated score of sensory evidence reaches a threshold. In Drosophila, αβ core Kenyon cells (αβc KCs) of the mushroom bodies integrate odor-evoked synaptic inputs to spike threshold at rates that parallel the speed of olfactory choices. Here we perform a causal test of the idea that the biophysical process of synaptic integration underlies the psychophysical process of bounded evidence accumulation in this system. Injections of single brief, EPSP-like depolarizations into the dendrites of αβc KCs during odor discrimination, using closed-loop control of a targeted opsin, accelerate decision times at a marginal cost of accuracy. Model comparisons favor a mechanism of temporal integration over extrema detection and suggest that the optogenetically evoked quanta are added to a growing total of sensory evidence, effectively lowering the decision bound. The subthreshold voltage dynamics of αβc KCs thus form an accumulator memory for sequential samples of information.
Isolation of the parent triplet titanocene via NHC stabilisation
We present the synthesis and characterization of the parent isolable monomeric triplet titanocene complex, stabilized by the N-heterocyclic carbene (NHC) IMe4. Investigated by SQUID magnetometry and quantum-chemical calculations, reactivity studies of the titanium precursor [Cp2Ti(btmsa)] (2) with the NHC IiPr2Me2 and the zirconocene complex [Cp2Zr(py)(btmsa)] (1) revealed divergent reactivity patterns, highlighting the role of steric and electronic effects in stabilization.
Serum neurofilament light chain and structural and Functional nerve fiber loss in painful and painless diabetic polyneuropathy.
AIMS: To explore associations between the axonal protein Neurofilament Light (NfL) and severity of Diabetic Polyneuropathy (DPN) and pain. METHODS: We performed cross-sectional analysis of a subset of the PiNS/DOLORisk cohort of people with DPN with and without neuropathic pain. Biobank samples were analyzed for serum NfL (s-NfL) using single molecule array. DPN was defined by Toronto criteria for probable or confirmed DPN. Painful DPN (PDPN) was evaluated according to IASP criteria. Measures of DPN severity included clinical DPN scales, Quantitative Sensory Testing (QST) and Intraepidermal Nerve Fiber Density (IENFD). RESULTS: Participants with confirmed (N = 172) or probable DPN (N = 29) were included. There was no s-NfL difference between participants with DPN (N = 79, 22.8 ng/L [IQR 17.4; 31.3]) and PDPN (N = 122, 22.2 ng/L [16.0; 34.4]). S-NfL was not associated with pain severity or DPN severity evaluated by clinical DPN scales. Higher s-NfL was associated with lower IENFD (13.6 % [95 % CI 3.1; 22.9], unit = 1 fiber/mm, N = 24) and more pronounced loss of nerve fiber function measured by QST (p-trend = 0.02). CONCLUSIONS: Higher s-NfL was associated with nerve fiber dysfunction and loss quantified by QST and IENFD, but not with pain or clinical DPN scales. S-NfL may reflect the severity of nerve fiber damage underlying DPN.
Searching Skills Toolkit: Finding the Evidence, Second Edition
Searching Skills Toolkit is an expert guide to help you find the clinical evidence you need more easily and effectively. Clearly presented with useful tips and advice, flow charts, diagrams and real-life clinical scenarios, it shows the best methods for finding quality evidence. From deciding where to start, to building a search strategy, refining results and critical appraisal, it is a step-by-step guide to the process of finding healthcare evidence, and is designed for use by all health and social care professionals. This second edition has been expanded with new chapters on searching for sources to support evidence-based management decision making and how to better enable your patients to make informed choices. It has also been fully updated to include new web sources, open source reference management software, and new training resources and exercises. Searching Skills Toolkit is an ideal reference for doctors, nurses, allied health professionals, managers and decision makers, researchers and students.
Patient and Public Involvement Toolkit
Providing information to implement a new core healthcare requirement – patient involvement Including real case scenarios to illustrate the principles of effective PPI Following the unique Toolkit series format of flowcharts and layouts that guide the reader through each section.