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Deletion of AMPA receptor GluA1 subunit gene (Gria1) causes circadian rhythm disruption and aberrant responses to environmental cues
AbstractDysfunction of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and circadian rhythm disruption. To investigate the role of GluA1 in circadian and sleep behaviour, we used wheel-running, passive-infrared, and video-based home-cage activity monitoring to assess daily rest–activity profiles of GluA1-knockout mice (Gria1−/−). We showed that these mice displayed various circadian abnormalities, including misaligned, fragmented, and more variable rest–activity patterns. In addition, they showed heightened, but transient, behavioural arousal to light→dark and dark→light transitions, as well as attenuated nocturnal-light-induced activity suppression (negative masking). In the hypothalamic suprachiasmatic nuclei (SCN), nocturnal-light-induced cFos signals (a molecular marker of neuronal activity in the preceding ~1–2 h) were attenuated, indicating reduced light sensitivity in the SCN. However, there was no change in the neuroanatomical distribution of expression levels of two neuropeptides―vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP)―differentially expressed in the core (ventromedial) vs. shell (dorsolateral) SCN subregions and both are known to be important for neuronal synchronisation within the SCN and circadian rhythmicity. In the motor cortex (area M1/M2), there was increased inter-individual variability in cFos levels during the evening period, mirroring the increased inter-individual variability in locomotor activity under nocturnal light. Finally, in the spontaneous odour recognition task GluA1 knockouts’ short-term memory was impaired due to enhanced attention to the recently encountered familiar odour. These abnormalities due to altered AMPA-receptor-mediated signalling resemble and may contribute to sleep and circadian rhythm disruption and attentional deficits in different modalities in schizophrenia.
Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.
PURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations. METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies. RESULTS: We characterize a clinically variable disorder with cardinal features including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition. CONCLUSION: Our studies comprehensively characterise INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.
Neural signatures of risk-taking adaptions across health, bipolar disorder, and lithium treatment
Abstract Cognitive and neural mechanisms underlying bipolar disorder (BD) and its treatment are still poorly understood. Here we examined the role of adaptations in risk-taking using a reward-guided decision-making task. We recruited volunteers with high (n = 40) scores on the Mood Disorder Questionnaire, MDQ, suspected of high risk for bipolar disorder and those with low-risk scores (n = 37). We also recruited patients diagnosed with BD who were assigned (randomized, double-blind) to six weeks of lithium (n = 19) or placebo (n = 16) after a two-week baseline period (n = 22 for FMRI). Participants completed mood ratings daily over 50 (MDQ study) or 42 (BD study) days, as well as a risky decision-making task and functional magnetic resonance imaging. The task measured adaptation of risk taking to past outcomes (increased risk aversion after a previous win vs. loss, ‘outcome history’). While the low MDQ group was risk averse after a win, this was less evident in the high MDQ group and least so in the patients with BD. During fMRI, ‘outcome history’ was linked to medial frontal pole activation at the time of the decision and this activation was reduced in the high risk MDQ vs. the low risk MDQ group. While lithium did not reverse the pattern of BD in the task, nor changed clinical symptoms of mania or depression, it changed reward processing in the dorsolateral prefrontal cortex. Participants’ modulation of risk-taking in response to reward outcomes was reduced as a function of risk for BD and diagnosed BD. These results provide a model for how reward may prime escalation of risk-related behaviours in bipolar disorder and how mood stabilising treatments may work.
Synaptic Targets and Cellular Sources of CB1 Cannabinoid Receptor and Vesicular Glutamate Transporter-3 Expressing Nerve Terminals in Relation to GABAergic Neurons in the Human Cerebral Cortex.
Cannabinoid receptor 1 (CB1) regulates synaptic transmission through presynaptic receptors in nerve terminals, and its physiological roles are of clinical relevance. The cellular sources and synaptic targets of CB1-expressing terminals in the human cerebral cortex are undefined. We demonstrate a variable laminar pattern of CB1-immunoreactive axons and electron microscopically show that CB1-positive GABAergic terminals make type-2 synapses innervating dendritic shafts (69%), dendritic spines (20%) and somata (11%) in neocortical layers 2-3. Of the CB1-immunopositive GABAergic terminals, 25% were vesicular-glutamate-transporter-3 (VGLUT3)-immunoreactive, suggesting GABAergic/glutamatergic co-transmission on dendritic shafts. In vitro recorded and labelled VGLUT3 or CB1-positive GABAergic interneurons expressed cholecystokinin, vasoactive-intestinal-polypeptide and calretinin, had diverse firing, axons and dendrites, and included rosehip, neurogliaform and basket cells, but not double bouquet or axo-axonic cells. CB1-positive interneurons innervated pyramidal cells and GABAergic interneurons. Glutamatergic synaptic terminals formed type-1 synapses and some were positive for CB1 receptor with a distribution that appeared different from that in GABAergic terminals. From the sampled VGLUT3-positive terminals, 60% formed type-1 synapses with dendritic spines (80%) or shafts (20%) and 52% were also positive for VGLUT1, suggesting intracortical origin. Some VGLUT3-positive terminals were immunopositive for vesicular-monoamine-transporter-2, suggesting 5-HT/glutamate co-transmission. Overall, the results show that CB1 regulates GABA release mainly to dendritic shafts of both pyramidal cells and interneurons and predict CB1-regulated co-release of GABA and glutamate from single cortical interneurons. We also demonstrate the co-existence of multiple vesicular glutamate transporters in a select population of terminals probably originating from cortical neurons and innervating dendritic spines in the human cerebral cortex.
An analysis of heavy silicone oil treatment for inferior proliferative vitreoretinopathy
Abstract Purpose Proliferative vitreoretinopathy (PVR) is a complication of retinal detachment which requires multiple vitreoretinal surgical interventions and frequent use of oil endotamponade. In this study, we conducted an in-depth analysis of complications associated with the use of heavy silicone oil in the management of inferior PVR. Methods A retrospective cohort study of 20 eyes that underwent vitrectomy for inferior PVR with use of heavy silicone oil (Densiron 68) between March 2021 and October 2022 at Oxford Eye Hospital. Complications were classified into major categories relating to intraocular pressure, inflammation, lens, and oil emulsification/migration. Visual outcomes and surgical success rate were also evaluated. Results Fill-induced pressure spikes (> 30 mmHg) within 14 days post-surgery were common after Densiron tamponade, especially in patients previously on glaucoma drops. The number of glaucoma drugs were increased in 45% of patients during Densiron tamponade. In 20% of cases, an increased medication was continued long-term after Densiron removal. Significant cataract progression occurred in all phakic patients. In 25% of pseudophakic cases, posterior capsule opacification was noted. Inflammatory complications, such as anterior uveitis, were rare and any cystoid macular oedema was transient. No unexplained acute loss of vision following Densiron removal was encountered. The anatomical success rate at 30 days after Densiron removal was 70%. The mean (± SD) best-corrected visual acuities were 1.04 (± 0.79), 0.85 (± 0.62) and 0.50 (± 0.51) logMAR prior, during and after Densiron tamponade, respectively. Conclusion The outcomes in this cohort treated with Densiron 68 were comparable to previously reported anatomical and functional results in cases with inferior PVR. IOP and lens-related complications require additional treatment during or after Densiron tamponade. Inflammatory complications rarely occurred over tamponade durations of around three months. Trial registration Analyses were conducted as an internal quality improvement audit and as such did not require external IRB review.
Hip Fracture Intervention Study for Prevention of Hypotension Trial: a Pilot Randomized Controlled Trial
BACKGROUND: Hypotension during anesthesia for surgery for hip fracture is common and associated with myocardial injury, stroke, acute kidney injury, and delirium. We hypothesized that maintaining intraoperative blood pressure close to patients’ preoperative values would reduce these complications compared to usual care. METHODS: A pilot feasibility patient- and assessor-blinded parallel group randomized controlled trial. People with unilateral hip fracture aged ≥70 years with capacity to give consent before surgery were eligible. Participants were allocated at random before surgery to either tight blood pressure control (systolic blood pressure ≥80% preoperative baseline and mean arterial blood pressure ≥75 mm Hg) or usual care. Feasibility outcomes were protocol adherence, primary outcome data completeness, and recruitment rate. The composite primary outcome was myocardial injury, stroke, acute kidney injury or delirium within 7 days of surgery. RESULTS: Seventy-six participants were enrolled, and 12 withdrew before randomization. Sixty-four participants were randomized, 30 were allocated to control, and 34 to intervention. There was no crossover, all 64 participants received their allocated treatment, primary outcome was known for all participants. The composite primary outcome occurred in 14 of 30 participants in the control group compared with 23 of 34 participants in the intervention group (P = .09), relative risk 1.45 (95% confidence interval [CI], 0.93–2.27). CONCLUSIONS: A randomized controlled trial of tight intraoperative blood pressure control compared to usual care to reduce major postoperative complications after fractured neck of femur surgery is possible. However, the data would suggest a large sample size would be required for a definitive trial.
Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms
Abstract Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment. Adaptive immune cell-enriched is intrinsically linked with highly distinct B and T cell clonal selection, diversification, and differentiation. Using TCR data, we see the largest clonal expansions in CD8 effector memory, senescent cells, and highly activated regulatory T cells which are induced within the tumour from naïve cells. We identify pathways that potentially lead to a suppressive microenvironment, including investigational targets TIGIT/PVR and SIRPA/CD47. Analysis of patients from the APACT clinical trial shows that myeloid enrichment had a shorter overall survival compared to those with adaptive cell enrichment. Strategies for rationale therapeutic development in this disease include boosting of B cell responses, targeting immunosuppressive macrophages, and specific Treg cell depletion approaches.
Clinical value of cell-based assays in the characterisation of seronegative myasthenia gravis
ObjectivePatients with myasthenia gravis without acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) antibodies detected by radioimmunoprecipitation assays (RIAs) are classified as seronegative myasthenia gravis (SNMG). Live cell-based assays (l-CBAs) can detect additional antibodies to clustered AChR, MuSK and low-density lipoprotein receptor-related protein 4 (LRP4), but positivity rates are variable and both clinical relevance and utility of CBA platforms remain unclear.MethodsSera from 82 patients with SNMG were tested by l-CBAs. Human embryonic kidney cells were transfected to individually express clustered AChR, MuSK or LRP4; or transfected to jointly express both clustered adult AChR and MuSK. Sera from 30 and 20 patients positive by RIA for AChR or MuSK antibodies were used as comparators.Results53 of 82 (72%) patients with SNMG had generalised and 29 (28%) had ocular disease. The clustered AChR CBA detected antibodies in 16 of 82 patients (19.5%; including 4 patients with solely fetal AChR antibodies), while 7 of 82 (8.5%) patients had MuSK antibodies. A novel exploratory combined adult AChR-MuSK l-CBA efficiently detected all these antibodies in a subset of the SNMG cohort. No LRP4 antibodies were identified. Overall, patients with SNMG with clustered AChR antibodies, CBA-positive MuSK-MG or triple seronegative were younger, had less severe disease than patients with RIA-positive MG and had a better clinical outcome when immunotherapy was started soon after disease onset, although the time interval from onset to immunotherapy was not different when compared with patients with RIA-positive MG.ConclusionAround one-third of patients with SNMG had AChR or MuSK antibodies by l-CBAs, which were efficiently detected with a combined l-CBA. The results in this large and unselected cohort of patients with MG demonstrate the diagnostic usefulness of performing CBAs and the importance of making these tests more widely available.
Intra-Areal Visual Topography in Primate Brains Mapped with Probabilistic Tractography of Diffusion-Weighted Imaging
Abstract Noninvasive diffusion-weighted magnetic resonance imaging (dMRI) can be used to map the neural connectivity between distinct areas in the intact brain, but the standard resolution achieved fundamentally limits the sensitivity of such maps. We investigated the sensitivity and specificity of high-resolution postmortem dMRI and probabilistic tractography in rhesus macaque brains to produce retinotopic maps of the lateral geniculate nucleus (LGN) and extrastriate cortical visual area V5/MT based on their topographic connections with the previously established functional retinotopic map of primary visual cortex (V1). We also replicated the differential connectivity of magnocellular and parvocellular LGN compartments with V1 across visual field positions. Predicted topographic maps based on dMRI data largely matched the established retinotopy of both LGN and V5/MT. Furthermore, tractography based on in vivo dMRI data from the same macaque brains acquired at standard field strength (3T) yielded comparable topographic maps in many cases. We conclude that tractography based on dMRI is sensitive enough to reveal the intrinsic organization of ordered connections between topographically organized neural structures and their resultant functional organization.
Dynamic response of the vertical vergence system
Purpose. Earlier reports suggested that the vertical vergence system has a narrow disparity range and a gain which fails to compensate for disparity even at low frequencies. This contrasts with the small fixation disparities reported in the clinical literature for disparate stimuli of up to several degrees. The displays used in earlier reports either suffered from correspondence ambiguity, were not described adequately, or did not provide a strong stimulus for vertical fusional movements. We investigated the frequency response of vertical vergence for several amplitudes using a well-defined textured stimulus which filled a large binocular field. Methods. The magnetic scleral search coil technique (Robinson, 1963) was used to record the movements of both eyes in two subjects. Dichoptic stimuli were projected on the screens mounted on opposite sides of the coil frame and were viewed through mirrors in a Wheatstone stereoscope configuration. The stimulus was a textured display which subtended 65° visual angle and consisted of various geometric shapes which provided a strong unambiguous fusional stimulus. The two images were oscillated in counterphase at frequencies of 0.05, 0.1, 1.0, 2.0 and 4.0 Hz for amplitudes of 0.25, 0.5, 1.0, 2.0 and 4.0° of peak disparity. Results. Vergence gain was nearly unity and phase lag was small for low frequency disparity modulation. At high frequencies phase lag increased and gain fell indicating a low pass response. The response was nonlinear showing decreased gain at high frequencies. At the highest frequencies and amplitudes, diplopia occurred as the response deteriorated. Conclusions. When using a stimulus designed to optimize a vertical vergence response, a compensatory low frequency vertical vergence response was obtained. This work demonstrates a low pass response of the vertical vergence system with a nonlinear dependence on stimulus amplitude.
Structural and Functional Characteristics of Color Vision Changes in Choroideremia
Color vision is considered a marker of cone function and its assessment in patients with retinal pathology is complementary to the assessments of spatial vision [best-corrected visual acuity (BCVA)] and contrast detection (perimetry). Rod-cone and chorioretinal dystrophies—such as choroideremia—typically cause alterations to color vision, making its assessment a potential outcome measure in clinical trials. However, clinical evaluation of color vision may be compromised by pathological changes to spatial vision and the visual field. The low vision Cambridge Color Test (lvCCT) was developed specifically to address these latter issues. We used the trivector version of the lvCCT to quantify color discrimination in a cohort of 53 patients with choroideremia. This test enables rapid and precise characterization of color discrimination along protan, deutan, and tritan axes more reliably than the historically preferred test for clinical trials, namely the Farnsworth Munsell 100 Hue test. The lvCCT demonstrates that color vision defects—particularly along the tritan axis—are seen early in choroideremia, and that this occurs independent of changes in visual acuity, pattern electroretinography and ellipsoid zone area on optical coherence tomography (OCT). We argue that the selective loss of tritan color discrimination can be explained by our current understanding of the machinery of color vision and the pathophysiology of choroideremia.
Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds.
IMPORTANCE: Cerebral small vessel disease (SVD) is associated with various cerebrovascular outcomes, but data on sex differences in SVD are scarce. OBJECTIVE: To investigate whether the frequency, severity, and distribution of cerebral microbleeds (CMB), other SVD markers on magnetic resonance imaging (MRI), and outcomes differ by sex. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used pooled individual patient data from the Microbleeds International Collaborative Network, including patients from 38 prospective cohort studies in 18 countries between 2000 and 2018, with clinical follow-up of at least 3 months (up to 5 years). Participants included patients with acute ischemic stroke or transient ischemic attack with available brain MRI. Data were analyzed from April to December 2023. MAIN OUTCOMES AND MEASURES: Outcomes of interest were presence of CMB, lacunes, and severe white matter hyperintensities determined on MRI. Additionally, mortality, recurrent ischemic stroke, and intracranial hemorrhage during follow-up were assessed. Multivariable random-effects logistic regression models, Cox regression, and competing risk regression models were used to investigate sex differences in individual SVD markers, risk of recurrent cerebrovascular events, and death. RESULTS: A total of 20 314 patients (mean [SD] age, 70.1 [12.7] years; 11 721 [57.7%] male) were included, of whom 5649 (27.8%) had CMB. CMB were more frequent in male patients, and this was consistent throughout different age groups, locations, and in multivariable models (female vs male adjusted odds ratio [aOR], 0.86; 95% CI, 0.80-0.92; P
Epidemiology of neuropathic pain: an analysis of prevalence and associated factors in UK Biobank
Abstract Introduction: Previous epidemiological studies of neuropathic pain have reported a range of prevalences and factors associated with the disorder. Objectives: This study aimed to verify these characteristics in a large UK cohort. Methods: A cross-sectional analysis was conducted of 148,828 UK Biobank participants who completed a detailed questionnaire on chronic pain. The Douleur Neuropathique en Quatre Questions (DN4) was used to distinguish between neuropathic pain (NeuP) and non-neuropathic pain (non-NeuP) in participants with pain of at least 3 months' duration. Participants were also identified with less than 3 months' pain or without pain (NoCP). Multivariable regression was used to identify factors associated with NeuP compared with non-NeuP and NoCP, respectively. Results: Chronic pain was present in 76,095 participants (51.1%). The overall prevalence of NeuP was 9.2%. Neuropathic pain was significantly associated with worse health-related quality of life, having a manual or personal service type occupation, and younger age compared with NoCP. As expected, NeuP was associated with diabetes and neuropathy, but also other pains (pelvic, postsurgical, and migraine) and musculoskeletal disorders (rheumatoid arthritis, osteoarthritis, and fibromyalgia). In addition, NeuP was associated with pain in the limbs and greater pain intensity and higher body mass index compared with non-NeuP. Female sex was associated with NeuP when compared with NoCP, whereas male sex was associated with NeuP when compared with non-NeuP. Conclusion: This is the largest epidemiological study of neuropathic pain to date. The results confirm that the disorder is common in a population of middle- to older-aged people with mixed aetiologies and is associated with a higher health impact than non-neuropathic pain.
The Kidney-Immune-Brain Axis: The Role of Inflammation in the Pathogenesis and Treatment of Stroke in Chronic Kidney Disease.
Cardiovascular diseases such as stroke are a major cause of morbidity and mortality for patients with chronic kidney disease (CKD). The underlying mechanisms connecting CKD and cardiovascular disease are yet to be fully elucidated, but inflammation is proposed to play an important role based on genetic association studies, studies of inflammatory biomarkers, and clinical trials of anti-inflammatory drug targets. There are multiple sources of both endogenous and exogenous inflammation in CKD, including increased production and decreased clearance of proinflammatory cytokines, oxidative stress, metabolic acidosis, chronic and recurrent infections, dialysis access, changes in adipose tissue metabolism, and disruptions in intestinal microbiota. This review focuses on the mechanisms of inflammation in CKD, dialysis and associated therapies, its proposed impact on stroke pathogenesis and prognosis, and the potential role of anti-inflammatory agents in the prevention and treatment of stroke in patients with CKD.
A Once-Calibration Brain-Computer Interface to Enhance Convenience for Continuous BCI Interventions in Stroke Patients
Brain-computer interfaces (BCIs) provide a means of translating neural activity into movement for stroke rehabilitation. Electroencephalography (EEG)-based motor imagery (MI) is a cognitive strategy to enhance motor recovery after stroke. However, traditional MI-BCI systems require extensive calibration before conducting online experiments, thus constraining their practicality. To enhance convenience, we propose a once-calibration strategy (ONCS) that allows each subject to perform only one calibration in continuous BCI interventions over one month. By using supervised and transfer learning to update the model with previous online data, repeated calibrations are eliminated. Furthermore, personalized channel selection (PCS) is designed to reduce the number of channels through the lowest event-related desynchronization (ERD). Compared to the traditional repeated calibration strategy (RECS), RECS for intra- and inter-subject models, the proposed ONCS for inter-subject (ONCS-inter) models achieves better classification performance using 28 channels. Wherein, the ONCS-inter shows statistically significant improvements (p<0.05, one-tailed test). When using PCS for channel selection, ONCS-inter outperforms ONCS for intra-subject (ONCS-intra) (p<0.01, for 16, 18,..., 28 channels, two-tailed test) and surpasses RECS (p<0.05 for all channels, two-tailed test). Remarkably, ONCS-inter exceeds the best results achieved with traditional RECS, even with only 2 channels. Extensive comparison and ablation studies demonstrate the effectiveness of our proposed ONCS combined with inter-subject models and a few channels in maintaining classification accuracy. The proposed ONCS with PCS holds promise for enhancing the convenience of continuous BCI interventions within one month for stroke patients.