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What do you get when you cross an artist with a scientist? It's not a trick question, but the basis of a project called Silent Signal, which brought together six animation artists and six leading biomedical scientists, to create experimental animated artworks exploring new ways of thinking about the human body.
Hierarchical temporal prediction captures motion processing from retina to higher visual cortex
Visual neurons respond selectively to specific features that become increasingly complex in their form and dynamics from the eyes to the cortex. Retinal neurons prefer localized flashing spots of light, primary visual cortical (V1) neurons moving bars, and those in higher cortical areas, such as middle temporal (MT) cortex, favor complex features like moving textures. Whether there are general computational principles behind this diversity of response properties remains unclear. To date, no single normative model has been able to account for the hierarchy of tuning to dynamic inputs along the visual pathway. Here we show that hierarchical application of temporal prediction - representing features that efficiently predict future sensory input from past sensory input - can explain how neuronal tuning properties, particularly those relating to motion, change from retina to higher visual cortex. This suggests that the brain may not have evolved to efficiently represent all incoming information, as implied by some leading theories. Instead, the selective representation of sensory inputs that help in predicting the future may be a general neural coding principle, which when applied hierarchically extracts temporally-structured features that depend on increasingly high-level statistics of the sensory input.
Simple spectral transformations capture the contribution of peripheral processing to cortical responses to natural sounds
Processing in the sensory periphery involves various mechanisms that enable the detection and discrimination of sensory information. Despite their biological complexity, could these processing steps sub-serve a relatively simple transformation of sensory inputs, which are then transmitted to the CNS? Here we explored both biologically-detailed and very simple models of the auditory periphery to find the appropriate input to a phenomenological model of auditory cortical responses to natural sounds. We examined a range of cochlear models, from those involving detailed biophysical characteristics of the cochlea and auditory nerve to very pared-down spectrogram-like approximations of the information processing in these structures. We tested the capacity of these models to predict the time-course of single-unit neural responses recorded in the ferret primary auditory cortex, when combined with a linear non-linear encoding model. We show that a simple model based on a log-spaced, log-scaled power spectrogram with Hill-function compression performs as well as biophysically-detailed models of the cochlea and the auditory nerve. These findings emphasize the value of using appropriate simple models of the periphery when building encoding models of sensory processing in the brain, and imply that the complex properties of the auditory periphery may together result in a simpler than expected functional transformation of the inputs.
Simple spectral transformations capture the contribution of peripheral processing to cortical responses to natural sounds
Processing in the sensory periphery involves various mechanisms that enable the detection and discrimination of sensory information. Despite their biological complexity, could these processing steps sub-serve a relatively simple transformation of sensory inputs, which are then transmitted to the CNS? Here we explored both biologically-detailed and very simple models of the auditory periphery to find the appropriate input to a phenomenological model of auditory cortical responses to natural sounds. We examined a range of cochlear models, from those involving detailed biophysical characteristics of the cochlea and auditory nerve to very pared-down spectrogram-like approximations of the information processing in these structures. We tested the capacity of these models to predict the time-course of single-unit neural responses recorded in the ferret primary auditory cortex, when combined with a linear non-linear encoding model. We show that a simple model based on a log-spaced, log-scaled power spectrogram with Hill-function compression performs as well as biophysically-detailed models of the cochlea and the auditory nerve. These findings emphasize the value of using appropriate simple models of the periphery when building encoding models of sensory processing in the brain, and imply that the complex properties of the auditory periphery may together result in a simpler than expected functional transformation of the inputs.
Pitch discrimination performance of ferrets and humans on a go/no-go task
ABSTRACTAnimal models are widely used to examine the neurophysiological basis of human pitch perception, and it is therefore important to understand the similarities and differences in pitch processing across species. Pitch discrimination performance is usually measured using two-alternative forced choice (2AFC) procedures in humans and go/no-go tasks in animals, potentially confounding human-to-animal comparisons. We have previously shown that pitch discrimination thresholds of ferrets on a 2AFC task are markedly poorer than those reported for go/no-go tasks in other non-human species (Walker et al., 2009). To better compare the pitch discrimination performance of ferret with other species, here we measure pitch change detection thresholds of ferrets and humans on a common, appetitive go/no-go task design. We found that ferrets’ pitch thresholds were ~10 times larger than that of humans on the go/no-go task, and were within the range of thresholds reported in other non-human species. Interestingly, ferrets’ thresholds were 100 times larger than human thresholds on a 2AFC pitch discrimination task using the same stimuli. These results emphasize that sensory discrimination thresholds can differ across tasks, particularly for non-human animals. Performance on our go/no-go task is likely to reflect different neurobiological processes than that on our 2AFC task, as the former required the subjects only to detect a pitch change while the latter required them to label the direction of the pitch change.ABBREVIATIONS2AFC2-Alternative Forced ChoiceF0Fundamental FrequencyHIGHLIGHTSPitch discrimination thresholds of ferrets were 10 times larger than those of humans on a go/no-go taskFerrets’ pitch thresholds are similar to those reported for a range of other mammalsPitch thresholds of ferrets, but not humans, were drastically better on the go/no-go task than a 2AFC task using the same stimuli
Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.
OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024.
Noise suppression of proton magnetic resonance spectroscopy improves paediatric brain tumour classification.
Proton magnetic resonance spectroscopy (1 H-MRS) is increasingly used for clinical brain tumour diagnosis, but suffers from limited spectral quality. This retrospective and comparative study aims at improving paediatric brain tumour classification by performing noise suppression on clinical 1 H-MRS. Eighty-three/forty-two children with either an ependymoma (ages 4.6 ± $$ \pm $$ 5.3/9.3 ± $$ \pm $$ 5.4), a medulloblastoma (ages 6.9 ± $$ \pm $$ 3.5/6.5 ± $$ \pm $$ 4.4), or a pilocytic astrocytoma (8.0 ± $$ \pm $$ 3.6/6.3 ± $$ \pm $$ 5.0), recruited from four centres across England, were scanned with 1.5T/3T short-echo-time point-resolved spectroscopy. The acquired raw 1 H-MRS was quantified by using Totally Automatic Robust Quantitation in NMR (TARQUIN), assessed by experienced spectroscopists, and processed with adaptive wavelet noise suppression (AWNS). Metabolite concentrations were extracted as features, selected based on multiclass receiver operating characteristics, and finally used for identifying brain tumour types with supervised machine learning. The minority class was oversampled through the synthetic minority oversampling technique for comparison purposes. Post-noise-suppression 1 H-MRS showed significantly elevated signal-to-noise ratios (P < .05, Wilcoxon signed-rank test), stable full width at half-maximum (P > .05, Wilcoxon signed-rank test), and significantly higher classification accuracy (P < .05, Wilcoxon signed-rank test). Specifically, the cross-validated overall and balanced classification accuracies can be improved from 81% to 88% overall and 76% to 86% balanced for the 1.5T cohort, whilst for the 3T cohort they can be improved from 62% to 76% overall and 46% to 56%, by applying Naïve Bayes on the oversampled 1 H-MRS. The study shows that fitting-based signal-to-noise ratios of clinical 1 H-MRS can be significantly improved by using AWNS with insignificantly altered line width, and the post-noise-suppression 1 H-MRS may have better diagnostic performance for paediatric brain tumours.
Oncogenic cell tagging and single-cell transcriptomics reveal cell type-specific and time-resolved responses to Vhl inactivation in the kidney.
Defining the initial events in oncogenesis and the cellular responses they entrain, even in advance of morphological abnormality, is a fundamental challenge in understanding cancer initiation. As a paradigm to address this, we longitudinally studied the changes induced by loss of the tumor suppressor gene von Hippel Lindau (VHL), which ultimately drives clear cell renal cell carcinoma. Vhl inactivation was directly coupled to expression of a tdTomato reporter within a single allele, allowing accurate visualization of affected cells in their native context and retrieval from the kidney for single-cell RNA-sequencing. This strategy uncovered cell-type specific responses to Vhl inactivation, defined a proximal tubular cell class with oncogenic potential, and revealed longer term adaptive changes in the renal epithelium and the interstitium. Oncogenic cell tagging also revealed markedly heterogeneous cellular effects including time-limited proliferation and elimination of specific cell types. Overall, this study reports an experimental strategy for understanding oncogenic processes in which cells bearing genetic alterations can be generated in their native context, marked, and analyzed over time. The observed effects of loss of Vhl in kidney cells provide insights into VHL tumor suppressor action and development of renal cell carcinoma.
Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches.
Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
Frequency and outcomes of gastrostomy insertion in a longitudinal cohort study of atypical parkinsonism.
BACKGROUND: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) show a high prevalence and rapid progression of dysphagia, which is associated with reduced survival. Despite this, the evidence base for gastrostomy is poor, and the optimal frequency and outcomes of this intervention are not known. We aimed to characterise the prevalence and outcomes of gastrostomy in patients with these three atypical parkinsonian disorders. METHOD: We analysed data from the natural history and longitudinal cohorts of the PROSPECT-M-UK study with up to 60 months of follow-up from baseline. Survival post-gastrostomy was analysed using Kaplan-Meier survival curves. RESULTS: In a total of 339 patients (mean age at symptom onset 63.3 years, mean symptom duration at baseline 4.6 years), dysphagia was present in >50% across all disease groups at baseline and showed rapid progression during follow-up. Gastrostomy was recorded as recommended in 44 (13%) and performed in 21 (6.2%; MSA 7, PSP 11, CBS 3) of the total study population. Median survival post-gastrostomy was 24 months compared with 12 months where gastrostomy was recommended but not done (p = 0.008). However, this was not significant when correcting for age and duration of symptoms at the time of procedure or recommendation. CONCLUSIONS: Gastrostomy was performed relatively infrequently in this cohort despite the high prevalence of dysphagia. Survival post-gastrostomy was longer than previously reported, but further data on other outcomes and clinician and patient perspectives would help to guide use of this intervention in MSA, PSP and CBS.
Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice.
Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here, we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21, or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.