Biology subjects

Woods, W.

Publications and source records attributed to Woods, W..

8 recordsLinked to original sources

bioRxiv2024

Cortical connectivity, local dynamics and stability correlates of global conscious states

Consciousness emerges from complex neural processes, yet its precise neurobiological correlates remain uncertain. Here a space-time-resolved inference-based framework is applied to estimate the neurophysiological variables of a wholecortex model and analyze the neural mechanism correlates of global consciousness by way of a correlation analysis between behavioural and neural variable time-series. Using magnetoencephalography (MEG) data from 15 participants under Xenon-induced anesthesia, interconnected neural mass models (NMMs) were developed and time-evolving regional neurophysiological variables and inter-regional connectivity strengths were inferred from the data. Analyses revealed significant correlations between consciousness levels and inter-regional connectivity, particularly in posterior parietal, occipital, and prefrontal regions. Moreover, results support a parietal, rather than frontal, network backbone to facilitate global consciousness. Regional-level analyses further identified correlates of consciousness within the posterior parietal and occipital regions. Lastly, reductions in consciousness were linked to stabilized cortical dynamics, reflected by changes in the eigenmodes of the system. This framework provides a novel, inference-based approach to investigating consciousness, offering a time-resolved perspective on neural mechanism correlates during altered states.

neuroscience↗

bioRxiv2024

SPLICER: A Highly Efficient Base Editing Toolbox That Enables In Vivo Therapeutic Exon Skipping

Exon skipping technologies enable exclusion of targeted exons from mature mRNA transcripts, which has broad applications in molecular biology, medicine, and biotechnology. Existing exon skipping techniques include antisense oligonucleotides, targetable nucleases, and base editors, which, while effective for specific applications at some target exons, remain hindered by shortcomings, including transient effects for oligonucleotides, genotoxicity for nucleases and inconsistent exon skipping for base editors. To overcome these limitations, we created SPLICER, a toolbox of next-generation base editors consisting of near-PAMless Cas9 nickase variants fused to adenosine or cytosine deaminases for the simultaneous editing of splice acceptor (SA) and splice donor (SD) sequences. Synchronized SA and SD editing with SPLICER improves exon skipping, reduces aberrant outcomes, including cryptic splicing and intron retention, and enables skipping of exons refractory to single splice-site editing. To demonstrate the therapeutic potential of SPLICER, we targeted APP exon 17, which encodes the amino acid residues that are cleaved to form the A{beta} plaques in Alzheimers disease. SPLICER reduced the formation of A{beta}42 peptides in vitro and enabled efficient exon skipping in a mouse model of Alzheimers disease. Overall, SPLICER is a widely applicable and efficient toolbox for exon skipping with broad therapeutic applications.

bioengineering↗

bioRxiv2022

Space-time resolved inference-based whole-brain neurophysiological mechanism imaging: application to resting-state alpha rhythm

Neural mechanisms are complex and difficult to image. This paper presents a new space-time resolved whole-brain imaging framework, called Neurophysiological Mechanism Imaging (NMI), that identifies neurophysiological mechanisms within cerebral cortex at the macroscopic scale. By fitting neural mass models to electromagnetic source imaging data using a novel nonlinear inference method, population averaged membrane potentials and synaptic connection strengths are efficiently and accurately imaged across the whole brain at a resolution afforded by source imaging. The efficiency of the framework enables return of the augmented source imaging results overnight using high performance computing. This suggests it can be used as a practical and novel imaging tool. To demonstrate the framework, it has been applied to resting-state magnetoencephalographic source estimates. The results suggest that endogenous inputs to cingulate, occipital, and inferior frontal cortex are essential modulators of resting-state alpha power. Moreover, endogenous input and inhibitory and excitatory neural populations play varied roles in mediating alpha power in different resting-state sub-networks. The framework can be applied to arbitrary neural mass models and has broad applicability to image neural mechanisms in different brain states. HighlightsO_LIThe whole-brain imaging framework can disclose the neurophysiological substrates of complicated brain functions in a spatiotemporal manner. C_LIO_LIDeveloped a semi-analytical Kalman filter to estimate neurophysiological variables in the nonlinear neural mass model efficiently and accurately from large-scale electromagnetic time-series. C_LIO_LIThe semi-analytical Kalman filter is 7.5 times faster and 5% more accurate in estimating model parameters than the unscented Kalman filter. C_LIO_LIProvided several group-level statistical observations based on neurophysiological variables and visualised them in a whole-brain manner to show different perspectives of neurophysiological mechanisms. C_LIO_LIApplied the framework to study resting-state alpha oscillation and found novel relationships between local neurophysiological variables in specific brain regions and alpha power. C_LI

neuroscience↗

bioRxiv2021

Brain Networks Detectable by fMRI during On-Line Self Report of Hallucinations in Schizophrenia

An analysis of an internationally shared functional magnetic resonance imaging (fMRI) data involving healthy participants and schizophrenia patients extracted brain networks involved in listening to radio speech and capture hallucination experiences. A multidimensional analysis technique demonstrated that for radio-speech sound files, a brain network matching known auditory perception networks emerged, and importantly, displayed speech-duration-dependent hemodynamic responses (HDRs), confirming fMRI detection of these speech events. In the hallucination-capture data, although a sensorimotor (response) network emerged, it did not show hallucination-duration-dependent HDRs. We conclude that although fMRI retrieved the brain network involved in generating the motor responses indicating the start and end of an experienced hallucination, the hallucination event itself was not detected. Previous reports on brain networks detected by fMRI during hallucination capture is reviewed in this context.

neuroscience↗

bioRxiv2020

Epigenetic engineering of yeast reveals dynamic molecular adaptation to methylation stress and genetic modulators of specific DNMT3 family members

Cytosine methylation is a ubiquitous modification in mammalian DNA generated and maintained by several DNA methyltransferases (DNMTs) with partially overlapping functions and genomic targets. To systematically dissect the factors specifying each DNMTs activity, we engineered combinatorial knock-in of human DNMT genes in Komagataella phaffii, a yeast species lacking endogenous DNA methylation. Time-course expression measurements captured dynamic network-level adaptation of cells to DNMT3B1-induced DNA methylation stress and showed that coordinately modulating the availability of S-adenosyl methionine (SAM), the essential metabolite for DNMT-catalyzed methylation, is an evolutionarily conserved epigenetic stress response, also implicated in several human diseases. Convolutional neural networks trained on genome-wide CpG-methylation data learned distinct sequence preferences of DNMT3 family members. A simulated annealing interpretation method resolved these preferences into individual flanking nucleotides and periodic poly(A) tracts that rotationally position highly methylated cytosines relative to phased nucleosomes. Furthermore, the nucleosome repeat length defined the spatial unit of methylation spreading. Gene methylation patterns were similar to those in mammals, and hypo- and hypermethylation were predictive of increased and decreased transcription relative to control, respectively, in the absence of mammalian readers of DNA methylation. Introducing controlled epigenetic perturbations in yeast thus enabled characterization of fundamental genomic features directing specific DNMT3 proteins.

genomics↗

bioRxiv2019

Cortical excitation-inhibition ratio mediates the effect of pre-attentive auditory processing deficits on interpersonal difficulties

Several lines of evidence identify aberrant excitatory-inhibitory neural processes across autism and schizophrenia spectrum disorders, particularly within the psychosocial domain. Such neural processes include increased excitatory glutamate and reduced inhibitory GABA concentrations, which may affect auditory pre-attentive processing as indexed by the mismatch negativity (MMN); thus, an excitation-inhibition imbalance might lead to aberrant MMN, which might in turn drive the relationship between the MMN and psychosocial difficulties. This research has the potential to enhance the neurochemical understanding of the relationship between electrophysiology (MMN) and behavioural/clinical measures (psychosocial difficulties).\n\nThirty-eight adults (18 male, 18-40 years) completed the Schizotypal Personality Questionnaire (SPQ) and Autism-Spectrum Quotient (AQ). Glutamate and GABA concentrations in bilateral superior temporal cortex (STC) were quantified using proton magnetic resonance spectroscopy (1H-MRS) while auditory MMN to a duration deviant was measured with magnetoencephalography. Spearman correlations probed the relationships between STC glutamate/GABA ratios, MMN amplitude and latency, and AQ and SPQ dimensions. Mediation effects of glutamate/GABA ratios on the relationship between MMN and AQ-SPQ dimensions were probed using causal mediation analysis.\n\nOnly SPQ-interpersonal and AQ-communication were significantly correlated with right hemisphere glutamate/GABA ratios and MMN latency (ps<.05), which were themselves correlated (p=.038). Two mediation models were investigated, with right MMN latency as predictor and SPQ-interpersonal and AQ-communication as outcome variables. Right STC glutamate/GABA ratios significantly mediated the relationship between MMN latency and SPQ-interpersonal scores ({beta}=86.6, p=.033), but only partially mediated the relationship between MMN latency and AQ-communication scores ({beta}=21.0, p=.093).\n\nThese findings support the growing body of literature pointing toward an excitation-inhibition imbalance that is central to psychosocial functioning across multi-dimensional spectrum disorders, such as autism and schizophrenia, and provides neurochemical indicators of the processes that underlie psychosocial dysfunction.

neuroscience↗

bioRxiv2019

In search of Universal Cortical Power Changes Linked to NMDA-Antagonist based Anesthetic Induced Reductions in Consciousness.

B. AbstractO_ST_ABSBackground.C_ST_ABSDespite their intriguing nature, investigations of the neurophysiology of N-methyl-D-aspartate (NMDA)-antagonists Xenon (Xe) and nitrous oxide (N2O) are limited and have revealed inconsistent frequency-dependent alterations, in spectral power and functional connectivity. Discrepancies are likely due to using low resolution electroencephalography restricted to sensor level changes, concomitant anesthetic agent administration and dosage. Our intention was to describe the effects of equivalent stepwise levels of Xe and N2O administration on oscillatory source power using a crossover design, to explore universal mechanisms of NMDA-based anesthesia.\n\nMethods.22 healthy males participated in a study of simultaneous magnetoencephalography and electroencephalography recordings. In separate sessions, equivalent subanesthetic doses of gaseous anesthetic agents N2O and Xe (0.25, 0.50, 0.75 equi MAC-awake) and 1.30 MAC-awake Xe (for Loss of Responsiveness) were administered. Source power in various frequency bands was computed and statistically assessed relative to a conscious baseline.\n\nResults.Delta (l-4Hz) and theta (4-8Hz) band power was significantly increased at the highest Xe concentration (42%, 1.30 MAC-awake) relative to baseline for both magnetoencephalography and electroencephalography source power (p<0.005). A reduction in frontal alpha (8-13 Hz) power was observed upon N2O administration, and shown to be stronger than equivalent Xe dosage reductions (p=0.005). Higher frequency activity increases were observed in magnetoencephalographic but not encephalographic signals for N2O alone with occipital low gamma (30-49Hz) and widespread high gamma (51-99Hz) rise in source power.\n\nConclusions.Magnetoencephalography source imaging revealed unequivocal and widespread power changes in dissociative anesthesia, which were divergent to source electroencephalography. Loss of Responsiveness anesthesia at 42% Xe (1.30 MAC-awake) demonstrated, similar to inductive agents, low frequency power increases in frontal delta and global theta. N2O sedation yielded a rise in high frequency power in the gamma range which was primarily occipital for lower gamma bandwidth (3049 Hz) and substantially decreased alpha power, particularly in frontal regions.\n\nClinical trial number and Registry URLNot applicable.\n\nPrior PresentationsPelentritou Andria, Kuhlmann Levin; Lee Heonsoo; Cormack John; Mcguigan Steven; Woods Will; Sleigh Jamie; Lee UnCheol; Muthukumaraswamy Suresh; Liley David. Searching For Universal Cortical Power Changes Linked To Anesthetic Induced Reductions In Consciousness. The Science of Consciousness April 4th 2018. Tucson, Arizona, USA.\n\nSummary StatementNot applicable.

neuroscience↗

bioRxiv2018

Prediction-error signals to violated expectations about person identity and head orientation are doubly-dissociated across the dorsal and ventral visual streams

Predictive coding theories of perception suggest the importance of constantly updated internal models of the world in predicting future sensory inputs. One implication of such models is that cortical regions whose function is to resolve particular stimulus attributes should also signal prediction violations with respect to those same stimulus attributes. Previously, through carefully designed experiments, we have demonstrated early-mid latency EEG/MEG prediction-error signals in the dorsal visual stream to violated expectations about stimulus orientation/trajectory, with localisations consistent with cortical areas processing motion and orientation. Here we extend those methods to simultaneously investigate the predictive processes in both dorsal and ventral visual streams. In this MEG study we employed a contextual trajectory paradigm that builds expectations using a series of image presentations. We created expectations about both face orientation and identity, either of which can subsequently be violated. Crucially this paradigm allows us to parametrically test double dissociations between these different types of violations. The study identified double dissociations across the type of violation in the dorsal and ventral visual streams, such that the right fusiform gyrus showed greater evidence of prediction-error signals to Identity violations than to Orientation violations, whereas the left angular gyrus and postcentral gyrus showed the opposite pattern of results. Our results suggest comparable processes for error checking and context updating in high-level expectations instantiated across both perceptual streams. Perceptual prediction-error signalling is initiated in regions associated with the processing of different stimulus properties.\n\nSignificance StatementVisual processing occurs along what and where information streams that run, respectively along the ventral and dorsal surface of the posterior brain. Predictive coding models of perception imply prediction-error detection processes that are instantiated at the level where particular stimulus attributes are parsed. This implies that, for instance, when considering face stimuli, signals arising through violated expectations about the person identity of the stimulus should localise to the ventral stream, whereas signals arising through violated expectations about head orientation should localise to the dorsal stream. We test this in a magnetoencephalography source localisation study. The analysis confirmed that prediction-error signals to identity versus head-orientation occur with similar latency, but activate doubly-dissociated brain regions along ventral and dorsal processing streams.

neuroscience↗