Biology subjects

O'Sullivan, S.

Publications and source records attributed to O'Sullivan, S..

3 recordsLinked to original sources

bioRxiv2025

Very low amplitude muscle activity increases probability of motor evoked potentials in healthy individuals and in ALS

IntroductionIn many clinical and research settings, transcranial magnetic stimulation (TMS) intensities are standardised based on resting motor threshold (RMT). It is well-established that contraction of the target muscle increases motor evoked potential (MEP) amplitude and correspondingly decreases RMT. As such, when estimating RMT it is crucial to ensure the target muscle is relaxed. Typically trials in which baseline electromyographic (EMG) amplitude exceeds a specified threshold are rejected. The influence of motor activity below typical rejection thresholds on MEP amplitudes has yet to be established. MethodsWe retrospectively analysed TMS-EMG data collected during RMT measurement in 45 healthy controls (1761 datapoints) and 35 people with amyotrophic lateral sclerosis (ALS, 1238 datapoints). Trials where root mean squared (RMS) baseline EMG amplitude exceeded 10{micro}V were rejected. Generalised linear mixed-effects models were used to assess effects of muscle activity below this rejection threshold on probability of evoking an MEP with peak-to-peak amplitude [≥]50{micro}V. ResultsGreater sub-rejection-threshold activity significantly increases MEP probability in controls (p<0.0004) and people with ALS (p=0.0010). Models predicted a 31-38% increase in MEP probability when baseline RMS-EMG amplitude increased from 1{micro}V to 9{micro}V. Sub-rejection- threshold baseline activity was significantly greater in ALS than controls (p=0.0055). DiscussionWe have shown for the first time that higher EMG amplitudes below a typical rejection threshold markedly increase probability of evoking an MEP with peak-to-peak amplitude [≥]50{micro}V. Researchers should take measures to account for effects of sub-rejection-threshold activity on RMT, particularly in populations where baseline activity may be elevated, such as in ALS.

neuroscience↗

bioRxiv2024

Bounding phenotype transition probabilities via conditional complexity

By linking genetic sequences to phenotypic traits, genotype-phenotype maps represent a key layer in biological organisation. Their structure modulates the effects of genetic mutations which can contribute to shaping evolutionary outcomes. Recent work based on algorithmic information theory introduced an upper bound on the likelihood of a random genetic mutation causing a transition between two phenotypes, using only the conditional complexity between them. Here we evaluate how well this bound works for a range of genotype-phenotype maps, including a differential equation model for circadian rhythm, a matrix-multiplication model of gene regulatory networks, a developmental model of tooth morphologies for ringed seals, a polyomino-tile shape model of biological self-assembly, and the HP lattice protein model. By assessing three levels of predictive performance, we find that the bound provides meaningful estimates of phenotype transition probabilities across these complex systems. These results suggest that transition probabilities can be predicted to some degree directly from the phenotypes themselves, without needing detailed knowledge of the underlying genotype-phenotype map.

biophysics↗

bioRxiv2018

DISC1 regulates N-Methyl-D-Aspartate receptor dynamics: Abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness

The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-Methyl-D-Aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.

neuroscience↗