Biology subjects

Gregory, E.

Publications and source records attributed to Gregory, E..

6 recordsLinked to original sources

bioRxiv2026

Declining autophagy drives age-related axonal decay through microtubule alterations

The microtubule cytoskeleton plays a pivotal role in maintaining axonal integrity, and its deterioration has been closely associated with neuronal decay during ageing. Autophagy, a crucial cellular degradation process, is essential for sustaining neuronal homeostasis and its dysregulation has been implicated in various neurodegenerative diseases. Changes in autophagy are also associated with ageing. However, the mechanisms by which autophagy dysfunction contributes to neuronal atrophy in the ageing brain remain poorly understood. In this study, we unveil the significant involvement of autophagy in preserving axonal architectural integrity during ageing through regulation of the microtubule cytoskeleton. Our findings indicate that autophagic activity declines in neurons of the aged brain, and the inhibition of autophagy exacerbates age-related alterations in axonal and synaptic microtubules. This dysfunction correlates with an increase in established hallmarks of ageing, including swellings and thinning of axons plus synaptic terminal breakdown. Conversely, pharmacological and genetic strategies to enhance autophagic activity not only rescued age-related microtubule changes, but also inhibited the formation of axonal swellings, the thinning of axons and the deterioration of synaptic terminals. Mechanistically, we find that reactive oxygen species (ROS), a consequence of impaired autophagy, lead to alterations in microtubule networks. In addition, enhancing Eb1 expression can counteract the detrimental effects of deficient autophagy, effectively blocking axonal and synaptic microtubule deterioration. These findings underscore that alterations in autophagy are a critical driver of axonal deterioration during ageing, operating through modifications to the microtubule cytoskeleton as a downstream target. Our findings deliver a cascade of events that underlie neuronal ageing.

cell biology↗

bioRxiv2026

Objective Quality Assessment for Precision Functional MRI Data

Precision functional mapping (PFM) enables individual-level characterization of brain network organization but requires substantially more and higher-quality fMRI data than is standard. Despite its growing use, objective criteria for data sufficiency and quality needed to ensure interpretable and replicable individual-level results remain unclear. Here, we introduce the Network Similarity Index (NSI), an objective measure of the extent to which functional connectivity (FC) patterns in an individual dataset express the large-scale network structure required for PFM. NSI captures the integrity of low-spatial-frequency, coherent network organization and denoising fidelity, and aligns closely with blinded expert assessments of PFM usability. NSI also accounts for variability in the rate at which FC becomes reliable across individuals. Here, we provide an open-source framework for NSI-based data quality evaluation and models for linking NSI values with expert-judged PFM suitability. This framework can also inform expected returns from additional data collection, enabling principled decisions about data sufficiency and replication in precision fMRI research.

neuroscience↗

bioRxiv2025

Proximity to an SGC-DLPFC Individualized Functional Target and outcomes in large rTMS clinical trials for Treatment-Resistant Depression

BackgroundTargeting methods for repetitive transcranial magnetic stimulation (rTMS) in patients with depression now include the use of individual functional scans to target specific functional connectivity (FC) patterns obtained from functional magnetic resonance imaging (fMRI). Potential biomarkers of rTMS response include target FC with the subgenual anterior cingulate cortex (SGC) or the causal depression circuit (CDC), each of which may be candidates for individualized functional targets (iFTs). We assessed the relationship of these two approaches to clinical outcomes in two large rTMS clinical trials. Methods501 subjects with moderate to severe depression underwent 4-6 weeks of daily rTMS to the left dorsolateral prefrontal cortex (DLPFC), targeted using neuronavigation to a common group-based functional target. Resting-state scans acquired at baseline were used to retrospectively compute iFTs using either SGC-DLPFC or CDC-DLPFC FC. The Euclidean distance from the group-based target used in the trial to the centre of gravity of each iFT was computed and correlated with outcomes. ResultsMost subjects iFTs were within 2cm of their group-based target. Proximity to either the SGC- or CDC-iFT was not associated with better outcomes. Sensitivity analyses accounting for treatment target FC, methodology, data quality, or treatment parameters did not change the results. ConclusionsProximity to SGC- or CDC-derived iFTs was not associated with better outcomes in patients who received neuronavigated rTMS to a group-based target. Prospective randomized clinical trials comparing neuronavigated group-based target to neuronavigated iFTs are needed.

neuroscience↗

bioRxiv2023

Pancreatic Tumor-Derived Extracellular Vesicles Stimulate Schwann Cell Phenotype Indicative of Perineural Invasion via IL-8 Signaling

Pancreatic cancer remains a pre-eminent cause of cancer-related deaths with late-stage diagnoses leading to an 11% five-year survival rate. Moreover, perineural invasion (PNI), in which cancer cells migrate into adjacent nerves, occurs in an overwhelming majority of patients, further enhancing tumor metastasis. PNI has only recently been recognized as a key contributor to cancer progression; thus, there are insufficient treatment options for the disease. Attention has been focused on glial Schwann cells (SC) for their mediation of pancreatic PNI. Under stress, SCs dedifferentiate from their mature state to facilitate the repair of peripheral nerves; however, this signaling can also re-direct cancer cells to accelerate PNI. Limited research has explored the mechanism that causes this shift in SC phenotype in cancer. Tumor-derived extracellular vesicles (TEV) have been implicated in other avenues of cancer development, such as pre-metastatic niche formation in secondary locations, yet how TEVs contribute to PNI has not been fully explored. In this study, we highlight TEVs as initiators of SC activation into a PNI-associated phenotype. Proteomic and pathway assessments of TEVs revealed an elevation in interleukin-8 (IL-8) signaling and nuclear factor kappa B (NF{kappa}B) over healthy cell-derived EVs. TEV-treated SCs exhibited higher levels of activation markers, which were successfully neutralized with IL-8 inhibition. Additionally, TEVs increased NF{kappa}B subunit p65 nuclear translocation, which may lead to increased secretion of cytokines and proteases indicative of SC activation and PNI. These findings present a novel mechanism that may be targeted for the treatment of pancreatic cancer PNI. Statement of SignificanceIdentifying pancreatic tumor extracellular vesicles as key players in Schwann cell activation and perineural invasion by way of IL-8 will educate for more specialized and effective targets for an under-valued disease.

cancer biology↗

bioRxiv2021

Implementation of a TMS-fMRI system: A primer

Transcranial magnetic stimulation (TMS) is a non-invasive and non-pharmacological intervention, approved for the treatment of individuals diagnosed with treatment-resistant depression. This well-tolerated approach uses magnetic pulses to stimulate specific brain regions and induce changes in brain networks at multiple levels of human functioning. Combining TMS with other neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), offers new insights into brain functioning, and allows to map out the causal alterations brought on by TMS interventions on neural network connectivity and behaviour. However, the implemention of concurrent TMS-fMRI brings on a number of technical challenges that must be overcome to ensure good quality of functional images. The goal of this study was thus to investigate the impact of TMS pulses in an MR-environment on the quality of BRAINO phantom images, in terms of the signal of the images, the temporal fluctuation noise, the spatial noise and the signal to fluctuation noise ratio, at the University of British Columbia (UBC) Neuroimaging facility. The results of our analyses replicated those of previous sites, and showed that the present set-up for concurrent TMS-fMRI ensures minimal noise artefact on functional images obtained through this multimodal approach. This step was a key stepping stone for future clinical trials at UBC.

neuroscience↗

bioRxiv2019

Functions of ventral visual cortex after bilateral hippocampal loss

Repeated stimuli elicit attenuated responses in visual cortex relative to novel stimuli. This adaptation phenomenon can be considered a form of rapid learning and a signature of perceptual memory. Adaptation occurs not only when a stimulus is repeated immediately, but also when there is a lag in terms of time and other intervening stimuli before the repetition. But how does the visual system keep track of which stimuli are repeated, especially after long delays and many intervening stimuli? We hypothesized that the hippocampus supports long-lag adaptation, given that it learns from single experiences, maintains information over delays, and sends feedback to visual cortex. We tested this hypothesis with fMRI in an amnesic patient, LSJ, who has encephalitic damage to the medial temporal lobe resulting in complete bilateral hippocampal loss. We measured adaptation at varying time lags between repetitions in functionally localized visual areas that were intact in LSJ. We observed that these areas track information over a few minutes even when the hippocampus is unavailable. Indeed, LSJ and controls were identical when attention was directed away from the repeating stimuli: adaptation occurred for lags up to three minutes, but not six minutes. However, when attention was directed toward stimuli, controls now showed an adaptation effect at six minutes but LSJ did not. These findings suggest that visual cortex can support one-shot perceptual memories lasting for several minutes but that the hippocampus is necessary for adaptation in visual cortex after longer delays when stimuli are task-relevant.

neuroscience↗