Biology subjects

Godfrey, K.

Publications and source records attributed to Godfrey, K..

8 recordsLinked to original sources

bioRxiv2026

Neurite Complexity and Plasticity Markers Track Synaptic Vesicle Density in the Living Human Brain: A Multimodal PET-MRI-EEG Study

Neuroplasticity, the brain's capacity to reorganise its structure and function, is a transdiagnostic feature across psychiatric and neurodegenerative diseases and a putative mechanism of action for pharmacological interventions. [11C]-UCBJ positron emission tomography (PET), which quantifies synaptic vesicle glycoprotein 2A (SV2A) density, offers the most direct in vivo measure of human synaptic density, but its relationship to complementary, more scalable neuroimaging measures of structural and functional plasticity remains uncharacterised. We combined [11C]-UCBJ PET, diffusion weighted imaging (DWI/NODDI), resting-state functional magnetic resonance imaging (rs-fMRI), and electroencephalography (EEG)-based sensory tasks (roving mismatch negativity, MMN; visual long-term potentiation, vLTP) in 18 healthy volunteers to test the relationship between synaptic terminal SV2A density and complementary structural and functional neuroplasticity measures, and whether these relationships were reproducible following pharmacological challenge with ketamine (n = 11) or N,N-dimethyltryptamine (DMT; n = 7). There were no statistically significant differences in PET-derived SV2A binding potential (BPND), DWI-derived neurite orientation dispersion (ODI) and structural weighted degree (SWD), EEG-derived MMN repetition suppression, and late-phase vLTP P2 potentiation, 1 to 8 days following DMT and ketamine exposure compared to baseline. BPND was coupled with ODI across cortical regions before and after pharmacological challenge, and this relationship was tighter within visual, attentional, and frontoparietal control brain networks. SWD showed a weaker, more spatially restricted association with BPND, primarily in regions belonging to the limbic and visual brain networks, but was not replicated post-drug. No consistent association was found between BPND and functional weighted degree (FWD), derived from rs-fMRI, at baseline or after pharmacological challenge. Frontotemporal BPND was positively associated with MMN repetition suppression (r = 0.61), and occipital BPND with late-phase vLTP P2 potentiation (r = 0.54), with the MMN-BPND association replicating after pharmacological challenge (r = 0.49). These findings link synaptic terminal SV2A density in the living human brain to neurite architecture and the capacity for short-term and Hebbian-like long-term synaptic plasticity, while dissociating these relationships from generic functional connectivity and magnitude of sensory-evoked responses. These data provide cross-modal validation for DWI- and EEG-derived measures as biological indices and surrogate measures of human synaptic plasticity.

neuroscience↗

bioRxiv2025

Large-scale single-cell phylogenetic mapping of clonal evolution in the human aging esophagus

The human somatic genome evolves throughout our lifespan, producing mosaic individuals comprising clones harboring different mutations across tissues. While clonal expansions in the hematopoietic system have been extensively characterized and reported to be nearly ubiquitous, clonal mosaicism (CM) has more recently also been described across multiple solid tissues. However, outstanding questions remain about the parameters and processes of human somatic evolution in non-cancerous solid human tissues, including when clones arise, how they evolve over time, and what mechanisms lead to their expansion. Questions of timing and clonal dynamics can be addressed through phylogenetic reconstruction, which serves as a temporal microscope, while uncovering the mechanisms of expansion necessitates simultaneous phenotypic profiling. To address this gap, here we develop Single-cell Miniaturized Automated Reverse Transcription and Primary Template-directed Amplification (SMART-PTA) for joint single-cell whole-genome and whole-transcriptome sequencing for large scale and cost efficient interrogation of solid tissue CM. We established a workflow that generates hundreds of matched single-cell whole genome and transcriptome libraries within a week. We profiled phenotypically normal esophagus tissue from four aged donors and used somatic variants to build high-resolution single-cell lineages from >2,700 cells with accompanying transcriptomic information, reconstructing >70 years of somatic evolution. T cell expansions identified from T cell receptor (TCR) sequences validated the clonal structure of the single-nucleotide variant (SNV)-based phylogenies and phylogenetic cross-correlation analysis showed that epithelial cells had higher degrees of shared ancestry by spatial location compared to immune cells. Mapping mutation signatures to the phylogenetic tree revealed the emergence of tobacco/alcohol exposure-related signatures later in life, consistent with the donors exposure histories. We identified variants in driver genes that were previously reported in the phenotypically normal esophagus, detecting clonal expansions harboring mutations in genes including TP53 and FAT1. We mapped the evolution of clones with both monoallelic as well as biallelic TP53 loss, including a clone associated with high expression of cell cycling genes and higher chromosome instability. Leveraging the matched transcriptome data, we uncovered cell type biases in mutant clones, with a higher proportion of TP53 or FAT1-mutant cells in an earlier basal epithelial cell state compared to wild-type cells. We further observed copy-neutral loss of heterozygosity (CNLOH) events on chromosome 9q that spanned the NOTCH1 locus in up to [~]35% of epithelial cells. Mapping CNLOH events to the phylogenetic tree revealed a striking pattern in which CNLOH was separately acquired many times, reflecting convergent evolution. Cells with CNLOH events were biased towards the earlier basal epithelial state, suggestive of a selective advantage that leads to prevalent recurrence of chr9q CNLOH. Together, we demonstrate that SMART-PTA is an efficient, scalable approach for single-cell whole-genome and whole-transcriptome profiling to build phenotypically annotated single-cell phylogenies with enough throughput and power for application to normal tissue somatic evolution. Moreover, we reconstruct the evolutionary history of the esophageal epithelium at high scale and resolution, providing a window into the dynamics and processes that shape clonal expansions in phenotypically normal tissues throughout a lifespan.

genomics↗

bioRxiv2025

Detecting neuroplastic effects induced by ketamine in healthy human subjects: a multimodal approach

We investigated ketamines neuroplastic effects in healthy human subjects using integrated Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) measures before and 1-8 days after a single psychedelic dose of ketamine (1 mg/kg, intravenous). Eleven participants underwent two PET/MRI scans with [11C]-UCBJ (synaptic density/plasticity), 1H-MRS (Glutamate and GABA), and resting-state fMRI (intrinsic brain activity, functional connectivity, graph-theoretic metrics), before and after ketamine. While group-level analyses showed only trend-level increases in PET synaptic markers, we observed significantly elevated Anterior Cingulate Cortex (ACC) glutamate levels post-ketamine. Functional connectivity analyses revealed decreased within-network integrity, particularly in high-order networks like the default mode network (DMN), alongside increased low-to-high-order network integration. Our multimodal analysis showed that increased [11C]-UCBJ volume distribution (VT), a putative index of synaptic plasticity, correlated with reduced intrinsic activity in DMN regions and decreased influence of the posterior cingulate cortex (PCC) in global network dynamics. By linking molecular and network-level changes, our results point to the PCC as a central hub where ketamine may reshape brain hierarchies in the long term, providing new directions for understanding its therapeutic mechanisms and developing targeted treatments.

neuroscience↗

bioRxiv2024

Human brain changes after first psilocybin use

Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is unknown. In a placebo-controlled, within-subjects, electroencephalography, and magnetic resonance imaging study in 28 healthy, entirely psychedelic-naive participants, anatomical and functional brain changes were detected from one-hour to one-month after a single high-dose (25 mg) of psilocybin. Increases in cognitive flexibility, psychological insight, and well-being were seen at one-month. Diffusion imaging done before and one-month after 25mg psilocybin revealed decreased axial diffusivity bilaterally in prefrontal-subcortical tracts that correlated with decreased brain network modularity over the same time period. Decreased modularity also correlated with improved well-being. Increased cortical signal entropy at 1- and 2-hours post-dosing predicted improved psychological well-being at one-month. Next-day psychological insight mediated the entropy to well-being relationship. All effects were exclusive to 25mg psilocybin; no effects occurred with a 1mg psilocybin placebo dose.

neuroscience↗

bioRxiv2024

Experienced meditators show greater forward travelling cortical alpha wave strengths

Mindfulness meditation involves training attention, commonly towards the current sensory experience, with an attitude of non-judgemental awareness. Theoretical perspectives suggest meditation alters the brains predictive processing mechanisms, increasing the synaptic gain and precision with which sensory information is processed, and reducing the generation or elaboration of higher-order beliefs. Recent research suggests that forwards and backwards travelling cortical alpha waves provide an indication of these predictive processing functions. Here, we used electroencephalography (EEG) to test whether the strength of forwards and backwards travelling cortical alpha waves differed between experienced meditators and a matched sample of non-meditators, both during an eyes-closed resting state (N = 97) and during a visual cognitive (Go/No-go) task (N = 126). Our results showed that meditators produced stronger forwards travelling cortical alpha waves compared to non-meditators, both while resting with their eyes closed and during task performance. Meditators also exhibited weaker backwards travelling cortical alpha wave strength while resting with their eyes closed. These results may be indicative of a neural mechanism underpinning enhanced attention associated with meditation practice, as well as a potential neural marker of the reductions in resting mind-wandering that are suggested to be associated with meditation practice. The results also support models of brain function that suggest attention modification can be achieved by mental training aimed at increased processing of sensory information, which might be indexed by greater strength of forwards travelling cortical alpha waves.

neuroscience↗

bioRxiv2024

EEG is better when cleaning effectively targets artifacts

Electroencephalography (EEG) is a useful tool to measure neural activity. However, EEG data are usually contaminated with non-neural artifacts, including voltage shifts generated by eye movements and muscle activity, and other artifacts that are less easily characterizable. The confounding influence of artifacts is often addressed by decomposing data into components, subtracting probable artifactual components, then reconstructing data back into the electrode space. This approach is commonly applied using independent component analysis (ICA). Here, we demonstrate the counterintuitive finding that due to imperfect component separation, component subtraction can artificially inflate effect sizes for event-related potentials (ERPs) and connectivity measures, bias source localisation estimates, and remove neural signals. To address this issue, we developed a method that targets cleaning to the artifact periods of eye movement components and artifact frequencies of muscle components. When tested across different EEG systems and cognitive tasks, our results showed that the targeted artifact reduction method is effective in cleaning artifacts while also reducing the artificial inflation of ERP and connectivity effect sizes and minimizing source localisation biases. Our results suggest EEG pre-processing is better when targeted cleaning is applied, as this improves preservation of neural signals and mitigates effect size inflation and source localisation biases that result from approaches which subtract artifact components across the entire time-series. These improvements enhance the reliability and validity of EEG data analysis. Our method is provided in the freely available RELAX pipeline, which includes a graphical user interface for ease of use and is available as an EEGLAB plugin (https://github.com/NeilwBailey/RELAX).

neuroscience↗

bioRxiv2020

Multiplex detection of "Candidatus Liberibacter asiaticus" and Spiroplasma citri by qPCR and droplet digital PCR

"Candidatus Liberibacter asiaticus" (CLas) and Spiroplasma citri are phloem-limited bacteria that infect citrus and are transmitted by insect vectors. S. citri causes citrus stubborn disease (CSD) and is vectored by the beet leafhopper in California. CLas is associated with the devastating citrus disease, Huanglongbing (HLB), and is vectored by the Asian citrus psyllid. CLas is a regulatory pathogen spreading in citrus on residential properties in southern California and is an imminent threat to spread to commercial citrus plantings. CSD is endemic in California and has symptoms in citrus that can be easily confused with HLB. Consequently, a multiplex qPCR and duplex droplet digital PCR (ddPCR) were developed for simultaneous detection of CLas and S. citri. The multiplex qPCR assay was designed to detect multicopy genes of CLas - RNR (5 copies) and S. citri - SPV1 ORF1 (13 copies), respectively, and citrus cytochrome oxidase (COX) as internal positive control. Absolute quantitation of these pathogens was achieved by duplex ddPCR as a supplement for marginal qPCR results. Duplex ddPCR allowed higher sensitivity than qPCR for detection of CLas and S. citri. ddPCR showed higher resilience to inhibitors and yielded highly reproducible results. The multiplex qPCR assay has the benefit of testing both pathogens at reduced cost and can serve to augment the official regulatory protocol for CLas detection in California. Moreover, the ddPCR provided unambiguous absolute detection of CLas and S. citri at very low concentrations without any standards for pathogen titer.

microbiology↗

bioRxiv2018

Classification of electrophysiological and morphological types in mouse visual cortex

Understanding the diversity of cell types in the brain has been an enduring challenge and requires detailed characterization of individual neurons in multiple dimensions. To profile morpho-electric properties of mammalian neurons systematically, we established a single cell characterization pipeline using standardized patch clamp recordings in brain slices and biocytin-based neuronal reconstructions. We built a publicly-accessible online database, the Allen Cell Types Database, to display these data sets. Intrinsic physiological and morphological properties were measured from over 1,800 neurons from the adult laboratory mouse visual cortex. Quantitative features were used to classify neurons into distinct types using unsupervised methods. We establish a taxonomy of morphologically- and electrophysiologically-defined cell types for this region of cortex with 17 e-types and 35 m-types, as well as an initial correspondence with previously-defined transcriptomic cell types using the same transgenic mouse lines.

neuroscience↗