Biology subjects

Coxon, J.

Publications and source records attributed to Coxon, J..

11 recordsLinked to original sources

bioRxiv2026

Effect of dopamine D2 blockade on behavioural and electrophysiological measures of inhibitory control

Inhibitory control is an essential executive function that encompasses both the stopping of an action in response to an unexpected stop signal (reactive response inhibition) and slowing of responses in anticipation of stopping (proactive response inhibition). Fronto-basal-ganglia circuits are thought to differentially contribute to response inhibition, with the indirect pathway implicated in proactive inhibition. Given the high expression of dopamine D2 receptors in the indirect pathway, pharmacological blockade of D2 receptors is expected to impact proactive inhibition, as indicated by response times on Go trials. The current study aimed to investigate this experimentally and study the effect of 600 mg of sulpiride, a D2 receptor antagonist, on behavioural and electrophysiological measures of proactive and reactive inhibition in humans. Human participants (N=24) completed an anticipated response version of the stop-signal task on either sulpiride or placebo in a double-blind within-subjects design. Sulpiride led to increased variability of Go response times and attenuation of the frontocentral negativity/readiness potential, considered to be a signature of proactive inhibition. In contrast, sulpiride had no effect on stop-signal reaction time or event-related potential components associated with reactive inhibition. These findings suggest that D2 receptor blockade selectively alters processes involved in proactive inhibition while leaving reactive inhibition unaffected, consistent with a key role for the indirect basal ganglia pathway in proactive response inhibition.

neuroscience↗

bioRxiv2026

Investigating cross-memory interactions of timing structures

Motor and episodic memories are classically conceptualised as distinct memory domains. However, both memory sequences are characterised by order and timing of their elements. Generalisation has been previously documented between these different memories, with a shared ordinal structure facilitating learning. However, it is unclear whether this generalisation also applies to the timing structure of a sequence. In a between-subject design, healthy adults (N = 143) learned and reproduced motor and episodic memory sequences with either the same or different timing structures. Contrary to expectations, recall of an episodic timeline was poorer when preceded by learning a motor sequence with the same timing structure. Motor sequence reproduction was not affected by prior episodic encoding. The findings do not support the hypothesis of cross-domain generalisation of timing structure between episodic and motor memories. However, the observed interference may suggest some overlap in the mechanism encoding timing information between memory systems.

neuroscience↗

bioRxiv2025

Generalisation between motor and declarative memory sequences: A conceptual replication of Mosha & Robertson (2016)

Motor and declarative memory systems have been traditionally considered distinct. However, a study by Mosha and Robertson (2016) reported striking evidence of generalisation between motor and declarative learning. Specifically, learning improved if the current task (e.g. motor sequence) shared the same high-level ordinal structure as an earlier task (e.g. word list), demonstrating cross-domain transfer of unstable memories. This finding has significant implications for our understanding and conceptualisation of memory taxonomies but has not been replicated. Here, healthy adult participants (N = 125) completed a word list and motor sequence task in counterbalanced order with either a shared or distinct sequence structure. In contrast to Mosha & Robertson (2016), we found that a shared ordinal structure between the declarative and motor sequence tasks did not facilitate performance. Overall, our results challenge the robustness of cross-domain generalisation, and underscore the complexity of cross-memory interactions.

neuroscience↗

bioRxiv2025

High frequency oscillations and the 1/f slope vary across a spectrum of depression severity

Depression is a highly prevalent mental disorder that impacts an individuals functioning, societal productivity, and quality of life. It is associated with disrupted neural activity (e.g., balance of excitation-inhibition) across networks implicated in emotional processing, such as between prefrontal and limbic regions. High frequency oscillations measured with electroencephalography (i.e., beta and gamma rhythms) differ between healthy individuals and those with depression, and predict treatment outcomes following pharmacological intervention. However, to date research has focussed on binary comparisons between individuals with a clinical depression diagnosis relative to healthy control populations, providing limited insight into how these measures may shift as a function of illness severity. To establish the utility of EEG measures as potential biomarkers for depression, an improved understanding across the spectrum of symptom profiles is required. Here, we aimed to bridge this gap and investigate changes in high frequency beta and gamma oscillations and the 1/f slope in resting-state EEG across a spectrum of mild to severe depression symptom presentations. In line with expectations, we demonstrate graded alterations to gamma and beta power and the 1/f slope across a spectrum of depression severity. Our findings provide critical new insights into the neurophysiological signature of depression symptoms, and highlight the utility of EEG markers to inform future precision psychiatry approaches to more effectively assess and treat depression. HighlightsO_LIHigh frequency brain oscillations are associated with depression severity C_LIO_LIExcitation-inhibition balance is altered in depression C_LIO_LIThese neural markers could inform precision psychiatry approaches C_LI

neuroscience↗

bioRxiv2025

High-intensity cardiovascular exercise facilitates online motor skill learning, with no effect of BDNF genotype

Previous studies have demonstrated that exercise can influence motor skill learning. However, the specific components of learning primed by exercise remain unclear. This study examined the effect of a preceding bout of high intensity interval training (HIIT) on the acquisition of a novel motor skill. The investigation focused on whether improvement in skill across the session was attributable to online gains during active practice or offline rest periods between practice blocks. There was also exploration as to whether common polymorphisms of the BDNF and DRD2/ANKK1 genes that regulate plasticity, learning, and memory, influenced the relationship between exercise and motor learning. It was demonstrated that HIIT enhanced skill acquisition, but that the effects of HIIT priming were not specifically attributable to within-session online or offline learning processes. Contrary to research on overnight consolidation, there was no interaction between BDNF, nor DRD2/ANKK1 genotype, with exercise primed skill learning.

neuroscience↗

bioRxiv2024

Default mode and motor networks facilitate early learning of implicit motor sequences: a multimodal MR spectroscopy and fMRI study

Learning new motor skills is a fundamental process that involves the sequencing of actions. Skill develops with practice and time, and manifests as performance that is fast and accurate. Although we know that learning can occur through an implicit process in the absence of conscious awareness, and across multiple temporal scales, the precise neural mechanisms mediating implicit motor sequence learning remain poorly understood. Similarly, the capacity for interventions with known influence on learning and memory, such as cardiovascular exercise, to facilitate implicit learning is yet to be clearly established. Here, we investigated the neuroplasticity of implicit motor sequence learning and the effect of acute exercise priming. Healthy adults (39.5% female) aged 22.55 {+/-} 2.69 years were allocated to either a high-intensity exercise (HIIT) group (n = 16) or to a very low-intensity control group (n = 17). Following exercise, participants performed a serial reaction time task. MR spectroscopy estimates of sensorimotor gamma-aminobutyric acid (GABA) were acquired before and after exercise, and during task performance, and resting-state fMRI was acquired at the end of the protocol. We show that early stages of learning are linked to default mode network connectivity, while the overall degree of learning following sustained practice is associated with motor network connectivity. Sensorimotor GABA concentration was linked to the early stages of learning, and GABA concentration was modulated following HIIT, although the two were not related. Overall, via integration of multiple neuroimaging modalities we demonstrate that interactions between hippocampal and motor networks underlie implicit motor sequence learning. Key points summary- Motor learning occurs across different temporal scales and can arise implicitly in the absence of conscious awareness. - Explicit motor learning is linked to the brains primary inhibitory neurotransmitter, GABA, and interactions across motor and hippocampal networks. - Whether these same neural mechanisms are implicated in implicit learning is unclear. Similarly, the capacity to influence learning via priming with cardiovascular exercise is yet to be clearly established. - We show that early implicit learning is underpinned by default mode network connectivity and sensorimotor GABA concentration, while total learning following sustained practice is linked to motor network connectivity. We also found that HIIT exercise elevated sensorimotor GABA concentration, but not the magnitude of implicit learning. - Overall, our results highlight shared involvement of default mode and motor networks in implicit motor sequence learning.

neuroscience↗

bioRxiv2024

Using TMS-EEG to study the intricate interplay between GABAergic inhibition and glutamatergic excitation during reactive and proactive motor inhibition

Transcranial magnetic stimulation (TMS) studies have provided insight into the neurotransmission underlying motor inhibition but are limited to the primary motor cortex (M1). To investigate {gamma}-aminobutyric acid (GABA) and glutamatergic neurotransmission across the broader motor inhibition network, we combined TMS with electroencephalography (EEG). The N45 and N100 components of the TMS-evoked potentials (TEPs) have been liked to GABAa and GABAb signaling, respectively, whereas the N15, P30 and P60 TEPs are believed to reflect glutamatergic neurotransmission. This study investigates how these components are modulated during reactive and proactive motor inhibition. Twenty-four healthy participants completed two TMS-EEG sessions targeting either the left M1 or the pre-supplementary motor area (preSMA) at rest and during a stop-signal task. We compared TEP amplitudes across TMS conditions (active/sham) and trial types and assessed their relationship with task performance. Participants with a higher N45 amplitude over M1 at rest demonstrated a faster stop-signal reaction time. Active TMS during successful motor inhibition evoked higher N15 amplitudes over preSMA than during uncertain go trials, suggesting that an early excitatory signal from preSMA is crucial for reactive inhibition. In contrast, proactive inhibition was linked to lower P30 amplitudes in M1, possibly reflecting reduced motor facilitation. These findings provide novel empirical insights into the neurophysiological mechanisms underpinning motor inhibition, emphasizing the importance of a coordinated balance between inhibitory processes in M1 and early glutamatergic excitatory signals from preSMA for effective inhibition.

neuroscience↗

bioRxiv2020

The effects of multi-day rTMS and cardiorespiratory fitness on working memory and local GABA concentration

Working memory (WM) refers to the capacity to temporarily retain and manipulate finite amounts of information; a critical process in complex behaviours such as reasoning, comprehension, and learning. This cognitive function is supported by a parietal-prefrontal network and linked to the activity of key neurotransmitters, such as gamma-aminobutyric acid (GABA). Impairments in WM are seen in a range of psychiatric and neurological disorders, and there are currently no effective treatments. In this study, we analysed secondary outcome measures from a trial investigating the effects of multi-day rTMS on cognition. Participants received four days of 20 Hz rTMS to an individualised region of left parietal cortex in one week, and an individualised region of pre-supplementary motor area (pre-SMA) in a separate week. We assessed changes to WM function before and after each week of stimulation (N = 39), and changes to GABA concentration before and after stimulation in week one using MR spectroscopy (N = 18 per stimulation condition). We hypothesised that parietal rTMS would enhance WM and alter GABA concentration at the site of stimulation, but this was not observed. Instead, we report some evidence of improved WM function following the first week of pre-SMA rTMS stimulation, and a generalised increase in GABA concentration across both parietal and pre-SMA voxels following pre-SMA rTMS. Additionally, we found that higher cardiorespiratory fitness was associated with greater WM improvement following pre-SMA stimulation. This study does not support the use of parietal multi-day rTMS for the enhancement of working memory. In contrast, the results suggest that increasing cardiorespiratory fitness may provide a novel approach to enhance the effects of pre-SMA rTMS on cognition.

neuroscience↗

bioRxiv2020

The effects of regular aerobic exercise on hippocampal structure and function

Regular exercise has numerous benefits for brain health, including the structure and function of the hippocampus. The hippocampus plays a critical role in memory function, and is altered in a number of psychiatric disorders associated with memory impairments (e.g. depression and schizophrenia), as well as healthy ageing. While many studies have focussed on how regular exercise may improve hippocampal integrity in older individuals, less is known about these effects in young to middle-aged adults. Therefore, we assessed the associations of regular exercise and cardiorespiratory fitness with hippocampal structure and function in these age groups. We recruited 40 healthy young to middle-aged adults, comprised of two groups (n = 20) who self-reported either high or low levels of exercise, according to World Health Organisation guidelines. We assessed cardiorespiratory fitness using a graded exercise test (VO2max) and hippocampal structure via manual tracing of T1-weighted magnetic resonance images. We also assessed hippocampal function using magnetic resonance spectroscopy to derive estimates of NAA concentration and hippocampal-dependent associative memory and pattern separation tasks. We observed evidence of increased N-acetyl-aspartate concentration and associative memory performance in individuals engaging in high levels of exercise. However, no differences in hippocampal volume or pattern separation capacity were observed between groups. Cardiorespiratory fitness was positively associated with hippocampal volume (left, right, and bilateral), N-acetyl-aspartate concentration, and pattern separation. However, no association was observed between cardiorespiratory fitness and associative memory. Therefore, we provide evidence that higher levels of exercise and cardiorespiratory fitness are associated with improved hippocampal structure and function. Exercise may provide a low-risk, effective method of improving hippocampal integrity in an early-to-mid-life stage.

neuroscience↗

bioRxiv2020

A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival probability of tuberculous meningitis patients treated with adjunctive dexamethasone

Tuberculous meningitis (TBM) remains the most devastating form of tuberculosis (TB) with high mortality despite effective antimicrobial treatment. As mortality has been linked to excessive inflammation, anti-inflammatory glucocorticoids are now routinely used as adjunctive treatment with antimicrobial therapy. However, they reduce mortality by only ~ 30%, raising the possibility that only a subset of TBM deaths are caused by inflammatory pathophysiology. Studies in Vietnam found that the survival benefit of adjunctive glucocorticoids was limited to individuals with a common promoter variant in the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoid expression. The variant constitutes a C/T transition with TT homozygotes having increased expression over CT heterozygotes and CC homozygotes. In Vietnam, the LTA4H TT genotype predicted survival, consistent with dexamethasone benefiting only those individuals with a dysregulated hyper-inflammatory response. However, a study of TBM patients in Indonesia did not find the LTA4H TT genotype to confer a significant survival benefit. Given the potential of personalized life-saving anti-inflammatory therapies guided by LTA4H genotype, we have used Bayesian methods to analyze the data from both studies. Bayesian analysis reveals that the LTA4H TT genotype confers survival benefit in both the Vietnam and Indonesia cohorts that begins within days and continues long-term. However, its benefit is nullified in the most severe cases where other factors cause early mortality. LTA4H TT genotype is associated with increased survival in HIV-positive patients also. Thus, our analysis extends the association of LTA4H genotype with TBM survival to populations outside of Vietnam and to HIV-positive patients. Patient LTA4H genotyping used in conjunction with disease severity assessment may help to target glucocorticoids to patients most likely to benefit from this broadly-acting immunosuppressive regimen despite its significant adverse effects.

molecular biology↗

bioRxiv2019

Metabolic response to Parkinson’s disease recapitulated by the haploinsufficient phenotype of diploid yeast cells hemizygous for the adrenodoxin reductase gene

Adrenodoxin reductase, a widely conserved mitochondrial P450 protein, catalyses essential steps in steroid hormone biosynthesis and is highly expressed in the adrenal cortex. The yeast adrenodoxin reductase homolog, Arh1p, is involved in cytoplasmic and mitochondrial iron homeostasis and is required for activity of enzymes containing an Fe-S cluster. In this paper, we investigated the response of yeast to the loss of a single copy of ARH1, an oxidoreductase of the mitochondrial inner membrane, which is among the few mitochondrial proteins that is essential for viability in yeast. The phenotypic, transcriptional, proteomic, and metabolic landscape indicated that Saccharomyces cerevisiae successfully adapted to this loss, displaying an apparently dosage-insensitive cellular response. However, a considered investigation of transcriptional regulation in ARH1-impaired yeast highlighted that a significant hierarchical reorganisation occurred, involving the iron assimilation and tyrosine biosynthetic processes. The interconnected roles of the iron and tyrosine pathways, coupled with oxidative processes, are of interest beyond yeast since they are involved in dopaminergic neurodegeneration associated with Parkinsons disease. The identification of similar responses in yeast suggest that this simple eukaryote could have potential as a model system for investigating the regulatory mechanisms leading to the initiation and progression of early disease responses in humans.

systems biology↗