Biology subjects

Harrison, N. A.

Publications and source records attributed to Harrison, N. A..

7 recordsLinked to original sources

bioRxiv2026

Breathlessness catastrophising after COVID-19 involves both interoceptive and visceromotor connectivity

Persistent breathlessness is common after COVID-19, yet its severity typically correlates weakly with objective clinical measures. This discordance is often attributed to perceptual inference amplified by anxiety. Because breathing involves a closed perception-action loop, breathlessness may also reflect alterations in interoceptive and visceromotor pathways. We acquired 7-tesla resting-state functional MRI in 53 post-COVID patients with varying breathlessness and estimated functional connectivity across 18 pre-defined interoceptive and visceromotor regions. Linear regression identified two connections associated with breathlessness catastrophising: reduced dorsal periaqueductal grey-posterior insula (dPAG-PoI1) and increased basolateral amygdala-dorsal anterior cingulate (BLA-dACC) connectivity. The dPAG-PoI1 association was stronger in patients who had required mechanical ventilation, whereas the BLA-dACC association was attenuated at higher generalised anxiety. These findings are consistent with two potentially separable contributions to symptom burden: weakened interoceptive signalling between brainstem and sensory cortex, and heightened visceromotor influence of threat processing on autonomic control, rather than anxiety-driven misperception alone.

neuroscience↗

bioRxiv2026

Age and IFN-β-induced changes in glial morphometry can be captured by in vivo diffusion-weighted magnetic resonance spectroscopy.

IntroductionNeuroinflammation is increasingly implicated in age-related cognitive decline, neurodegeneration and neuropsychiatric disorders. During systemic inflammation, microglia are rapidly activated, simultaneously changing their shape and releasing cytokines that perturb neuronal function. This change in glial morphology alters their intracellular diffusion properties and provides a potentially measurable signature of their activation state. Diffusion-weighted magnetic resonance spectroscopy (dMRS) shows promise in detecting these changes. Here, we combined IFN-{beta} challenge with dMRS to assess changes in metabolite diffusion in healthy young and older adults. We hypothesised that IFN-{beta} would increase diffusion of choline-containing compounds (tCho) but not N-acetylaspartate + N-acetylaspartylglutamate (tNAA), age would be associated with an increase in tCho diffusion and concentration, lower tNAA concentration and increased effects of IFN-{beta}. MethodsWe recruited 15 young (mean 25.2 {+/-} 5.1 years, 6 male) and 15 older (mean 62.6 {+/-} 4.1 years, 5 male) healthy volunteers, each tested twice, once after IFN-{beta} and once after placebo. Physiological and behavioural responses were recorded hourly, and blood samples taken at baseline, 4 and 6.5 hours post-injection. dMRS occurred at [~]4.5 hours at 3T, using a semi-LASER sequence with four diffusion weightings (b = 0 and 3 x 3500 s/mm{superscript 2}), in 4.5 cm3 VOIs in the left thalamus and corona radiata. Apparent Diffusion Coefficients (ADCs) of tCho, tNAA and creatine+phosphocreatine (tCr) were calculated from averaged spectra using custom MATLAB software. ResultsIFN-{beta} administration produced a significant increase in thalamic tCho diffusivity compared with placebo (t(28) = -2.15, p = 0.040), with no change in tNAA or tCr ADC, or tCho concentrations. IFN-{beta}-related increases in tCho ADC positively correlated with increases in circulating IL-6 (R{superscript 2} = 0.14, p = 0.040). Age-related effects were also evident during the placebo condition, with older participants showing lower thalamic tNAA diffusivity (t(27) = 2.86, p = 0.008), lower tNAA/tCr in both grey and white matter (grey: t(27) = 2.49, p = 0.023; white: t(27) = 2.94, p = 0.007), and higher white-matter tCho/tCr (t(27) = -2.23, p = 0.034). ConclusiondMRS detected IFN-{beta}-induced increases in thalamic tCho diffusivity corresponding with peripheral inflammation, supporting its sensitivity to acute inflammation-induced changes in glial morphology. Age-related differences in tNAA diffusion and concentrations further highlight metabolite-specific ageing effects. HighlightsO_LIdMRS detects increased thalamic total choline diffusivity following IFN-{beta}-induced inflammation. C_LIO_LIIFN-{beta}-related changes in total choline diffusivity are associated with peripheral IL-6 responses. C_LIO_LIAgeing is linked to reduced NAA diffusion and higher white-matter tCho/tCr C_LIO_LIdMRS is sensitive to inflammation- and age-related neurochemical changes in vivo. C_LI

immunology↗

bioRxiv2025

Developing Interferon-β as a safe in-vivo experimental-medicine model of human inflammation.

BackgroundInflammation is increasingly implicated in a wide range of neuropsychiatric disorders ranging from depression through age- and infection-related cognitive decline to dementia. Arguably, the most important evidence supporting an aetiological role for inflammation in these conditions in humans has come from studies of patients receiving IFN- therapeutically or longitudinal follow-up of patients after naturalistic infections (e.g., hepatitis C). These experimental medicine-type approaches have identified a discrete set of brain regions e.g. amygdala-hippocampus-hypothalamus, insula and anterior cingulate as well as dopamine-rich subcortical structures that are particularly sensitive to systemic inflammation. Coupled with renewed interest in developing novel immune-targeted therapies for neuropsychiatric disorders as diverse as depression and neurodegenerative disorders, this has highlighted the urgent need for a safe, reliable in-vivo experimental medicine model of inflammation that can be used across the age range. To date, this need has been partially addressed by access to short-acting forms of Interferon-alpha or human (GMP) grade lipopolysaccharide (LPS). However, unpegylated IFN- is no longer commercially available and the costs and cardiovascular monitoring requirements of low-dose (i.e. 0.8-1ng/Kg i.v. endotoxin) LPS are prohibitive and particularly challenging to use in older or more vulnerable populations. AimDevelop a new experimental model of human inflammation that elicits robust sickness responses within a few hours but with minimal cardiovascular effects, thus avoiding the need for continuous cardiac monitoring and ensuring applicability across diverse experimental contexts and participant groups from the young to the elderly. MethodsUsing a randomized, placebo-controlled, repeated measures cross-over design, physiological, behavioural, immune and transcriptomic responses were collected from 30 healthy volunteers (15 young [18-34] and 15 old [60-75]) following both IFN-{beta} (EXTAVIA(R) [100 {micro}g]) and saline (placebo) injections. ResultsIFN-{beta} induced a robust systemic immune response, evidenced by significant increases in temperature, heart rate, immune cell activation (lymphocytes, monocytes and neutrophils) and levels of IFN-{beta}, IL-10 and TNF- cytokines. These physiological changes were accompanied by significant increases in negative mood, tiredness, tension and sickness symptoms aa well as by a decrease in vigour. ConclusionsFN-{beta} is a safe and robust new experimental model of mild acute inflammation, This minimally invasive and effective design can induce transient changes in systemic inflammation in healthy individuals from 18-75. A more refined, ecologically valid model similar to the mild inflammation typically reported in psychiatric disorders like depression or cognitive impairment.

immunology↗

bioRxiv2024

Disarming emotional memories using Targeted Memory Reactivation during Rapid Eye Movement sleep

Emotional responses are dampened across sleep, and this is thought to be mediated by neural reactivation during Rapid Eye Movement (REM) Sleep. Such reactivation can be triggered by targeted memory reactivation (TMR), a technique in which a tone previously associated with a memory during wake is re-presented during subsequent sleep. Prior work has shown that TMR in REM reduces arousal responses to negative stimuli. The present study builds on this by measuring autonomic responses and brain activity as well as behaviour. Participants rated the arousal of 48 affective images, paired with semantically matching sounds. Half of these sounds were cued during REM in the subsequent overnight sleep cycle. Participants rated the images in a Magnetic Resonance Imaging (MRI) scanner with pulse oximetry 48 hours after encoding, and again after two weeks. Results showed that TMR during REM was also associated with reduced brain activity in the two primary nodes of the Salience Network (SN): the Anterior Insula and dorsal Anterior Cingulate Cortex (dACC), as well as the orbitofrontal cortex, subgenual cingulate, and left amygdala, all of which are known to be important for emotional processing. TMR markedly reduced the emotional heart rate deceleration (HRD) response, and also reduced subjective arousal ratings for highly arousing images, while increasing ratings for less arousing images. We conclude that REM TMR can facilitate a decrease in physiological and neurological responses to arousal. These findings have potential implications for the use of TMR in treatment of depression and anxiety disorders. HighlightsO_LITMR in REM sleep reduces Salience Network responses to emotional pictures. C_LIO_LITMR in REM sleep reduces heart rate deceleration to emotional pictures. C_LIO_LITMR in REM sleep reduces subjective arousal ratings of highly arousing images. C_LIO_LITMR in REM sleep provides a promising potential avenue for treatment of PTSD. C_LI

neuroscience↗

bioRxiv2022

Two differentiated brain systems micro-structurally associated with obesity

The relationship between obesity and brain structure is incompletely understood. Using diffusion-weighted MRI from [~]30,000 UK Biobank participants we test the hypothesis that obesity (waist-to-hip ratio, WHR) is associated with regional differences in two micro-structural MRI metrics: isotropic volume fraction (ISOVF), an index of free water, and intra-cellular volume fraction (ICVF), an index of neurite density. We observed significant associations with obesity in two coupled but distinct brain systems: a prefrontal-temporal-striatal system associated with ISOVF and a medial temporal-occipital-striatal system associated with ICVF. The ISOVF[~]WHR system colocated with expression of genes enriched for innate immune functions, decreased glial density, and high mu opioid (MOR) and other neurotransmitter receptor density. Conversely, the ICVF[~]WHR system co-located with expression of genes enriched for G-protein coupled receptors and decreased density of MOR and other receptors. To test whether these distinct brain phenotypes might differ in terms of their underlying shared genetics or relationship to maps of the inflammatory marker C-reactive Protein (CRP), we estimated the genetic correlations between WHR and ISOVF (rg = 0.026, P = 0.36) and ICVF (rg = 0.112, P < 9 x 10-4) as well as comparing correlations between WHR maps and equivalent CRP maps for ISOVF and ICVF (p<0.05). These correlational results are consistent with a two-way mechanistic model whereby genetically determined differences in neurite density in the medial temporal system may contribute to obesity, whereas water content in the prefrontal system could reflect a consequence of obesity mediated by innate immune system activation.

neuroscience↗

bioRxiv2020

Sexually dimorphic development of depression-related brain networks during healthy human adolescence

We hypothesized that there are sexual differences in human brain network development underlying the female > male divergence in adolescent depression. We tested for sex differences in parameters of brain network development (accelerated longitudinal fMRI, N=298 healthy adolescents, each scanned 1 to 3 times). Sexually divergent development of functional connectivity was located in default mode network (DMN), limbic cortex, and subcortical nuclei. Females had a more "disruptive" pattern of development, where weak functional connectivity at age 14 became stronger during adolescence. This fMRI-derived map of divergent adolescent development was co-located with (i) a map of functional dysconnectivity associated with adult major depressive disorder (MDD); and (ii) an adult brain gene expression pattern enriched for genes on the X chromosome, neurodevelopmental genes, and risk genes for MDD. Sexual divergence in disruptive development of DMN, limbic and subcortical functional networks is potentially relevant to the increased risk of depression in adolescent females.

neuroscience↗

bioRxiv2020

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Results showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. We also found that MPH-induced variations in DAT-and NET-enriched FC were significantly correlated with inter-individual differences in effects of MPH on key behavioural responses associated with the reinforcement-learning task. Our findings show that MPH-related FC changes are specifically associated with DAT and provide evidence that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to distinct molecular targets.

neuroscience↗