Biology subjects

Wall, M. B.

Publications and source records attributed to Wall, M. B..

13 recordsLinked to original sources

bioRxiv2026

Longitudinal fMRI reveals altered developmental trajectories of functional network organisation associated with adolescent cannabis use

Adolescence is a critical period of brain development during which the endocannabinoid system continues to mature. These developmental changes may contribute to age-related differences in the association between cannabis use and large-scale functional network organisation, yet this association remains incompletely characterised. We hypothesised that regular cannabis use would be associated with differential one-year changes in resting-state functional connectivity between adolescents and adults. Resting-state fMRI data at two time points, one year apart, were analysed from 66 participants (31 aged 16-17 years; 35 aged 26-29 years) including 29 with regular cannabis use and 37 age-matched cannabis-naive controls. Seed-to-voxel analyses examined longitudinal changes in functional connectivity across age and cannabis-use groups. Year change, age by user-group interactions were identified in salience and default mode network connectivity, including divergent changes in anticorrelations with medial prefrontal, thalamic, cerebellar and juxtapositional regions. Directionality of effects differed by network and region. Additional main effects of user group were observed for executive control and associative striatal connectivity, with the cannabis-use group showing decreased positive connectivity and reduced anticorrelation, respectively. Changes in functional connectivity were developmentally dissociable and predominantly observed in regions contributing to attentional and transmodal processing. These findings suggest that cannabis may be associated with alterations in the maturational refinement of higher-order neural systems, potentially reflecting age-related differences in neurobiological sensitivity to cannabis exposure. Considering developmental stage may therefore be important for characterising cannabis-related neurobiological differences and may have implications for understanding age-dependent vulnerability to cannabis-related psychiatric outcomes.

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bioRxiv2025

Receptor-enriched analysis of functional connectivity (REACT) for understanding cannabinoid neuropsychopharmacology

BackgroundCannabis is one of the most widely used psychoactive substances in the world and is increasingly investigated as a treatment for neuropsychiatric conditions. Cannabis contains delta-9-tetrahydrocannabinol (THC), which is thought to underlie its main psychoactive effects, and cannabidiol (CBD), which has been proposed to modulate the effects of THC on the brain. Both have activity at CB1 receptors, whilst THC also binds to CB2 receptors. However, it is unclear how THCs effects on brain function are related to cannabinoid receptors, or how CBD co-administration affects this. We aimed to investigate the effects of vaporised THC and the moderating effects of CBD on CB1 and CB2 receptor- enriched functional connectivity. MethodsForty-eight participants (24 adolescents and 24 adults) who used cannabis 0.5-3 days/week (mean=1.5 days/week) participated in a randomised, crossover, placebo- controlled, double-blind experiment where they inhaled vaporised cannabis containing either THC-only (8mg/75kg person), THC+CBD (8 mg THC + 24 mg CBD/75 kg person) or no psychoactive compounds (placebo). Resting-state functional MRI data were collected approximately 50 minutes post-administration. Receptor distribution maps were derived from positron emission tomography (PET) imaging for CB1 receptors and the Allen Human Brain Atlas (AHBA) for CB2 receptors. Receptor-Enriched Analysis of Connectivity by Targets (REACT) analytical methodology was used to investigate changes in functional connectivity related to specific receptor targets. ResultsInhalation of both THC-only and THC+CBD cannabis induced significant decreases in CB1 and CB2 receptor-enriched functional connectivity compared to placebo. The THC+CBD condition showed more extensive reductions than THC-only cannabis for both CB1- and CB2- enriched functional connectivity, affecting regions including the dorsolateral prefrontal cortex, cingulate cortex, insula, hippocampus, amygdala, and putamen. Higher THC plasma levels were associated with greater decreases in functional connectivity in the THC+CBD condition. Exploratory analyses identified significant positive and negative relationships between subjective drug effects and receptor-enriched functional connectivity in a region- dependent manner. ConclusionsCannabis with and without CBD decreased resting-state functional connectivity in networks associated with CB1 and CB2 receptor distribution. Co-administration of CBD with THC appears to enhance these effects. The REACT analytical methodology identified changes in CB1- and CB2-enriched functional connectivity are related to THC and CBD plasma levels as well as subjective drug effects across a range of regions.

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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.

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bioRxiv2025

Dissociable effects of LSD and MDMA on striato-cortical connectivity in healthy subjects

IntroductionLysergic acid diethylamide (LSD) and 3,4-Methylenedioxymethamphetamine (MDMA) are widely used psychoactive drugs and their potential use in psychiatric medicine is currently generating interest. The mechanism by which these drugs may assist recovery in addiction, mood disorders and post-traumatic stress disorder (PTSD) is still not well understood. Most investigations of the effects of these drugs on brain activity have focussed on cortical resting-state networks, however the striatum is a key reward and motivation hub of the brain and aberrant striatal processing may be part of the pathophysiology of these disorders. Consequently, we investigated striatal connectivity following acute MDMA and LSD administration. MethodResting-state fMRI (rs-fMRI) data were acquired, and seed-voxel functional connectivity analyses were used with the striatum subdivided into three seed regions: the associative, limbic, and sensorimotor striatum. Within-network connectivity was measured using group mean network maps and whole-brain connectivity (seed-to-voxel) was also examined. ResultsNeither MDMA nor LSD significantly changed within-network connectivity of any of the three striatal seed regions. However, striatal connectivity with other brain regions was significantly altered with both MDMA and LSD. Most notably, MDMA reduced connectivity between the limbic striatum and the amygdala, while LSD increased connectivity between the associative striatum and the frontal, sensorimotor, and visual cortices. ConclusionChanges in connectivity were mostly observed outside the standard striatal networks, consistent with previous findings that psychedelics reduce network modularity or between-network segregation and increase connectivity across standard networks.

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bioRxiv2024

The relationship between brain activation and mitochondrial complex I protein levels during cognitive function in healthy humans: an BCPP-EF PET and functional MRI study of task switching

Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be non-invasively measured using [18F]BCPP-EF positron emission tomography (PET). Neurological conditions associated with mitochondria complex I pathology are also associated with altered blood oxygen level dependent (BOLD) response and impairments in cognition. To evaluate the link between mitochondrial complex I, cognition and associated neural activity, 23 cognitively healthy adults underwent a [18F]BCPP-EF PET scan and a functional magnetic resonance imaging (fMRI) scan during which they performed a task switching exercise. We found significant positive associations between [18F]BCPP-EF volume of distribution (VT), which measures mitochondrial complex I levels and the task switching fMRI response (Partial Least Squares (PLS) Canonical Analysis (CA), first component r=0.51, p=0.03). Exploratory Pearsons correlations showed significant positive associations between mitochondrial complex I levels and the fMRI response in regions including the dorsolateral prefrontal cortex (r=0.61, p=0.0019), insula (r=0.46, p=0.0264) parietal-precuneus (r=0.51, p=0.0139) and anterior cingulate cortex (r=0.45, p=0.0293). Mitochondrial complex I levels across task-relevant regions were also predictive of task switching accuracy (PLS-Regression (PLS-R), R2=0.48, RMSE=0.154, p=0.011) and of switch cost (PLS-R, R^2=0.38, RMSE=0.07, p=0.048). Our findings suggest that higher mitochondrial complex I levels may underlie an individuals ability to exhibit a stronger BOLD response during task switching and are predictive of better task switching performance. This provides the first evidence linking the BOLD response with mitochondrial complex I and suggests a possible biological mechanism for aberrant BOLD response in conditions associated with mitochondrial complex I dysfunction, that should be tested in future studies.

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bioRxiv2024

Spontaneous brain activity and synaptic density in schizophrenia: a combined UCB-J PET and fMRI study

Schizophrenia is associated with altered Amplitude of Low Frequency Fluctuations (ALFF), a functional Magnetic Resonance Imaging (fMRI) measure of spontaneous brain activity at rest. ALFF in healthy controls has been linked with presynaptic density levels measured by [11C]UCB-J positron emission tomography (PET). Given the growing body of evidence for low presynaptic density levels in schizophrenia, we set out to test if altered [11C]UCB-J binding may be associated with changes in ALFF in schizophrenia, and secondly to test whether the relationships between ALFF and [11C]UCB-J binding differ at the group level. Subjects with schizophrenia had higher ALFF in the medial prefrontal cortex and other regions, in line with published meta-analyses. In control subjects, there was a significant positive relationship between [11C]UCB-J distribution volume ratio (DVRcs) and ALFF in the medial prefrontal cortex (r=0.54, p=0.0365, n=16), but not in subjects with schizophrenia (r=-0.14, p=0.5564, n=22); r-coefficients significantly differed between groups (Zobserved=2.07, p=0.019). At the whole brain level, there were significant positive correlations between [11C]UCB-J DVRcs and ALFF in control subjects in the putamen, insular cortex, precentral gyrus and occipital regions, while in the schizophrenia group, there were significant positive correlations in the bilateral dorsolateral prefrontal cortex and negative correlations in the cuneus, parietal lobule and supramarginal gurus. Correlation coefficients were significantly different between groups across all cortical and subcortical regions with both higher and lower correlation coefficients in the control group. Our results suggest a link between spontaneous brain activity and presynaptic density in control subjects and that this relationship may be disrupted in schizophrenia patients, despite higher ALFF in this group, indicating altered neurobiological mechanisms. Widespread significant differences in ALFF-[11C]UCB-J DVRcs correlation coefficients between controls and schizophrenia subjects highlight the complexity of synaptic dysfunction in schizophrenia and underscore the need for further research to explore the underlying biological mechanisms.

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bioRxiv2022

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

Cannabis use is highly prevalent in adolescents however little is known about its effects on adolescent brain function. Resting-state functional Magnetic Resonance Imaging was used in matched groups of cannabis users (N=70, 35 adolescents16-17 years old, 35 adults 26-29 years old) and non-users (N=70, 35 adolescents/35 adults). Pre-registered analyses examined the connectivity of seven major cortical and sub-cortical brain networks (default mode network, executive control network, salience network, hippocampal network, and three striatal networks) using seed-based analysis methods with cross-sectional comparisons between user groups, and age groups. Cannabis users (across both age-groups), relative to controls, showed localised increases in connectivity only in the executive control network analysis. All networks showed localised connectivity differences based on age group, with the adolescents generally showing weaker connectivity than adults; consistent with developmental effects. Mean connectivity across entire network regions of interest (ROIs) was also significantly decreased in the executive control network in adolescents. However, there were no significant interactions found between age-group and user-group in any of the seed-based or ROI analyses. There were also no associations found between cannabis use frequency and any of the derived connectivity measures. Chronic cannabis use is associated with changes to connectivity of the executive control network, which may reflect allostatic or compensatory changes in response to regular cannabis intoxication. However, these associations were not significantly different in adolescents compared to adults.

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bioRxiv2022

Increased low-frequency brain responses to music after psilocybin therapy for depression

Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following psychedelic therapy. Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of the second of two psilocybin dosing sessions. Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Somewhat consistently, voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions. These data suggest a specific effect of PT on the brains response to a hedonic stimulus (music), implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.

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bioRxiv2020

The acute effects of cannabidiol on emotional processing and anxiety: a neurocognitive imaging study

BackgroundThere is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally-induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. We therefore sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety. MethodsWe conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during fMRI) and cognitive (emotional appraisal) measures as well as subjective response to experimentally-induced anxiety. ResultsCBD did not produce effects on BOLD responses to emotional faces, cognitive measures of emotional processing, or modulate experimentally-induced anxiety, relative to placebo. ConclusionsGiven the rising popularity of CBD for its putative medical benefits, further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.

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bioRxiv2020

Individual and combined effects of Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) on striato-cortical connectivity in the human brain

Cannabidiol (CBD) and {Delta}9-tetrahydrocannabinol (THC) are two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have somewhat opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Across two placebo-controlled, double-blind studies, we examine the effects of THC, CBD, and THC+CBD on the functional connectivity of striatal sub-divisions (associative, limbic, and sensorimotor) using resting-state functional Magnetic Resonance Imaging (fMRI) and seed-based functional connectivity analyses. Study 1 (N=17; inhaled 8mg THC, 8mg THC+10mg CBD, placebo) showed strong disruptive effects of both THC and THC+CBD conditions on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum, which was alleviated in the THC+CBD condition such that it did not differ from placebo. In Study 2 (N=23, oral 600mg CBD, placebo) CBD increased connectivity in the associative network, but relatively minor decreases/disruptions were found in the limbic and sensorimotor. In conclusion, THC strongly disrupts striato-cortical networks, and this effect is selectively mitigated in the limbic striatum when co-administered with CBD. When administered alone, 600mg oral CBD has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis related disorders, and the development of cannabinoid therapeutics.

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bioRxiv2017

A short, robust brain activation control task optimised for pharmacological fMRI studies

Functional magnetic resonance imaging (fMRI) is a popular method for examining pharmacological effects on the brain; however the BOLD response is an indirect measure of neural activity, and as such is vulnerable to confounding effects of pharmacological probes. Controlling for such non-specific effects in pharmacological fMRI studies is therefore an important consideration. We have developed two variants of a standardized control task that are short (5 minutes duration) simple (for both the subject and experimenter), widely applicable, and yield a number of readouts in a spatially diverse set of brain networks. The tasks consist of four functionally discreet three-second trial types (plus additional null trials) and contain visual, auditory, motor and cognitive (eye-movements, and working memory tasks in the two task variants) stimuli. Performance of the tasks was assessed in a group of 15 subjects scanned on two separate occasions, with test-retest reliability explicitly assessed using intra-class correlation coefficients. Both tasks produced robust patterns of brain activation in the expected brain regions, and reliability coefficients for the tasks were generally high, with four out of eight task conditions rated as excellent, and only one out of eight rated as poor. Voxel-wise reliability measures also showed good spatial concordances with the brain activation results. Either of the two task variants would be suitable for use as a control task in future pharmacological fMRI studies or for any situation where a short, reliable, basic task paradigm is required. Stimulus code is available online for re-use by the scientific community.

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bioRxiv2017

Effects of LSD on music-evoked brain activity

Music is a highly dynamic stimulus, and consists of distinct acoustic features, such as pitch, rhythm and timbre. Neuroimaging studies highlight a hierarchy of brain networks involved in music perception. Psychedelic drugs such as lysergic acid diethylamide (LSD) temporary disintegrate the normal hierarchy of brain functioning, and produce profound subjective effects, including enhanced music-evoked emotion. The primary objective of this study was to investigate the acute effects of LSD on music-evoked brain-activity under naturalistic music listening conditions. 16 healthy participants were enrolled in magnetic resonance imaging (fMRI) while listening to a 7-minute music piece under eyes-closed conditions on two separate visits (LSD (75 mcg) and placebo). Dynamic time courses for acoustic features were extracted from the music excerpts, and were entered into subject-level fMRI analyses as regressors of interest. Differences between conditions were assessed at group level subsequently, and were related to changes in music-evoked emotions via correlation analyses. Psycho-physiological interactions (PPIs) were carried out to further interrogate underlying music-specific changes in functional connectivity under LSD. Results showed pronounced cortical and subcortical changes in music-evoked brain activity under LSD. Most notable changes in brain activity and connectivity were associated with the component timbral complexity, representing the complexity of the musics spectral distribution, and these occurred in brain networks previously identified for music-perception and music-evoked emotion, and showed an association with enhanced music-evoked feelings of wonder under LSD. The findings shed light on how the brain processes music under LSD, and provide a neurobiological basis for the usefulness of music in psychedelic therapy.

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bioRxiv2017

The effect of smoking on the brain revealed by using electronic cigarettes with concurrent fMRI

Cigarette addiction is driven partly by the physiological effects of nicotine, but also by the distinctive sensory and behavioural aspects of smoking, and understanding the neural effects of such processes is vital. There are many practical difficulties associated with subjects smoking in the modern neuroscientific laboratory environment, however electronic cigarettes obviate many of these issues, and provide a close simulation of smoking tobacco cigarettes. We have examined the neural effects of smoking electronic cigarettes with concurrent functional Magnetic Resonance Imaging (fMRI). The results demonstrate the feasibility of using these devices in the MRI environment, and show brain activation in a network of cortical (motor cortex, insula, cingulate, amygdala) and sub-cortical (putamen, thalamus, globus pallidus, cerebellum) regions. Concomitant relative deactivations were seen in the ventral striatum and orbitofrontal cortex. These results reveal the brain processes involved in (simulated) smoking for the first time, and validate a novel approach to the study of smoking, and addiction more generally.

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