Biology subjects

Ertl, N.

Publications and source records attributed to Ertl, N..

9 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.

neuroscience↗

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↗

bioRxiv2026

Structural and functional MRI signatures of Gambling Disorder: a case-control study

Gambling disorder (GD) is a behavioural addiction that may help identify addiction-related neural features without the direct neurobiological effects of a primary substance of dependence. We examined regional grey matter volume (GMV) and resting-state functional connectivity (rsFC) in the same well-characterised sample. Eighteen men with GD and 21 matched healthy controls underwent high-resolution structural and resting-state functional MRI. GMV was quantified across 214 cortical and subcortical regions, and seed-based rsFC analyses focused on striatal subdivisions and mesocorticolimbic regions. Group differences were evaluated using permutation testing and cluster-corrected mixed-effects modelling. GD was associated with lower GMV in the ventromedial prefrontal cortex, orbitofrontal regions and other cortical and subcortical areas, alongside higher GMV in a subset of limbic and default-mode regions. Participants with GD also showed lower connectivity between the limbic striatum and the hippocampus, thalamus and putamen. In exploratory analyses, somatomotor connectivity was positively associated with gambling severity (Problem Gambling Severity Index: Spearman's rho = 0.71, p = 0.003, false-discovery-rate-adjusted q = 0.016). Structural and functional findings overlapped spatially in regions associated with valuation, memory, reward and habit formation, but regional GMV did not mediate group differences in rsFC. These findings are broadly consistent with corticostriatal models of GD and identify candidate circuit-level differences for independent replication. Larger, more diverse and longitudinal samples are required to establish their reproducibility, temporal direction and clinical relevance.

neuroscience↗

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.

neuroscience↗

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↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗