Neurite Complexity and Plasticity Markers Track Synaptic Vesicle Density in the Living Human Brain: A Multimodal PET-MRI-EEG Study
- 1Imperial College London
Abstract
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.
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BibTeX
@misc{agnorelli2026neurite,
title = {{Neurite Complexity and Plasticity Markers Track Synaptic Vesicle Density in the Living Human Brain: A Multimodal PET-MRI-EEG Study}},
author = {C. Agnorelli and J. Peill and D. L. Kurtin and O. Mallon and G. Sawicka and E. Shatalina and K. Godfrey and R. Murphy and K. Ahmad and L. K. L. Oestreich and R. Sumner and M. Alberti and M. Wall and N. Ertl and G. Searle and M. Clarke and K. Zhou and M. Osugo and U. Sarem and B. Weiss and K. Greenway and S. Jauhar and A. Fagiolini and R. Carhart-Harris and P. M. Matthews and E. Rabiner and D. Nutt and D. Erritzoe},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.758444},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.758444v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Neurite Complexity and Plasticity Markers Track Synaptic Vesicle Density in the Living Human Brain: A Multimodal PET-MRI-EEG Study
AU - C. Agnorelli
AU - J. Peill
AU - D. L. Kurtin
AU - O. Mallon
AU - G. Sawicka
AU - E. Shatalina
AU - K. Godfrey
AU - R. Murphy
AU - K. Ahmad
AU - L. K. L. Oestreich
AU - R. Sumner
AU - M. Alberti
AU - M. Wall
AU - N. Ertl
AU - G. Searle
AU - M. Clarke
AU - K. Zhou
AU - M. Osugo
AU - U. Sarem
AU - B. Weiss
AU - K. Greenway
AU - S. Jauhar
AU - A. Fagiolini
AU - R. Carhart-Harris
AU - P. M. Matthews
AU - E. Rabiner
AU - D. Nutt
AU - D. Erritzoe
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.758444
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.758444v1
AB - 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.
ER -