Neurite Complexity and Plasticity Markers Track Synaptic Vesicle Density in the Living Human Brain: A Multimodal PET-MRI-EEG Study
Claudio Agnorelli, Joseph Peill, Danielle Kurtin, Orla Mallon, Gabriela Sawicka, Ekaterina Shatalina, Kate Godfrey, Robin J Murphy, Kirran Ahmad, Lena K L Oestreich, Rachael Sumner, Manfredi Alberti, Matthew B. Wall, Natalie Ertl, Graham Searle, Mica Clarke, Katie Zhou, Martin Osugo, Usman Sarem, Brandon Weiss, Kyle T. Greenway, Sameer Jauhar, Andrea Fagiolini, Robin Carhart-Harris, Paul McMahan Matthews, Eugenii A Rabiner, David Nutt, David Erritzøe
bioRxiv (Cold Spring Harbor Laboratory) October 13, 2026 preprint DOI: 10.64898/2026.10.12.758444 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study with pharmacological challenge |
|---|---|
| Sample size | 18 |
| Population | Healthy volunteers |
| Interventions | Ketamine N |
| Duration | Assessments 1 to 8 days after drug exposure |
| Measures | [11C]-UCBJ PET SV2A binding potential (BPND), NODDI neurite orientation dispersion (ODI), structural weighted degree (SWD), functional weighted degree (FWD), roving mismatch negativity (MMN), visual long-term potentiation (vLTP) |
| Topics | Neuroplasticity |
| Key findings | Synaptic SV2A density measured by PET was coupled with diffusion-MRI neurite orientation dispersion across cortical regions and correlated with EEG measures of repetition suppression (r = 0.61) and long-term potentiation (r = 0.54), but showed no consistent association with resting-state functional connectivity. Ketamine and DMT produced no significant changes in any measure 1 to 8 days after exposure. The authors argue these results validate DWI- and EEG-derived measures as surrogate indices of human synaptic plasticity. |
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.