Detecting neuroplastic effects induced by ketamine in healthy human subjects: a multimodal approach
Claudio Agnorelli, Joseph Peill, Gabriela Sawicka, Danielle Kurtin, Ekaterina Shatalina, Kirran Ahmad, Matthew B Wall, Catarina Rua, Kate Godfrey, Natalie Erl, Graham Searle, Katie Zhou, Brandon Weiss, Andrea Fagiolini, Robin Carhart-Harris, Paul M. Matthews, Eugenii A. Rabiner, David Nutt, David Erritzøe
bioRxiv Preprint Server May 1, 2025 preprint DOI: 10.1101/2025.05.01.651686 via bioRxiv
Summary
AI-generated from the abstractA single psychedelic dose of ketamine (1 mg/kg, intravenous) alters brain chemistry and connectivity in healthy people for at least one to eight days. After the dose, glutamate levels in the anterior cingulate cortex rose significantly. Functional connectivity decreased within high-order networks such as the default mode network, while integration between low- and high-order networks increased. Increases in a PET marker of synaptic plasticity correlated with reduced intrinsic activity in default mode network regions and a diminished influence of the posterior cingulate cortex on global network dynamics. The posterior cingulate cortex appears to be a central hub through which ketamine may reshape brain hierarchies over the long term.
Study at a glance
| Characteristics | Observational cohort |
|---|---|
| Sample size | 11 |
| Population | Healthy human subjects |
| Intervention | Ketamine |
| Dose | 1 mg/kg, intravenous |
| Duration | 1-8 days after a single dose |
| Topics | Ketamine |
| Keywords | Dissociative anesthetic Psychotropic drug Brain research Neurobiology |
| Key finding | Ketamine increases anterior cingulate cortex glutamate levels and alters functional connectivity, with the posterior cingulate cortex acting as a hub for long-term brain network reorganization. |
Abstract
We investigated ketamine’s 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.