Abstract

Ketamine is a glutamatergic drug with dose-dependent dissociative and anesthetic properties.

At sub-anesthetic dosages, ketamine has been found to produce robust anti-depressant effects, emerging within few hours after single administration, lasting for several days. In the context of plasticity-promoting properties of ketamine highlighted in several pre-clinial studies, it has been proposed that its neuroplastogenic properties mediate the enduring therapeutic effects. To date, direct assessment of such effects in humans have been challenging due to poor specificity of available neuroimaging methods, such as magnetic resonance imaging (MRI). Recently, a novel positron emission tomography (PET) tracer has been developed, [11C]-UCB-J, which allows for in-vivo quantification of the synaptic vesicle 2A (SV2A) protein, ubiquitously expressed in presynaptic vesicle membrane. The tracer posseses outstanding imaging properties and has been validated as a reliable marker of synaptic density, providing an excellent tool for the measure of synaptogenesis in the living human brain. Our study employs a combination of multimodal neuroimaging techniques to assess the structural and functional neuroplastic effects of a single sub-anesthetic ketamine administration in healthy subjects.

Methods
A total of 12 healthy subjects receive a single intravenous ketamine infusion (1 mg/kg). Markers of structural neuroplasticity are measured at baseline and one week following injection with [11C]-UCB-J in combined PET/MRI paradigm. In addition, the visual long-term potentiation (vLTP) paradigm is performed during electroencephalography (EEG) recording to measure functional neuroplasticity one day and one week following ketamine exposure. Also, blood samples are collected for the analysis of plasticity-related markers. Lastly, participants perform the intra-extra dimensional set task to assess cognitive flexibility performance one day and one week after ketamine.

Results
Data collection is currently undergoing at the Centre for Psychedelic Research (Imperial College London). Preliminary results will be presented, coming from the analysis of the first half of the total sample size.

Conclusion
Our multi-modal approach represents a comprehensive assessment of neuroplasticity induced by ketamine in humans, in-vivo. The results obtained will provide novel insight in the characterization of ketamine mechanism of action with important implications for clinical practice.