Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.
Flora Moujaes, Jie Lisa Ji, Masih Rahmati, Joshua B Burt, Charles Schleifer, Brendan D Adkinson, Aleksandar Savič, Nicole Santamauro, Zailyn Tamayo, Caroline Diehl, Antonija Kolobaric, Morgan Flynn, Nathalie Rieser, Clara Fonteneau, Terry Camarro, Junqian Xu, Youngsun Cho, Grega Repovš, Sarah K Fineberg, Peter T Morgan, Erich Seifritz, Franz X Vollenweider, John H Krystal, John D Murray, Katrin H Preller, Alan Anticevic
eLife April 17, 2024 DOI: 10.7554/eLife.84173 via PubMed
Summary
AI-generated from the abstractKetamine is a promising treatment for treatment-resistant depression, but why people respond differently is poorly understood. In a single-blind placebo-controlled study, 40 healthy participants received acute ketamine. Using data-driven global brain connectivity, the neural and behavioral effects of ketamine were found to be multi-dimensional, reflecting robust inter-individual variability. Ketamine's principal neural gradient matched somatostatin and parvalbumin cortical gene expression patterns, while the mean effect did not. Behavioral symptom variation mapped onto distinct neural gradients resolvable at the single-subject level. These results highlight the importance of individual variation for developing precise pharmacological biomarkers in psychiatry.
Study at a glance
| Characteristics | Single-blind placebo-controlled study Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | Healthy participants |
| Intervention | Ketamine |
| Dose | initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr |
| Topics | Ketamine |
| Keywords | Data reduction FMRI Gene expression Human Inter-individual variation |
| Citations | 23 |
| Registration | NCT03842800 |
| Key finding | Ketamine's neural and behavioral effects are multi-dimensional and show robust inter-individual variability, with the principal neural gradient matching somatostatin and parvalbumin gene expression patterns. |
Abstract
Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). NCT03842800.