Ketamine induces multiple individually distinct whole-brain functional connectivity signatures

Moujaes, F.; Ji, J. L.; Rahmati, M.; Burt, J.; Schleifer, C. H.; Adkinson, B.; Savic, A.; Santamauro, N.; Tamayo, Z.; Diehl, C.; Kolobaric, A.; Flynn, M.; Rieser, N. M.; Fonteneau, C.; Camarro, T.; Xu, J.; Cho, Y.; Repovs, G.; Fineberg, S.; Morgan, P.; Seifritz, E.; Vollenweider, F. X.; Krystal, J.; Murray, J. D.; Preller, K. H.; Anticevic, A.

doi:10.1101/2022.11.01.514692

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bioRxiv · 10.1101/2022.11.01.514692

Ketamine induces multiple individually distinct whole-brain functional connectivity signatures

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Abstract

BackgroundKetamine 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 ketamines molecular mechanisms connect to its neural and behavioral effects. MethodsWe conducted a double-blind placebo-controlled study in which 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hour). We quantified resting-state functional connectivity via data-driven global brain connectivity, related it to individual ketamine-induced symptom variation, and compared it to cortical gene expression targets. ResultsWe found that: i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; ii) ketamines data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, implicating the role of SST and PVALB interneurons in ketamines acute effects; and iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. ConclusionsCollectively, these findings support the possibility for developing individually precise pharmacological biomarkers for treatment selection in psychiatry. FundingThis 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); Swiss Neuromatrix Foundation (Grant No. 2016-0111m Grant No. 2015 - 010); Swiss National Science Foundation under the frame-work of Neuron Cofund (Grant No. 01EW1908), Usona Institute (2015 - 2056).

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Moujaes, F., Ji, J. L., Rahmati, M., Burt, J., Schleifer, C. H., Adkinson, B., Savic, A., Santamauro, N., Tamayo, Z., Diehl, C., Kolobaric, A., Flynn, M., Rieser, N. M., Fonteneau, C., Camarro, T., Xu, J., Cho, Y., Repovs, G., Fineberg, S., Morgan, P., Seifritz, E., Vollenweider, F. X., Krystal, J., Murray, J. D., Preller, K. H., Anticevic, A.. 2022-11-01. Ketamine induces multiple individually distinct whole-brain functional connectivity signatures. https://doi.org/10.1101/2022.11.01.514692

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