Fig. 4: Neuroreceptor-based framework identifies the neuroreceptors and transporters mediating the effects of LSD and Modafinil.

A Schematic representation of the transition between brain states. (i) The neuroreceptor drive network, D_pre, (ii) dictates the extent to which individual neurochemicals acting through their receptors contribute to (iii) brain activity. (iv) The transition between brain states, such as before to after administration of a neuropharmacological agent, is mediated by a modulation network, M, that shifts the drive network from D_pre to D_post. (v) M can be determined by taking the inner product between the inverse of D_pre and D_post. Critically, all diagonal elements in the neuroreceptor drive networks are set to zero. Panel A is only for illustrative purposes and formal analyses are shown in panels B–J. B–G Mechanism of action of LSD. B Group-level neuroreceptor drive network after placebo administration, estimated from the drive values from each of the 19 neuroreceptors and transporters using Pearson correlation. Group-level neuroreceptor drive network is estimated by averaging the neuroreceptor drive network across participants. The network is organized according to the module organization identified in the HCP dataset. C Same as panel B, but after administration of LSD. D Differences between the LSD and placebo drive networks, assessed using paired samples t-tests. Correlation values were Fisher z-transformed prior to statistical testing. The top half of the network shows statistically significant changes (P < 0.05, FDR corrected), while the bottom half illustrates the magnitude of all pairwise changes. E Changes in drive network connectivity within and between (Btwn) modules, evaluated using a one-sample t-test to determine significant deviations from zero. Error bars show mean ± sem. F Group-level modulation network driving the shifts in brain activity from the placebo to the LSD-induced brain state. The modulation network is estimated by taking the inner product between the inverse of the Placebo (panel B) and the LSD Neuroreceptor drive network (panel C). G The first principal component of the modulation network determines the extent of modulation induced by each neuroreceptor and transporter in driving the transition from the placebo to LSD state. H–J Mechanism of action of Modafinil. Same as panels D, E, and G, but for Modafinil. **P < 0.01; *P < 0.05.