Manipulating brain connectivity with δ⁹-tetrahydrocannabinol: a pharmacological resting state FMRI study.

Klumpers LE, Cole DM, Khalili-Mahani N, Soeter RP, Te Beek ET, Rombouts SA, van Gerven JM

Resting state-functional magnetic resonance imaging (RS-FMRI) is a neuroimaging technique that allows repeated assessments of functional connectivity in resting state. While task-related FMRI is limited to indirectly measured drug effects in areas affected by the task, resting state can show direct CNS effects across all brain networks. Hence, RS-FMRI could be an objective measure for compounds affecting the CNS. Several studies on the effects of cannabinoid receptor type 1 (CB(1))-receptor agonist δ(9)-tetrahydrocannabinol (THC) on task-dependent FMRI have been performed. However, no studies on the effects of cannabinoids on resting state networks using RS-FMRI have been published. Therefore, we investigated the effects of THC on functional brain connectivity using RS-FMRI. Twelve healthy volunteers (9 male, 3 female) inhaled 2, 6 and 6 mg THC or placebo with 90-minute intervals in a randomized, double blind, cross-over trial. Eight RS-FMRI scans of 8 min were obtained per occasion. Subjects rated subjective psychedelic effects on a visual analog scale after each scan, as pharmacodynamic effect measures. Drug-induced effects on functional connectivity were examined using dual regression with FSL software (FMRIB Analysis Group, Oxford). Eight maps of voxel-wise connectivity throughout the entire brain were provided per RS-FMRI series with eight predefined resting-state networks of interest. These maps were used in a mixed effects model group analysis to determine brain regions with a statistically significant drug-by-time interaction. Statistical images were cluster-corrected, and results were Bonferroni-corrected across multiple contrasts. THC administration increased functional connectivity in the sensorimotor network, and was associated with dissociable lateralized connectivity changes in the right and left dorsal visual stream networks. The brain regions showing connectivity changes included the cerebellum and dorsal frontal cortical regions. Clear increases were found for feeling high, external perception, heart rate and cortisol, whereas prolactin decreased. This study shows that THC induces both increases and (to a lesser extent) decreases in functional brain connectivity, mainly in brain regions with high densities of CB(1)-receptors. Some of the involved regions could be functionally related to robust THC-induced CNS-effects that have been found in previous studies (Zuurman et al., 2008), such as postural stability, feeling high and altered time perception.