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

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

Risk seeking for losses modulates the functional connectivity of the default mode and left frontoparietal networks in young males

Value-based decision making (VBDM) is a principle that states that humans and other species adapt their behavior according to the dynamic subjective values of the chosen or unchosen options. The neural bases of this process have been extensively investigated using task-based fMRI and lesion studies. However, the growing field of resting-state functional connectivity (RSFC) may shed light on the organization and function of brain connections across different decision-making domains. With this aim, we used independent component analysis to study the brain network dynamics in a large cohort of young males (N = 145) and the relationship of these dynamics with VBDM. Participants completed a battery of behavioral tests that evaluated delay aversion, risk seeking for losses, risk aversion for gains, and loss aversion, followed by an RSFC scan session. We identified a set of large-scale brain networks and conducted our analysis only on the default mode network (DMN) and networks comprising cognitive control, appetitive-driven, and reward-processing regions. Higher risk seeking for losses was associated with increased connectivity between medial temporal regions, frontal regions, and the DMN. Higher risk seeking for losses was also associated with increased coupling between the left frontoparietal network and occipital cortices. These associations illustrate the participation of brain regions involved in prospective thinking, affective decision making, and visual processing in participants who are greater risk-seekers, and they demonstrate the sensitivity of RSFC to detect brain connectivity differences associated with distinct VBDM parameters

Endocannabinoids - at the crossroads between the gut microbiota and host metabolism

Various metabolic disorders are associated with changes in inflammatory tone. Among the latest advances in the metabolism field, the discovery that gut microorganisms have a major role in host metabolism has revealed the possibility of a plethora of associations between gut bacteria and numerous diseases. However, to date, few mechanisms have been clearly established. Accumulating evidence indicates that the endocannabinoid system and related bioactive lipids strongly contribute to several physiological processes and are a characteristic of obesity, type 2 diabetes mellitus and inflammation. In this Review, we briefly define the gut microbiota as well as the endocannabinoid system and associated bioactive lipids. We discuss existing literature regarding interactions between gut microorganisms and the endocannabinoid system, focusing specifically on the triad of adipose tissue, gut bacteria and the endocannabinoid system in the context of obesity and the development of fat mass. We highlight gut-barrier function by discussing the role of specific factors considered to be putative 'gate keepers' or 'gate openers', and their role in the gut microbiota-endocannabinoid system axis. Finally, we briefly discuss data related to the different pharmacological strategies currently used to target the endocannabinoid system, in the context of cardiometabolic disorders and intestinal inflammation