Functional brain connectomes reflect acute and chronic cannabis use

Abstract

Resting state fMRI has been employed to identify alterations in functional connectivity within or between brain regions following acute and chronic exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive component in cannabis. Most studies focused a priori on a limited number of local brain areas or circuits, without considering the impact of cannabis on whole-brain network organization. The present study attempted to identify changes in the whole-brain human functional connectome as assessed with ultra-high field (7T) resting state scans of cannabis users (N = 26) during placebo and following vaporization of cannabis. Two distinct data-driven methodologies, i.e. network-based statistics (NBS) and connICA, were used to identify changes in functional connectomes associated with acute cannabis intoxication and history of cannabis use. Both methodologies revealed a broad state of hyperconnectivity within the entire range of major brain networks in chronic cannabis users compared to occasional cannabis users, which might be reflective of an adaptive network reorganization following prolonged cannabis exposure. The connICA methodology also extracted a distinct spatial connectivity pattern of hypoconnectivity involving the dorsal attention, limbic, subcortical and cerebellum networks and of hyperconnectivity between the default mode and ventral attention network, that was associated with the feeling of subjective high during THC intoxication. Whole-brain network approaches identified spatial patterns in functional brain connectomes that distinguished acute from chronic cannabis use, and offer an important utility for probing the interplay between short and long-term alterations in functional brain dynamics when progressing from occasional to chronic use of cannabis.

Cannabis Use and Neuroadaptation: A Call for Δ9-Tetrahydrocannabinol Challenge Studies

“…At present, there is no objective assessment that can classify the neurocognitive state in individual cannabis users. Recent studies have suggested, however, that acute THC intoxication as assessed by subjective ratings of “high” produces a reproducible signature change in brain function that can be detected with neuroimaging techniques ( 42 , 68 ). The former study ( 68 ) conducted functional near-infrared spectroscopy (fNIRS) in cannabis users before and after receiving oral THC and placebo and found increased oxygenated hemoglobin concentration (HbO) in the prefrontal cortex of participants with a clinical rating of subjective intoxication.…”

“…Machine learning models using fNIRS time course features and connectivity matrices identified the intoxicated state with 76.4% accuracy ( 68 ). The latter study ( 42 ) used a data-driven independent component methodology to analyze fMRI resting state data to extract a distinct spatial connectivity pattern of hypoconnectivity involving the dorsal attention, limbic, subcortical and cerebellum networks, and of hyperconnectivity between the default mode and ventral attention network, that was associated with the feeling of a subjective “high” during THC intoxication ( 42 ). That same study also revealed a broad state of hyperconnectivity within whole-brain networks in chronic cannabis users compared to occasional cannabis users, which might be reflective of an adaptive network reorganization following prolonged cannabis exposure.…”

“…For example, an acute dose of THC has been found to increase glutamate ( 33 – 35 ) and dopamine ( 36 – 39 ) in the striatum of occasional users, whereas sober chronic cannabis users demonstrate a decrease of glutamate and glutamate-related metabolites ( 19 – 22 ), and lower levels of dopamine release ( 40 , 41 ). Likewise, fMRI studies have repeatedly shown hypoactivation in the mesocorticolimbic circuit during acute THC intoxication ( 32 , 33 , 35 ) in occasional users but hyperactivation in sober, chronic cannabis users ( 12 , 15 – 17 , 26 , 42 ). The intermediate mechanism might be CB1 receptor density that is known to fluctuate with cannabis frequency and represents a neuroadaptive response of the brain to regain homeostasis following sustained and repeated THC exposure ( 31 ).…”

“…Magnetic Resonance Spectroscopy (MRS) has been successfully used to quantify frontal and striatal glutamate concentrations in cannabis users during intoxication and when sober ( 33 , 34 ). fMRI measures of functional connectivity (FC) have provided functional associations within and between neural networks in cannabis users during intoxication ( 33 , 35 , 42 ) and when sober ( 15 – 17 , 42 ), and can be used as an indirect marker of striatal dopamine release during cannabis intoxication ( 33 , 81 ). Positron emission tomography (PET) can be used to determine CB1 receptor density at glutamatergic and GABAergic neurons in the striatum of cannabis users ( 60 , 62 ) and to determine dopamine displacement at D2/D3 receptors as a measure of dopamine transmission during cannabis intoxication ( 36 ).…”

“…With repeated cannabis use, CB1 receptors are downregulated as a neuroadaptive response to CB1 receptor overstimulation ( 60 , 62 ). In chronic users, this leads to reduced striatal dopamine ( 40 , 41 ) and glutamate ( 19 – 22 ), as well as hyperconnectivity within the mesocorticolimbic circuit ( 9 , 42 , 82 ) and neurocognitive dysfunction when sober ( 13 , 24 , 27 , 28 ). In these users, stimulation of CB1 receptors normalizes striatal dopamine and glutamate concentrations, functional connectivity and neurocognitive function during acute THC intoxication ( 35 ).…”