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  • The aim of the present


    The aim of the present study was to investigate the acute effects of THC on resting state Ch 55 neurophysiology, and to examine the impact of COMT genotype on these effects. Thirty-nine healthy volunteers participated in a randomised, placebo-controlled, crossover pharmacological MRI study. Acute effects of THC were assessed on resting state perfusion measured with ASL and on resting state connectivity measured with functional MRI. Consistent with previous neuroimaging studies (Mathew et al., 1997, Mathew et al., 2002, van Hell et al., 2011a), we anticipated increased perfusion after THC administration in the insula and frontal cortex. Given the particular role of COMT in prefrontal dopamine degradation (Chen et al., 2004, Tunbridge et al., 2006), we further hypothesised that COMT genotype would modulate perfusion in the executive network, which includes the dorsolateral prefrontal cortex.
    Experimental procedures This study is part of the Pharmacological Imaging of the Cannabinoid System (PhICS) project, the design and objectives of which are provided in a methodological paper (van Hell et al., 2011b).
    Discussion Our finding of increased perfusion after THC in bilateral insula and medial superior frontal cortex suggests a THC-induced elevation of neural activity in the salience network. This is a brain system with key nodes in the insular and frontal cortices, which plays a central role in the detection of behaviourally relevant stimuli and the initiation of appropriate responses to this salient input (Craig, 2009, Seeley et al., 2007, Sridharan et al., 2008, Uddin, 2015). In this network, the insula appears to be critically involved in the identification of salient information, as indicated by its fundamental role in behaviour that requires engagement of awareness, such as integration of inner body feelings (interoception), self-recognition, time perception, attention, and performance monitoring (Craig, 2009). Activation of the medial frontal cortex may be responsible for the initiation of subsequent behaviours (Craig, 2009, Uddin, 2015). Thus, elevated perfusion in the salience network after THC administration as shown in the current study most likely reflects a THC-induced increase in awareness and anticipation of salient information. This is consistent with the description of typical THC effects, including perceptual alterations, time distortion, and intensification of ordinary experiences such as eating and listening to music (Ashton, 2001, Hall and Degenhardt, 2009). Furthermore, the reported significant correlations between THC effects on perfusion in the insula and subjective measures of perception and relaxation further suggest that recruitment of brain areas within the salience network is involved in the main acute effects of THC. THC administration induced a significant reduction in resting state connectivity between the middle orbital frontal gyrus and precuneus. The middle orbital frontal gyrus (also called lateral orbitofrontal cortex) is thought to be particularly involved in the detection, processing and evaluation of non-rewarding or unpleasant information (Kringelbach and Rolls, 2004, Kringelbach, 2005). The precuneus is a key node in the default mode network, which is a brain system that is involved in conscious processes such as mind-wandering, and which is deactivated during performance of demanding cognitive tasks, thereby contributing to successful goal-directed behaviour (Buckner et al., 2008, Raichle et al., 2001). Reduced connectivity between the middle orbital frontal gyrus and precuneus could result in difficulties in communication between these regions, which may lead to the insufficient integration of negatively valent information in goal-oriented behaviour. Interestingly, this is further supported by studies that showed a significant increase in resting state connectivity between the middle orbital frontal gyrus and important nodes in the default mode network (precuneus and posterior cingulate cortex) in unmedicated patients with major depressive disorder, which was attenuated in patients that received medication (Cheng et al., 2016, Cheng et al., 2018).