Δ9‐tetrahydrocannabinol (THC), the main psychoactive substance of cannabis, is a partial agonist of the CB1 receptor (CB1R) and is the main pre‐synaptic target of the modulatory retrograde endocannabinoid signaling (Blithikioti et al, 2019). The effects of CB1R activation affects behavior related to motor, emotions, cognition and addiction. CB1Rs are widely distributed in the nervous system including the cerebellum (Moreno-Ruis, 2019). Cerebellar CB1Rs are found on axons of granule cells, basket, stellate cells and climbing fibers that project to efferent Purkinje cells (Ganesh et al, 2018, Moreno-Ruis, 2109).

The cerebellum receives extensive afferent input from the pontine nuclei, which receive input from prefrontal and association cortices in the cerebrum. Lesions to the posterior cerebellar hemispheres can lead to cerebellar cognitive affective syndrome, which features higher-level deficits beyond motor planning and execution (Ramnani, 2012; Schmahmann, 2004; Stoodley, 2012; Strick et al., 2009).

The cerebellum has been hypothesized to have a single generalizable function (D'Angelo & Casali, 2012; Ito, 2006; Schmahmann, 2004), given its uniform arrangement of neurons. This function is postulated to be modulation, which would extend to different domains based on the variety of functional inputs the cerebellum receives. This theory suggests that the cerebellum could optimize performance by modulating behavior according to context, acting as an oscillation dampener. As an example, the cerebellum may modulate emotional processes by integrating positive and negative affective inputs in the same way that it modulates fine motor control by integrating sensory inputs. Different parts of the cerebellum receive inputs from different parts of the brain, leading to a functional topography within the cerebellum that may reflect compartmentalization of modulatory processes (Stoodley & Schmahmann, 2009).

Specific structures in the posterior cerebellum, such as hemispheric lobule VI and Crus I, are particularly salient as neuromodulators (Moulton et al, 2014). A major conceptual model for addiction is the i-RISA (Impaired Response Inhibition and Salience Attribution) model (Goldstein & Volkow, 2002, 2011, Volkow et al.,2003; Volkow et al., 2010) which consists of four inter-connected circuits relating to memory, reward/saliency, executive control, and motivation/drive. The response to a reward is mediated by the interactions of these four components. With the cerebellum's postulated function as a multimodal modulator of cognition, affect, and aversion, the cerebellum is optimally configured to regulate brain processes directly involved in addiction. This addiction model proposes that the cerebellum plays an influential role in maintaining the homeostatic balance of the four circuits.

In rodents, the neuromodulatory role of the cerebellum on the reward pathway was investigated in one study where mice were assessed for hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward associated pathway. They found that dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (Holloway et al, 2019).

Although the frontal lobes have traditionally been considered the neural substrates of executive function (EF) and decision making, recent studies have suggested that other structures, such as the cerebellum, may be associated with these abilities. Two studies have shown that parts of the cerebellum are involved in decision making (Ding et al, 2017 and Cardoso Cde et al, 2014). The Cardoso study examined subjects from three groups: a group with cerebellar strokes, a second group with frontal lobe damage and a health control group and compared their performance in the IGT. They found that DM ability in those with cerebellar damage was more preserved in those with frontal lobe damage. Examining DM in relatives of suicide completers, Ding et al, (2017) found that healthy controls had greater BOLD activation in two regions of the cerebellum namely the Cerebellar culmen and the vermis when completing the IGT which was not observed in the relatives. Both studies conclude that the cerebellum may play an active role in DM. A study by Habas et al, (2009) exploring cerebellar connectivity with the intrinsic cortical networks such as salience and default mode networks found that the crus I and II, make contributions to parallel cortico-cerebellar loops involved in executive control, salience detection, and episodic memory/self-reflection. Parts of the neocerebellum take part in the executive control network implicated in working memory. Finally, a study by Shiroma et al (2016) examined benign cerebellar tumors and showed that the compression caused by these tumors affects hippocampal memory function.

Reviewing the role of the cerebellum in DM in cannabis users, Blithikioti et al, (2019), found increases in cerebellar gray matter volume after chronic cannabis use, alterations of cerebellar resting state activity after acute or chronic use and deficits in memory, decision making, and associative learning.

Collectively, the evidence suggests that the cerebellum may be intertwined with brain processes related to addiction, such as reward, motivational drive, saliency, inhibitory control, insight (Moulton et al, 2014) and decision making (Ding et al, 2017, Cardoso Cde et al, 2014 and Blithikioti et al, 2019). In addition, DM is intricately involved with the reward system: both are driven by dopamine and there is overlap between them in the neural bases of this aspect of cognition. Understanding this relationship if the key to improving users’ quality of life and clinical management.

The primary question we sought to address was: Do cannabis users show deficits in decision making as shown by several studies? If so, how is this reflected in in functional and structural connectivity? Our first objective, therefore, was to examine scores on the Iowa gambling task which is a standardized test of DM. Next, we used a resting state functional magnetic resonance imaging (rs-fMRI) technique through the application of independent component analysis (ICA) for resting state networks (RSNs) investigation - which is thought to represent inherent brain organization, which in turn influences brain function (Menon and Uddin, 2010). We aimed at testing cortico-cerebellar connectivity to assess the role of the cerebellum in cannabis addiction. We hypothesized that in CU, pre-occupation with cannabis related thoughts would lead to altered total network connectivity in users. Previous resting state studies have shown that the cerebellum contains a variety of functional networks associated with many parts of the neocortex, beyond motor areas. Individuals at risk for a cannabis use disorder showed key differences in cerebellar functional connectivity, with specific impacts on the dorsal attention and default mode networks was shown by Sweigert et al, (2019). Another study showed abnormal connectivity between the bilateral anterior cerebellum and a right caudate/nucleus accumbens striatal cluster in subjects at clinical high risk for psychosis (Osborne et al, 2020). Activation studies have shown that the cerebellum is involved in a variety of functions, even those unassociated with a motor component.

Cortico-cerebellar pseudo bulbar affect: The cortico-cerebellar pseudobulbar affect is a transient mood disorder which causes subjects to have outbursts of laughing and crying that is often inappropriate to the context (Parvizi et al, 2001, 2006, 2009). The pseudobulbar effect was also investigated using rsfMRI in subjects with ALS. They found increased functional connectivity between middle cerebellar peduncles and posterior cingulate cortex and decreased FC between middle cerebellar peduncles and left middle frontal gyrus in patients with PBA compared to patients without PBA (Trojsi et al, 2022). Both studies show the involvement of the cerebellum in the control of emotional expression/ dysregulation via the pons and thalamic nuclei. We hypothesize that a similar effect may be present in subjects who smoke cannabis.

To date, there have been no studies on this aspect of resting state corticocerebellar interactions between young adult CU and non-users.

A third aim was to assess anatomic connectivity in the white matter of cerebrocerebellar networks using diffusion tensor imaging (DTI), to determine if structural connectivity between these regions mirrored functional connectivity. A commonly used metric in DTI studies is fractional anisotropy (FA), which is a measure of white matter connectivity between regions of the brain (Basser and Pierpaoli, 1996). A study by our group (Levar Francis et al, 2018) found that the uncinate fasciculus was shorter in those who smoked cannabis. Only one study by Sweigert et al, (2019) looked at cerebellar structural connectivity in cannabis users. They found group differences in the middle cerebellar peduncle (MCP) and a correlation between the MCP and self-reported craving. In sum, although it is clear that cannabis affects FA, the direction and specificity of these effects is still a matter of debate.

FA alterations are complemented in alterations in cortical volume. In line with this, our fourth approach was to examine cortical volume (CV) in the nodes of corticocerebellar networks that were significantly different between the groups. In regard to the cerebellar volume, the most consistent findings were increases in cerebellar gray matter with chronic use (reviewed in Blithikioti et al, 2019). In sum, it is still unknown whether these are the only regions that show reductions, if some or all of the nodes are altered, and whether they relate to alterations in functional and structural connectivity.

While each of these studies using rsfMRI, DTI, and CT have provided insights into individual aspects of cannabis, there have been no published studies that have integrated all three methods. We used a staged approach that consisted of first examining decision making and then assessing rsfMRI, DTI, and cortical volume analyses. We investigated the following hypotheses: 1. Cannabis users would score significantly lower on the Iowa gambling tasks reflective of impulsive decision making. 2. Using cannabis would adversely affect functional connectivity of the cerebellum. 3. Cannabis users would show altered cerebellar structural connectivity and volume. We also sought to address other questions: 1. Is there a relationship between cerebellar functional connectivity and DM in cannabis users? 2. Are cerebellar functional connectivity, brain volume and structural connectivity correlated in cannabis users?