A multimodal investigation of cerebellar integrity associated with high‐risk cannabis use

Abstract

With legalization efforts across the United States, cannabis use is becoming increasingly mainstream. Various studies have documented the effects of acute and chronic cannabis use on brain structure and cognitive performance, including within the frontal executive control network, but little attention has been given to the effects on the cerebellum. Recent evidence increasingly points to the role of the cerebellum in various nonmotor networks, and the cerebellum's expression of cannabinoid receptors may pose particular vulnerabilities to the consequences of cannabis use. Using a combined approach of resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the present study aims to assess how cannabis use relates to the cerebellum's intrinsic functional connectivity and underlying white matter structure and whether these properties are associated with craving or severity of cannabis use. Resting-state fMRI and DTI data, as well as self-reports of substance use history, were analyzed from a sample of 26 adults at risk for cannabis use disorder (CUD) and an age-and sex-matched comparison group of 25 cannabis-naïve adults (control). Results demonstrated that individuals at risk for a CUD showed key differences in cerebellar functional connectivity, with specific impacts on the dorsal attention and default mode networks. In addition, group differences in white matter were localized to the middle cerebellar peduncle (MCP), with a relationship between lower MCP diffusivity and higher levels of self-reported craving. These findings lend further support to the cerebellum's role in key cognitive networks and potential consequences for substance use disorders.

Resting state functional connectivity in the default mode network: Relationships between cannabis use, gender, and cognition in adolescents and young adults

“…Contrary to other studies which found weaker connectivity between DMN and cerebellar areas in cannabis users in slightly older samples ( Sweigert et al, 2020 , Wetherill et al, 2015 ), we found that cannabis users demonstrated stronger connectivity between the left PCC and the cerebellum, specifically in the right cerebellum VII/Crus II, left cerebellum Crus I and II, and left cerebellum VIII in our adolescent/young adult sample. Studies have shown intrinsic connectivity between the DMN and Crus I, Crus II, and Lobule IX in healthy controls ( Bernard et al 2012 , Krienen and Buckner, 2009 , Wang et al, 2014 ).…”

Cannabis Affects Cerebellar Volume and Sleep Differently in Men and Women

“…Indeed, studies finding larger cerebellar volumes in cannabis users had very few or no female participants in the cannabis group: Wang et al: 25% female (5F/15M); Cousijn et al: 36% Female (12F/21M); Battistella et al: 0% Female (0F/31M); Wu and Yang: 25% female (5F/15M); Koenders et al: 25% female (5F/15M). Those findings contrast with the results in our 33% Female sample (56F/114M) and those of another related study (50% Female; 13F/13M) that found lower cerebellar microstructural integrity in adults at risk for CUD relative to controls ( 56 ). These findings underscore the importance of including an adequate number of female participants and of investigating sex differences in brain and behavioral outcomes for people with chronic substance use, for such differences appear to be prevalent throughout the addiction endophenotype ( 8 , 74 , 75 ).…”

“…The cerebellum has traditionally been studied for its role in balance and motor coordination (50), nociception (51), and motor cognition (52,53). Brain imaging studies in humans have shown that the cerebellum is sensitive to the acute and chronic effects of cannabis ( 8), including glucose metabolic activity (12, 54), volume, and resting-state activity (13,(55)(56)(57). Postmortem studies have found striking differences in the cerebellar structure of drug abusers relative to controls; one group showed increased autophagy biomarkers in the cerebellum of multi-substance drug abusers (58), while another found signs of neurodegeneration in the cerebellar cortex of people who were dependent on opioids, suggesting that drug addiction can negatively impact cerebellar structure (59).…”

Multimodal MRI data fusion reveals distinct structural, functional and neurochemical correlates of heavy cannabis use

“…60,61 Furthermore, according to fMRI studies, cannabis might modulate signalling pathways and functional connectivity (FC) from cerebellum to other brain regions such as thalamus and cortex. 27,62 These findings together with the present study corroborate the crucial role of cerebellar network in cognitive control of HCU. Second, there is a consistent body of literature supporting temporal lobe alterations underlying HCU.…”

“…In particular, we chose amplitude of low‐frequency fluctuations (ALFF) as primary measures of local intrinsic activity to facilitate comparability with previous research, particularly since several fMRI studies so far have shown abnormal ALFF in both patients with various substance‐use disorders and individuals with psychosis 23–26 . Second, acknowledging putative associations between HCU and demographic, clinical and psychopathological variables, we supposed that distinct measures of cannabis use (particularly life‐time and current use) will be significantly associated with transmodal components in distinct networks subserving executive control and reward networks 27–29 . Finally, we sought to better understand the relationship between HCU‐related brain networks and the underlying molecular features 30,31 .…”