Neuroimaging meta-analysis of cannabis use studies reveals convergent functional alterations in brain regions supporting cognitive control and reward processing

Abstract

Lagging behind rapid changes to state laws, societal views, and medical practice is the scientific investigation of cannabis's impact on the human brain. While several brain imaging studies have contributed important insight into neurobiological alterations linked with cannabis use, our understanding remains limited. Here, we sought to delineate those brain regions that consistently demonstrate functional alterations among cannabis users versus non-users across neuroimaging studies using the activation likelihood estimation meta-analysis framework. In ancillary analyses, we characterized task-related brain networks that co-activate with cannabis-affected regions using data archived in a large neuroimaging repository, and then determined which psychological processes may be disrupted via functional decoding techniques. When considering convergent alterations among users, decreased activation was observed in the anterior cingulate cortex, which co-activated with frontal, parietal, and limbic areas and was linked with cognitive control processes. Similarly, decreased activation was observed in the dorsolateral prefrontal cortex, which co-activated with frontal and occipital areas and linked with attention-related processes. Conversely, increased activation among users was observed in the striatum, which co-activated with frontal, parietal, and other limbic areas and linked with reward processing. These meta-analytic outcomes indicate that cannabis use is linked with differential, region-specific effects across the brain.

Keywords: Cannabis; activation likelihood estimation (ALE) meta-analysis; anterior cingulate cortex; cognitive control; dorsolateral prefrontal cortex (DL-PFC); functional magnetic resonance imaging (fMRI); marijuana; pain; reward processing; striatum.

Figure 1

Meta-analytic data pipeline. Schematic illustration of the meta-analytic tools employed to identify convergent functional alterations among cannabis users and provide enhanced interpretation of such alterations. Step 1 (literature search): Published papers that reported functional brain alterations among cannabis users relative to non-users were identified. Step 2 (primary meta-analysis): Statistical convergence among reported coordinates was assessed using GingerALE to produce separate maps delineating regions showing decreased activations (users < non-users) and increased activations (users > non-users). Step 3 (connectivity modeling): Using the BrainMap database, MACM was implemented to locate archived neuroimaging experiments that reported co-activations with resultant meta-analytic clusters. Step 4 (functional decoding): Quantitative forward-and reverse-inference analysis techniques were applied to determine which commonly used functional neuroimaging paradigms were associated with cannabis-affected regions. ALE: activation likelihood estimation; MACM: meta-analytic connectivity modeling.

Figure 2

Convergent functional alterations associated with cannabis use. Across studies, cannabis use was associated with differential regional alterations. Specifically, convergent decreases in activity among users were observed in two clusters, one encompassing the cingulate gyrus, anterior cingulate gyrus, and medial frontal gyrus (Cluster 1 (ACC), blue), and a second encompassing the middle frontal gyrus and precentral gyrus (Cluster 2 (DL-PFC), blue). Conversely, convergent increases in activity among users were observed in a single cluster encompassing the caudate, claustrum, putamen, and extending into the insula (Cluster 3 (Striatum), red). ALE maps were computed in Talairach space and thresholded (p_{cluster-corrected} < 0.01; p_voxel-level < 0.001). Labels and numbering correspond with those in Table 2. ACC: anterior cingulate cortex; ALE: activation likelihood estimation; DL-PFC: dorsolateral prefrontal cortex.

Figure 3

MACM of impacted regions. MACM delineated other brain areas showing significant co-activation with resultant meta-analytic clusters impacted by cannabis (yellow) when considering all neuroimaging experiments archived in the BrainMap database. Modeled co-activation maps (p_{cluster-corrected} < 0.01; p_voxel-level < 0.001) were visualized in Talairach space within the MRIcron environment. Cluster 1 (ACC, top row, blue) demonstrated co-activation with the insular cortex, caudate, medial frontal cortex, precuneus, fusiform gyrus, culmen, thalamus, and cingulate cortex. Cluster 2 (DL-PFC, middle row, purple) showed co-activation with the orbitofrontal cortex, fusiform gyrus, and occipital cortex. Cluster 3 (Striatum, bottom row, red) demonstrated co-activation with the insular cortex, frontal cortex, superior parietal lobule, fusiform gyrus, and culmen. See Supplemental Table 1 for coordinates. ACC: anterior cingulate cortex; DL-PFC: dorsolateral prefrontal cortex; MACM: meta-analytic connectivity modeling.

Figure 4

Functional decoding of primary meta-analytic clusters. Reverse-inference analysis characterized psychological processes that were significantly associated with functionally impacted brain regions among cannabis users. Meta-data term associations were visualized using Cytoscape version 3.4.0 (Shannon et al., 2003). Lines between meta-data terms (squares, task classifications) and meta-analytic clusters (circles, impacted brain regions) indicate that the observed probability reached statistical significance. Probabilities next to each line (p_{FDR-corrected} < 0.05) express the likelihood that a specific psychological process is engaged given activation in a specified brain region (P(Process|Activation)), where higher values indicated greater likelihoods. ACC: anterior cingulate cortex; DL-PFC: dorsolateral prefrontal cortex.