Cannabinoid modulation of functional connectivity within regions processing attentional salience

Abstract

There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli.

Figures

Figure 1

Summary results of direct comparison of the effects of delta-9-THC, CBD, and placebo while processing oddball relative to standard stimuli.

Figure 2

(a) Effects of delta-9-THC and CBD on inferior frontal connectivity (brain on the left side of panel; cross-hairs) with parahippocampal gyrus (brain on the right side of panel; cross-hairs) during visual oddball salience processing. The left side of the brain is shown on the left side of the images. (b) The bar graph (mean±SEM) shows that connectivity of the inferior frontal seed cluster with the parahippocampal gyrus (y axis; arbitrary units) in (a) was augmented by delta-9-THC but attenuated by CBD.

Figure 3

(a) Effects of delta-9-THC and CBD on dorsostriatal connectivity (brain on the left side of panel; cross-hairs) with ventral striatum (brain on top half of middle panel; cross-hairs) and inferior frontal gyrus (brain on bottom half of middle panel; cross-hairs) during visual oddball salience processing. The left side of the brain is shown on the left side of the images. (b) The bar graph (mean±SEM) shows that connectivity of the dorsostriatal seed cluster with the ventral striatum (y axis; arbitrary units) in (a) was attenuated by delta-9-THC but augmented by CBD. (c) The bar graph (mean±SEM) shows that connectivity of the dorsostriatal seed cluster with the inferior frontal gyrus (y axis; arbitrary units) in (a) was attenuated by delta-9-THC but augmented by CBD.

Figure 4

(a) Effects of delta-9-THC and CBD on hippocampal connectivity (brain on the left side of panel; cross-hairs) with anterior cingulate/medial prefrontal cortex (brain on top half of middle panel; cross-hairs) and middle frontal gyrus (brain on bottom half of middle panel; cross-hairs) during visual oddball salience processing. The left side of the brain is shown on the left side of the images. (b) The bar graph (mean±SEM) shows that connectivity of the hippocampal seed cluster with the anterior cingulate/medial prefrontal cortex (y axis; arbitrary units) in (a) was augmented by delta-9-THC but attenuated by CBD. (c) The bar graph (mean±SEM) shows that connectivity of the hippocampal seed cluster with the middle frontal gyrus (y axis; arbitrary units) in (a) was augmented by delta-9-THC but attenuated by CBD. (d) Effects of delta-9-THC and CBD on hippocampal connectivity (brain on the left side of panel; cross-hairs) with parahippocampal cortex (brain on the right side of panel; cross-hairs) during visual oddball salience processing. The left side of the brain is shown on the left side of the images. (e) The bar graph (mean±SEM) shows that connectivity of the hippocampal seed cluster with the parahippocampal cortex (y axis; arbitrary units) in (d) was attenuated by delta-9-THC but augmented by CBD.