Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience, Sagnik Bhattacharyya et al., 2015

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Sagnik Bhattacharyya, Irina Falkenberg, Rocio Martin-Santos, Zerrin Atakan1, Jose A Crippa, Vincent Giampietro, Mick Brammer and Philip McGuire

Neuropsychopharmacology, 2015, 40, 1343–1352

2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15



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.


Accumulating evidence suggest that regular cannabis use increases the risk of development of psychotic disorders (Kuepper et al, 2011; Moore et al, 2007). However, the extract of cannabis sativa has many different ingredients (Bhattacharyya et al, 2009a). Delta-9-tetrahydrocannabiol (delta-9-THC), the main psychoactive ingredient, is responsible for inducing transient psychotic and anxiety symptoms (Bhattacharyya et al, 2009a; D’Souza et al, 2004). In contrast, cannabidiol (CBD), another major ingredient may have anxiolytic (Crippa et al, 2009; Fusar-Poli et al, 2009) and antipsychotic-like effects (Zuardi et al, 2009) and may oppose the neural effects of delta-9-THC (Bhattacharyya et al, 2010) and block the psychotogenic (Bhattacharyya et al, 2010; Morgan and Curran, 2008) and cognitive (Morgan et al, 2010a, 2010b) effects of delta-9-THC. We have recently reported that the induction of psychotic symptoms by delta-9-THC may be related to its effects on the striatum and the prefrontal cortex, integral components of a network of brain areas involved in processing of salient information (Bhattacharyya et al, 2012c), consistent with emerging evidence regarding the role of aberrant salience attribution in psychosis (Jensen and Kapur, 2009; Palaniyappan and Liddle, 2012). Furthermore, we showed that CBD and delta-9-THC had opposite effects on the striatum, the hippocampus, and the inferior frontal gyrus,
which are key components of a network of brain areas involved in the processing of salience (Rubia et al, 2007; Strange and Dolan, 2001; Zink et al, 2006). The striatum is engaged when salient stimuli are encountered in an unexpected environmental context, with the level of activation linked to how salient they are (Zink et al, 2006). The hippocampus detects novelty by comparing past and present experience (Kumaran and Maguire, 2006), and is normally engaged when novelty contributes to stimulus
salience. The inferior prefrontal cortex has a central role in the control of both goal-directed and stimulus-related attention (Asplund et al, 2010), and its engagement during a salience detection task may be related to the attentional component of processing a salient stimulus. However, whether delta-9-THC and CBD modulate the integration of these key areas during the processing of salience has not
been examined. To date, only one previous study has examined the effect of delta-9-THC and CBD on the
functional integration of brain regions in the context of an emotional (fear) processing task (Fusar-Poli et al, 2010). The purpose of the present study was to specifically examine whether delta-9-THC and CBD had opposite effects on the functional integration (as indexed by functional connectivity) of areas involved in the processing of salient information, which we have previously shown to be modulated in different directions by these cannabinoids (Bhattacharyya et al, 2012c). Functional connectivity,
defined as temporal correlation between spatially remote neurophysiological events, can be computed from correlations between functional magnetic resonance imaging (fMRI) time series within an activated functional system (Friston, 2011), which however cannot provide estimates of directional influences between brain regions.

We hypothesized that relative to placebo, ingestion of delta-9-THC or CBD would be associated with modulation of the functional connectivity of the striatum, inferior frontal cortex, and hippocampus during a visuo-spatial attention allocation task. These regions were selected as seed clusters for the connectivity analysis on the basis of our previous finding that delta-9-THC and CBD have opposite effects on the blood oxygen level-dependent (BOLD) response in these regions during the oddball salience processing task and that the induction of psychotic symptoms by delta-9-THC was related to its the effect on activation in the striatum (Bhattacharyya et al, 2012c). Furthermore, these regions have been implicated in psychotic disorders such as schizophrenia (Meyer- Lindenberg, 2010; Vita et al, 2006). In particular, psychotic symptoms in schizophrenia have been related to increased dopaminergic activity in the striatum (Guillin et al, 2007) and may be exacerbated by cannabis use (D’Souza et al, 2005). Specifically, in light of the already noted antagonism between these two cannabinoid molecules (Bhattacharyya et al, 2010) and their opposing effect upon psychotic symptoms (Zuardi et al, 2012) we predicted that delta-9- THC and CBD would have an opposite effect on the functional connectivity within these regions. Furthermore, we predicted that the effect of delta-9-THC, but not of CBD, on functional connectivity within these brain regions would be correlated with its effects on performance. As the striatum and the inferior frontal cortex respectively have critical roles in salience attribution and allocation of attentional resources toward salient stimuli (Rubia et al, 2007; Zink et al, 2006), we predicted that such a relationship would exist between the effects of delta-9-THC on task performance and its effects on fronto-striatal connectivity.