Impaired functional connectivity of brain reward circuitry in patients with schizophrenia and cannabis use disorder: Effects of cannabis and THC

Abstract

Cannabis use disorder (CUD) occurs in up to 42% of patients with schizophrenia and substantially worsens disease progression. The basis of CUD in schizophrenia is unclear and available treatments are rarely successful at limiting cannabis use. We have proposed that a dysregulated brain reward circuit (BRC) may underpin cannabis use in these patients. In the present pilot study, we used whole-brain seed-to-voxel resting state functional connectivity (rs-fc) to examine the BRC of patients with schizophrenia and CUD, and to explore the effects of smoked cannabis and orally administered delta-9-tetrahydrocannabinol (THC) on the BRC. 12 patients with schizophrenia and CUD and 12 control subjects each completed two fMRI resting scans, with patients administered either a 3.6% THC cannabis cigarette (n=6) or a 15 mg THC capsule (n=6) prior to their second scan. Results revealed significantly reduced connectivity at baseline in patients relative to controls, with most pronounced hypoconnectivity found between the nucleus accumbens and prefrontal cortical BRC regions (i.e., anterior prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex). Both cannabis and THC administration increased connectivity between these regions, in direct correlation with increases in plasma THC levels. This study is the first to investigate interregional connectivity of the BRC and the effects of cannabis and THC on this circuit in patients with schizophrenia and CUD. The findings from this pilot study support the use of rs-fc as a means of measuring the integrity of the BRC and the effects of pharmacologic agents acting on this circuit in patients with schizophrenia and CUD.

Keywords: Brain reward circuitry; Cannabis use disorder; Nucleus accumbens; Resting state functional connectivity; Schizophrenia; fMRI.

Figure 1

Bilateral anatomically defined 6mm source ROIs used in the rs-fc analysis: sagittal; coronal; and axial slices are shown. MNI coordinates of the left NAc: −11, 9, −8; and for the right NAc: 8, 9, −8. Brain images are neurologically oriented.

Figure 2

Brain regions showing significant (p<0.05, FDR corrected) rs-fc to bilateral NAc source ROIs in (a) healthy control subjects and (b) patients with SCZ and CUD. (c) Between group contrast of controls > patients. Left medial, frontal, right medial, ventral views are depicted (left to right). Brain images are neurologically oriented.

Figure 3

Cannabis and THC induced increases in functional connectivity between the NAc and medial prefrontal regions. At baseline, functional connectivity between the NAc and a cluster comprised of the vACC and OFC was significantly reduced in patients with SCZ and CUD as compared to the control group. Subsequent to both cannabis and THC administration, functional connectivity between these regions of the BRC significantly increased, though connectivity remained decreased relative to controls. Error bars indicate standard deviation in Z score measures of NAc-to-MPFC connectivity at T1 and T2 in both patient groups. Functional connectivity values are depicted as z scores. Brain images are neurologically oriented.

Figure 4

Correlation between plasma THC and NAc rs-fc. BRC connectivity following cannabis and THC administration at T2 show a direct correlation with increases in plasma THC. (a) Left lateral and medial, (b) Right lateral and medial, (c) rostral and ventral views are shown as well as (d) bilateral NAc cluster (Peak MNI coordinates 6,16, −10) showing greatest positive correlation with plasma THC levels. Brain images are neurologically oriented.