title: 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.
authors.affiliation: Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Adina S
authors.initials: AS
authors.lastname: Fischer
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Whitfield-Gabrieli
authors.affiliation: Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Roth
authors.affiliation: Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Brunette
authors.affiliation: Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Electronic address: Alan.I.Green@dartmouth.edu.
authors.forename: Alan I
authors.initials: AI
authors.lastname: Green
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D001931:Brain Mapping; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D002188:Cannabis / Q000009:adverse effects; D013759:Dronabinol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008385:Marijuana Smoking / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D010865:Pilot Projects; D012146:Rest; D012201:Reward; D012559:Schizophrenia / Q000150:complications* / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000150:complications* / Q000503:physiopathology*
chemical_list: D063386:Cannabinoid Receptor Agonists; D013759:Dronabinol
keywords: Brain reward circuitry; Cannabis use disorder; Nucleus accumbens; Resting state functional connectivity; Schizophrenia; fMRI