Duncan G.J. Green, HBSc*; Jinhee Kim, PhD*; Stephen J. Kish, PhD; Rachel F. Tyndale, PhD; Matthew N. Hill, PhD; Antonio P. Strafella, MD, PhD; Junchao Tong, PhD; Tina McCluskey, MSc; Duncan J. Westwood, HBSc; Sylvain Houle, MD, PhD; Nancy J. Lobaugh, PhD; Isabelle Boileau, PhD
Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control.
Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest.
Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = −0.38, q = 0.04; dACC: r = –0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05).
Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity.
Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.
*These authors contributed equally to this work.
Submitted Jan. 22, 2020; Revised Jul. 3, 2020; Accepted Sept. 29, 2020.
Affiliations: From the Addiction Imaging Research Group, Toronto, Ont., Canada (Green, Westwood, Boileau); the Human Brain Lab, Toronto, Ont., Canada (Kish, Tong, McCluskey); the Campbell Family Mental Health Research Institute, Ont., Canada (Kim, Tyndale, Strafella, Houle, Lobaugh, Boileau); the Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Kim, Kish, Strafella, Tong, McCluskey, Houle, Lobaugh); the Departments of Psychiatry, Institute of Medical Sciences, University of Toronto, Toronto, Ont., Canada (Kish, Tyndale, Strafella, Houle, Boileau); the Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ont., Canada (Kish, Tyndale); the Institute of Medical Sciences, University of Toronto, Toronto, Ont., Canada (Green, Kish, Houle, Lobaugh, Boileau); the Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy & Psychiatry, University of Calgary, Calgary, Alta., Canada (Hill); the Morton and Gloria Shulman Movement Disorder Unit and E.J. Safra Parkinson Disease Program, Toronto Western Hospital, UHN, University of Toronto, Toronto, Ont., Canada (Strafella); and the Division of Neurology, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Lobaugh).
Funding: This study was supported in part by Canada Foundation for Innovation, the Ontario Ministry of Research and Innovation (S. Houle), The National Institute of Health and National Institute of Drug Abuse (NIH/NIDA R21 DA036024; I. Boileau), Canadian Institutes of Health Research FDN-154294 (R. Tyndale), and a Canada Research Chair in Pharmacogenomics (R. Tyndale).
Competing interests: M. Hill has served on scientific advisory boards for Lundbeck and Sophren Therapeutics. R. Tyndale has consulted for Quinn Emanuel and Ethismos on unrelated topics. No other competing interests declared.
Contributors: R. Tyndale, D. Westwood and I. Boileau designed the study. J. Kim, R. Tyndale, T. McCluskey, D. Westwood and I. Boileau acquired the data, which D. Green, J. Kim, S. Kish, R. Tyndale, M. Hill, A. Strafella, J. Tong, T. McCluskey, N. Lobaugh and I. Boileau analyzed. D. Green, J. Kim, D. Westwood, N. Lobaugh and I. Boileau wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Correspondence to: I. Boileau, Centre for Addiction and Mental Health, 250 College St., Toronto, ON, M5T 1R8; email@example.com