The functional and structural associations of aberrant microglial activity in major depressive disorder

Jasmine D Cakmak; Linshan Liu; Stefan E Poirier; Betsy Schaefer; Raju Poolacherla; Amer M Burhan; Priyadharshini Sabesan; Keith St Lawrence; Jean Théberge; Justin W Hicks; Elizabeth Finger; Lena Palaniyappan; Udunna C Anazodo

doi:10.1503/jpn.210124

The functional and structural associations of aberrant microglial activity in major depressive disorder

J Psychiatry Neurosci. 2022 Jun 2;47(3):E197-E208. doi: 10.1503/jpn.210124. Print 2022 May-Jun.

Affiliations

¹ From the Department of Neuroscience, Western University, London, Ont. (Cakmak, Schaefer, Sabesan, Palaniyappan); the Robarts Research Institute, Western University, London, Ont. (Cakmak, Palaniyappan); the Lawson Health Research Institute, London, Ont. (Liu, Poirier, Burhan, St. Lawrence, Théberge, Hicks, Finger, Anazodo); the Department of Medical Biophysics, Western University, London, Ont. (Poirier, Sabesan, St. Lawrence, Théberge, Hicks, Anazodo); the London Health Sciences Centre, London, Ont. (Schaefer, Poolacherla, Palaniyappan); the Department of Psychiatry, Western University, London, Ont. (Burhan, Théberge, Palaniyappan); the Department of Psychiatry, University of Toronto, Toronto, Ont. (Burhan); the Ontario Shores Centre for Mental Health Sciences, Whitby, Ont. (Burhan); the Department of Clinical Neurological Sciences, Western University, London, Ont. (Finger); the Department of Anesthesia and Perioperative Medicine, Western University, London, Ont. (Poolacherla).
² From the Department of Neuroscience, Western University, London, Ont. (Cakmak, Schaefer, Sabesan, Palaniyappan); the Robarts Research Institute, Western University, London, Ont. (Cakmak, Palaniyappan); the Lawson Health Research Institute, London, Ont. (Liu, Poirier, Burhan, St. Lawrence, Théberge, Hicks, Finger, Anazodo); the Department of Medical Biophysics, Western University, London, Ont. (Poirier, Sabesan, St. Lawrence, Théberge, Hicks, Anazodo); the London Health Sciences Centre, London, Ont. (Schaefer, Poolacherla, Palaniyappan); the Department of Psychiatry, Western University, London, Ont. (Burhan, Théberge, Palaniyappan); the Department of Psychiatry, University of Toronto, Toronto, Ont. (Burhan); the Ontario Shores Centre for Mental Health Sciences, Whitby, Ont. (Burhan); the Department of Clinical Neurological Sciences, Western University, London, Ont. (Finger); the Department of Anesthesia and Perioperative Medicine, Western University, London, Ont. (Poolacherla) lena.palaniyappan@mcgill.ca.

Abstract

Background: Major depressive disorder (MDD) is a debilitating mental illness that has been linked to increases in markers of inflammation, as well as to changes in brain functional and structural connectivity, particularly between the insula and the subgenual anterior cingulate cortex (sgACC). In this study, we directly related inflammation and dysconnectivity in treatment-resistant MDD by concurrently measuring the following: microglial activity with [¹⁸F]N-2-(fluoroethoxyl)benzyl-N-(4phenoxypyridin-3-yl)acetamide ([¹⁸F]FEPPA) positron emission tomography (PET); the severity of MDD; and functional or structural connectivity among insula or sgACC nodes.

Methods: Twelve patients with treatment-resistant MDD (8 female, 4 male; mean age ± standard deviation 54.9 ± 4.5 years and 23 healthy controls (11 female, 12 male; 60.3 ± 8.5 years) completed a hybrid [¹⁸F]FEPPA PET and MRI acquisition. From these, we extracted relative standardized uptake values for [¹⁸F]FEPPA activity and Pearson r-to-z scores representing functional connectivity from our regions of interest. We extracted diffusion tensor imaging metrics from the cingulum bundle, a key white matter bundle in MDD. We performed regressions to relate microglial activity with functional connectivity, structural connectivity and scores on the 17-item Hamilton Depression Rating Scale.

Results: We found significantly increased [¹⁸F]FEPPA uptake in the left sgACC in patients with treatment-resistant MDD compared to healthy controls. Patients with MDD also had a reduction in connectivity between the sgACC and the insula. The [¹⁸F]FEPPA uptake in the left sgACC was significantly related to functional connectivity with the insula, and to the structural connectivity of the cingulum bundle. [¹⁸F]FEPPA uptake also predicted scores on the Hamilton Depression Rating Scale.Limitations: A relatively small sample size, lack of functional task data and concomitant medication use may have affected our findings.

Conclusion: We present preliminary evidence linking a network-level dysfunction relevant to the pathophysiology of depression and related to increased microglial activity in MDD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Depressive Disorder, Major*
Diffusion Tensor Imaging
Female
Gyrus Cinguli / diagnostic imaging
Humans
Inflammation
Male
Microglia