Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder

Abstract

Importance: For a small percentage of obsessive-compulsive disorder (OCD) cases exhibiting additional neuropsychiatric symptoms, it was proposed that neuroinflammation occurs in the basal ganglia as an autoimmune response to infections. However, it is possible that elevated neuroinflammation, inducible by a diverse range of mechanisms, is important throughout the cortico-striato-thalamo-cortical circuit of OCD. Identifying brain inflammation is possible with the recent advance in positron emission tomography (PET) radioligands that bind to the translocator protein (TSPO). Translocator protein density increases when microglia are activated during neuroinflammation and the TSPO distribution volume (VT) is an index of TSPO density.

Objective: To determine whether TSPO VT is elevated in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex in OCD.

Design, setting, and participants: This case-control study was conducted at a tertiary care psychiatric hospital from May 1, 2010, to November 30, 2016. Participants with OCD (n = 20) and age-matched healthy control individuals (n = 20) underwent a fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide PET scan. It is a high-quality second-generation TSPO-binding PET radiotracer. All participants were drug and medication free, nonsmoking, and otherwise healthy.

Main outcomes and measures: The TSPO VT was measured in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex. Compulsions were assessed with the Yale-Brown Obsessive Compulsive Scale.

Results: In the OCD and healthy groups, the mean (SD) ages were 27.4 (7.1) years and 27.6 (6.6) years, respectively, and 11 (55%) and 8 (40%) were women, respectively. In OCD, TSPO VT was significantly elevated in these brain regions (mean, 32%; range, 31%-36% except anterior cingulate cortex, 24%; analysis of variance, effect of diagnosis: P < .001 to P = .004). Slightly lower elevations in TSPO VT (22%-29%) were present in other gray matter regions. The Yale-Brown Obsessive Compulsive Scale measure of distress associated with preventing compulsive behaviors significantly correlated with TSPO VT in the orbitofrontal cortex (uncorrected Pearson correlation r = 0.62; P = .005).

Conclusions and relevance: To our knowledge, this is the first study demonstrating inflammation within the neurocircuitry of OCD. The regional distribution of elevated TSPO VT argues that the autoimmune/neuroinflammatory theories of OCD should extend beyond the basal ganglia to include the cortico-striato-thalamo-cortical circuit. Immunomodulatory therapies should be investigated in adult OCD, rather than solely childhood OCD, particularly in cases with prominent distress when preventing compulsions.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Wilson, Houle, and Meyer have received operating grant funds for other studies from Janssen, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Lundbeck, and SK Life Sciences in the past 5 years. Dr Meyer has been a consultant to Mylan, Lundbeck, Takeda, Teva, and Trius in the past 5 years. None of these companies participated in the design or execution of this study or in the writing of the manuscript. Dr Meyer is an inventor on 4 patents of blood markers to predict brain inflammation and/or to diagnose affective disorders and a dietary supplement to reduce depressed mood in the postpartum period. Dr Meyer is arranging collaborations with nutraceutical companies for the dietary supplement. No other disclosures were reported.

Figures

Figure 1.. Elevated Translocator Protein Distribution Volume in Obsessive-Compulsive Disorder

Translocator protein distribution volume was significantly greater across brain regions assessed in participants with obsessive-compulsive disorder (n = 20) compared with healthy control individuals (n = 20). The single-nucleotide polymorphism rs6971 of the TSPO gene, which influences binding of second-generation translocator protein positron emission tomography radioligands, was included as a nuisance factor in the analyses of variance. Translocator protein distribution volume values represent raw values unadjusted for genotype. For this polymorphism, high-affinity homozygotes are denoted as HAB (high-affinity binding) and heterozygotes are denoted as MAB (mixed-affinity binding). The dark horizontal bars indicate the mean for each group.

Figure 2.. Greater Translocator Protein (TSPO) Distribution Volume (VT) in Orbitofrontal Cortex Is Correlated With Distress Associated With Preventing Compulsive Behaviors

Greater TSPO VT was significantly correlated with greater distress associated with preventing compulsive behaviors as reported on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The single-nucleotide polymorphism rs6971 of the TSPO gene influences binding of second-generation TSPO positron emission tomography radioligands, including fluorine F 18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide. For the purposes of the display, corrected TSPO VT values for genotype are shown. For this, a linear model of TSPO VT = b0+b1*genotype was applied and b1 = 4.158 in the obsessive-compulsive disorder data set. Because the effect of genotype corresponded to a b1 value of 4.158, mixed-affinity binding (MAB) TSPO VT values were raised by 4.158 to visually correct them to high-affinity binding (HAB) TSPO VT values. Note, for this data set, this approach provided visually similar TSPO VT value corrections as are found with the other approach of multiplying TSPO VT from MAB cases by 1.4. For this polymorphism, high-affinity homozygotes are denoted as HAB and heterozygotes are denoted as MAB.