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LOWER POSTERIOR CINGULATE CORTEX GLUTATHIONE LEVELS IN OBSESSIVE-COMPULSIVE DISORDER.

ABSTRACT: Several lines of evidence support the hypothesis that lower cerebral levels of glutathione (GSH), associated with increased oxidative stress, may contribute to obsessive-compulsive disorder (OCD). However, no studies to date have investigated brain GSH levels in individuals with OCD.Twenty-nine individuals with OCD and 25 age-, sex-, and race-matched comparison individuals without OCD underwent single voxel 2D J-resolved proton magnetic resonance spectroscopy (MRS) to examine GSH levels in the posterior cingulate cortex (PCC). MRS data were analyzed using LCModel and a simulated basis set. Group metabolite differences referenced to total creatine (Cr), as well as relationships between metabolite ratios and symptom severity as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), were analyzed using linear regression with adjustment for age, sex, and race.One OCD participant failed to produce usable PCC MRS data. We found significantly lower PCC GSH/Cr in OCD participants compared with non-OCD participants (? = -0.027 [95% CI: -0.049 to -5.9 × 10-3]; P = 0.014). PCC GSH/Cr was not significantly associated with total Y-BOCS score in the OCD group (? = 5.7 × 10-4 [95% CI: -4.8 × 10-3 to 5.9 × 10-3]; P = 0.83).Lower PCC GSH/Cr may be indicative of increased oxidative stress secondary to hypermetabolism in this brain region in OCD. Future MRS studies are warranted to investigate GSH levels in other brain regions that comprise the cortico-striato-thalamo-cortical circuit thought to be abnormal in OCD.

SUBMITTER: Brennan BP

PROVIDER: S-EPMC4774044 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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LOWER POSTERIOR CINGULATE CORTEX GLUTATHIONE LEVELS IN OBSESSIVE-COMPULSIVE DISORDER.

Brennan Brian P BP Jensen J Eric JE Perriello Christine C Pope Harrison G HG Jenike Michael A MA Hudson James I JI Rauch Scott L SL Kaufman Marc J MJ

Biological psychiatry. Cognitive neuroscience and neuroimaging 20160201 2

<h4>Background</h4>Several lines of evidence support the hypothesis that lower cerebral levels of glutathione (GSH), associated with increased oxidative stress, may contribute to obsessive-compulsive disorder (OCD). However, no studies to date have investigated brain GSH levels in individuals with OCD.<h4>Methods</h4>Twenty-nine individuals with OCD and 25 age-, sex-, and race-matched comparison individuals without OCD underwent single voxel 2D J-resolved proton magnetic resonance spectroscopy ( ...[more]

PMID: 26949749

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Project description:Background: Recent studies using magnetic resonance spectroscopy (1H-MRS) indicate that patients with obsessive-compulsive disorder (OCD) present abnormal levels of glutamate (Glu) and gamma aminobutyric acid (GABA) in the frontal and striatal regions of the brain. These abnormalities could be related to the hyperactivation observed in cortico-striatal circuits of patients with OCD. However, most of the previous 1H-MRS studies were not capable of differentiating the signal from metabolites that overlap in the spectrum, such as Glu and glutamine (Gln), and referred to the detected signal as the composite measure-Glx (sum of Glu and Gln). In this study, we used a two-dimensional JPRESS 1H-MRS sequence that allows the discrimination of overlapping metabolites by observing the differences in J-coupling, leading to higher accuracy in the quantification of all metabolites. Our objective was to identify possible alterations in the neurometabolism of OCD, focusing on Glu and GABA, which are key neurotransmitters in the brain that could provide insights into the underlying neurochemistry of a putative excitatory/inhibitory imbalance. Secondary analysis was performed including metabolites such as Gln, creatine (Cr), N-acetylaspartate, glutathione, choline, lactate, and myo-inositol. Methods: Fifty-nine patients with OCD and 42 healthy controls (HCs) underwent 3T 1H-MRS in the ventromedial prefrontal cortex (vmPFC, 30 × 25 × 25 mm3). Metabolites were quantified using ProFit (version 2.0) and Cr as a reference. Furthermore, Glu/GABA and Glu/Gln ratios were calculated. Generalized linear models (GLMs) were conducted using each metabolite as a dependent variable and age, sex, and gray matter fraction (fGM) as confounding factors. GLM analysis was also used to test for associations between clinical symptoms and neurometabolites. Results: The GLM analysis indicated lower levels of Glu/Cr in patients with OCD (z = 2.540; p = 0.011). No other comparisons reached significant differences between groups for all the metabolites studied. No associations between metabolites and clinical symptoms were detected. Conclusions: The decreased Glu/Cr concentrations in the vmPFC of patients with OCD indicate a neurochemical imbalance in the excitatory neurotransmission that could be associated with the neurobiology of the disease and may be relevant for the pathophysiology of OCD.

Project description:Importance:Monitoring one's performance is necessary for learning and adaptive behavior; however, heightened performance monitoring is a purported endophenotype of obsessive-compulsive disorder (OCD). The anterior cingulate cortex (ACC), a brain region implicated in the pathogenesis of OCD, is associated with performance monitoring. Whether performance monitoring early in development is an identifiable risk factor for OCD and whether early childhood performance monitoring is associated with later alterations in ACC volume are unknown. Objective:To determine whether an observed indicator of heightened performance monitoring during the preschool age is associated with later onset of OCD and altered dorsal ACC (dACC) volume through adolescence. Design, Setting, and Participants:This longitudinal observational cohort study was performed at an academic medical center as part of the Preschool Depression Study. A sample of 292 children oversampled for depression from September 22, 2003, through May 12, 2005, completed a performance-based observational task during which they received persistent negative evaluation. Blind raters behaviorally coded child performance monitoring. During the next 12 years, children completed annual diagnostic assessments; 133 completed the final behavioral follow-up and 152 contributed 1 to 3 magnetic resonance imaging scans. Follow-up was completed on August 14, 2017. Main Outcomes and Measures:Onset of DSM-5 diagnosis of OCD from baseline to the final behavioral assessment and whole-brain-adjusted dACC volume at the 3 waves of scanning. Results:Among the 292 preschool children who completed the baseline evaluation (51.4% boys; mean [SD] age, 4.5 [0.8] years), when controlling for demographic and clinical indicators, those who exhibited observed heightened performance monitoring were 2 times more likely to develop OCD (n = 35) during the next 12 years (odds ratio, 2.00; 95% CI, 1.06-3.78; P = .03). Multilevel modeling of dACC volume across the 3 scan waves (n = 152) demonstrated that heightened performance monitoring was associated with smaller right dACC volume (intercept estimate, -0.14; SE, 0.07; t = -2.17; P = .03). Conclusions and Relevance:An ecologically valid indicator of performance monitoring in early childhood was associated with onset of OCD and smaller dACC volumes in later childhood and adolescence. Early childhood observed performance monitoring is a readily observed risk factor of OCD that can be identified in preschool-aged children.

Project description:RationalePatients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function.ObjectiveIn this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD.MethodsWe studied OCD patients (n = 18) and controls (n = 18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of a dopamine receptor agonist, pramipexole 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest.ResultsThere were no significant group, drug, or interaction effects in the number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p = 0.089, partial ƞ2 = 0.1). In the imaging results, there was a significant interaction of group by drug (p = 0.013, partial ƞ2 = 0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p = 0.014, partial ƞ2 = 0.26, 1-β error probability = 0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD.ConclusionsOur data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

Dataset Information

LOWER POSTERIOR CINGULATE CORTEX GLUTATHIONE LEVELS IN OBSESSIVE-COMPULSIVE DISORDER.

Publications

LOWER POSTERIOR CINGULATE CORTEX GLUTATHIONE LEVELS IN OBSESSIVE-COMPULSIVE DISORDER.

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