Altered phospholipid and high-energy phosphate metabolism in the basal ganglia and thalamus of severe obsessive compulsive patients with treatment resistance: A phosphorus 31 nuclear magnetic resonance spectroscopy study.
Introduction
Despite heterogeneous results, proton magnetic resonance spectroscopy (1H-MRS) studies have suggested brain biochemical abnormalities (especially for N-AcetylAspartate, choline(Cho), and glutamate) in obsessive compulsive disorder (OCD). It is not yet possible to define the specific metabolic abnormalities in the brain of OCD patients. Our previous study found an increase of Cho and its ratios in the anterior cingulate cortex (ACC), striatum and thalamus, findings suggesting a neural membrane alteration on a large part of the cortico-striato-thalamo-cortical (CSTC) network in OCD(Hatchondo et al., 2017). While possible mechanisms for OCD symptoms have been suggested in animal models and neuropathological findings, they have not been confirmed by MRS studies(Aouizerate et al., 2004)
31P-MRS provides an in vivo assessment of two main pools of high energy phosphates(HEP), adenosine triphosphate(ATP) and phosphocreatine(PCr), as well as inorganic phosphate(Pi). ATP synthesized from adenosine diphosphate(ADP) and Pi in mitochondria is converted to PCr and is shuttled to the cytoplasm. PCr acts as a reservoir for HEP and the transfer of high-energy phosphate groups between ATP and PCr is a reversible reaction catalyzed by creatine kinases(CK) to generate ATP in response to energy demand. The reaction catalyzed by CKs given by is critical for maintaining stable ATP levels which are in turn critical for all energy requiring processes including ion pumping and the modification of the activity state of numerous enzymes. 31P-MRS also assesses differences in cellular membrane expansion and contraction by quantifying phosphocholine[PC], phosphoethanolamine[PE], phosphomonoesters[PMEs] and catabolites of membrane phospholipids with phosphodiesters[PDEs], glycerophosphocholine[GPC], and glycerophosphoethanolamine[GPE]. Because of their degree of mobility, GPE, GPC, PME and PDE can be quantified by time domain processing of the free induction decay, thus allowing a more refined analysis of the phospholipids catabolism/anabolism balance(Stanley, 2002).
Neural membrane integrity is essential to maintain synaptic transmission and therefore appropriate levels of neurotransmitters. In many neurodegenerative diseases (e.g. Alzheimer Disease or Huntington's disease), studies have shown modifications of membrane component balance(phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol)(Nitsch et al., 1992;Pettegrew, Panchalingam, Hamilton, and McClure, 2001) and increased levels of choline, suggesting a link between Cho and neuronal membrane degradation or even neuronal loss(Jenkins, Koroshetz, Beal, and Rosen, 1993;Meyerhoff et al., 1994). More specifically, multiple sclerosis patients exhibited high concentrations of Cho in the active demyelinating plaques(Arnold, Matthews, Francis, O'Connor, and Antel, 1992;Hattingen et al., 2011;Zaaraoui, Audoin, Pelletier, Cozzone, and Ranjeva, 2010a). Numerous studies have provided new insights in psychiatric disorders including bipolar disorders(Du et al., 2018;Shi et al., 2015) and schizophrenia(Haszto, Stanley, Iyengar, and Prasad, 2020;Weber-Fahr et al., 2013;Yuksel et al., 2015), highlighting alterations in both HEP and membrane phospholipids. Until now, no study has used 31P-MRS to explore brain metabolism in OCD.
The aim of our study was to describe and compare brain metabolic changes, and more specifically, phospholipid and high-energy phosphate metabolism, between severe OCD patients and healthy control subjects, using 3T 31P-MRS in basal ganglia and thalamus.
Section snippets
Materials and methods
This prospective, descriptive, transversal, comparative and single-center study was approved by the ethical committee of our Hospital and was performed in accordance with the guidelines of good clinical practice and the ethical standards of the Declaration of Helsinki(1964). All participants were provided with a complete description of the study during individual interview(written and oral information). All had given their written informed consent.
Clinical data
Fifty subjects were initially included. We subsequently excluded 3 OCD patients and 2 healthy controls due to poor MRS spectral quality. Finally, we retained 45 subjects: 23 patients with severe OCD and 22 healthy controls. All patients were taking SSRIs (Paroxetine, Fluoxetine, Sertraline, Escitalopram) and 12 patients were taking benzodiazepines in addition to the antidepressant medication. The demographic characteristics of the subjects are presented in Table 1.
31P-MRS: ocd vs healthy controls
As significant differences
Discussion
To our knowledge, this is the first 31P-MRS study performed on OCD patients. The mean age between OCD patients and controls was statistically different. As a result, we had to correct the data for age in the analysis. This study reveals modifications of phosphorus metabolites between patients with severe OCD and healthy controls in basal ganglia(striatum and thalamus). Significant results were found between the groups involving both bioenergetics and membrane metabolites. We also found
Authors’ contributions
Conceived and designed the experiments: LH, NJ, RG, CG. Performed the experiments: LH, CG, RG. Analyzed data: LH, CG. Statistical Analysis: JNV. Contributed materials/clinical analysis: NJ, LH, SM.
Declaration of Competing Interest
The authors of the paper “Altered phospholipid and high-energy phosphate metabolism in the basal ganglia and Thalamus of severe obsessive compulsive patients with treatment resistance: A phosphorus 31 nuclear magnetic resonance spectroscopy study.” report no potential conflict of interest.
Acknowledgments
We wish to thank Jeffrey Arsham, and Pr Luc Pellerin for the English-editing of this manuscript.
References (47)
- et al.
Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology
Prog. Neurobiol.
(2004) - et al.
The association of myelin oligodendrocyte glycoprotein gene and white matter volume in obsessive-compulsive disorder
J. Affect. Disord.
(2010) - et al.
Characterization of ATP transport into chromaffin granule ghosts. Synergy of ATP and serotonin accumulation in chromaffin granule ghosts
J. Biol. Chem.
(1996) - et al.
A critical review of magnetic resonance spectroscopy studies of obsessive-compulsive disorder
Biol. Psychiatry
(2013) - et al.
Abnormalities in High-Energy Phosphate Metabolism in First-Episode Bipolar Disorder Measured Using 31P-Magnetic Resonance Spectroscopy
Biol. Psychiatry
(2018) - et al.
Regionally distinct alterations in membrane phospholipid metabolism in schizophrenia: a Meta-analysis of Phosphorus Magnetic Resonance Spectroscopy Studies
Biol. Psychiatry Cogn. Neurosci. Neuroimaging
(2020) - et al.
1H magnetic resonance spectroscopy suggests neural membrane alteration in specific regions involved in obsessive-compulsive disorder
Psychiatry Res. Neuroimaging
(2017) - et al.
Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited
Neurosci. Biobehav. Rev.
(2008) - et al.
A Bayesian model of shape and appearance for subcortical brain segmentation
Neuroimage
(2011) - et al.
Brain circuitries of obsessive compulsive disorder: a systematic review and meta-analysis of diffusion tensor imaging studies
Neurosci. Biobehav. Rev.
(2013)