Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: A systematic review of the in vivo proton magnetic resonance spectroscopy findings

Abstract

Objective

To perform systematic analysis of current proton magnetic resonance spectroscopy (¹H MRS) findings in bipolar disorder (BD).

Method

We grouped the ¹H MRS studies documenting data on the metabolites of N-acetylaspartate (NAA), Choline (Cho), myo-inositol (mI), Glutamate (Glu)/Glutamine (Gln) and Creatine (Cr) separately, for each of the euthymic, manic, depressed adult and child/adolescent bipolar patients.

Results

For NAA resonance, 22 studies involving 328 adult bipolar and 349 control subjects were identified. NAA levels were lower in euthymic bipolar patients in the frontal lobe structures and hippocampus. Lithium seems to have an increasing effect on NAA in those brain regions. Available data in children indicates lower NAA levels in euthymic bipolar patients in dorsolateral prefrontal cortex (DLPFC) and cerebellar vermis. Existing data over 25 studies on 366 adult bipolar and 393 control subjects, although inconsistent, may suggest higher Cho/Cr ratios in the basal ganglia (BG) of euthymic bipolar patients. The metabolite mI seems to be increased both in euthymic and manic bipolar children, while most of the available data does not support such alteration in adults. Glu/Gln levels in adult bipolar patients were higher in all mood states compared to controls. Limited data in children supports such an alteration only in the euthymic state.

Conclusion

The studies reviewed in this paper suggest regional abnormalities of NAA, Cho and Glu/Gln in BD, with the DLPFC, prefrontal and anterior cingulate cortices, hippocampus, and BG being specifically implicated. Systematic analysis of ¹H MRS findings so far helps to define future strategies in this field for delineation of actual neurochemical framework in BD.

Introduction

Bipolar disorder (BD) presented by alternating episodes of mania and depression is associated with significant disability in social, marital and occupational functioning. Consequently, according to the World Health Organization, BD is among the 30 leading causes of global burden of disease (Haldane and Frangou, 2004). Type I BD (BDI) is characterized by episodes of mania, whereas hypomanic episodes define type II BD (BDII) (Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV), APA, 1994). Pathophysiological mechanisms underlying expression of BD are yet to be elucidated. Since with magnetic resonance spectroscopy (MRS), neurochemical information of the brain can be obtained in vivo, MRS studies hold considerable promise to illuminate brain mechanisms involved in BD (Glitz et al., 2002). Over the past decade a growing number of proton (¹H) MRS studies investigating the neurochemical basis of BD have been accumulated. However, there have been mixed results from these studies, preventing a conclusion on the direction of alterations expected on individual neurochemicals. Presentation of BD with three different mood states, each with a potentially distinct neurochemical profile, makes interpretation of the findings even more difficult. Thus, a structured documentation of the data obtained via ¹H MRS in BD is needed, first, to understand what has been found on individual neurochemicals and second, to determine the parts of the puzzle that require additional data. The first generation data obtained so far with ¹H MRS served to probe what type of alterations should be expected, in which brain regions and in which mood states. The next generation ¹H MRS studies should be driven by prior hypotheses for certain mood states in involved brain regions.

The ¹H MRS visible neurochemicals studied in this article are described in the following.

N-acetylaspartate (NAA)/N-acetylaspartylglutamate (NAAG): 2.02 ppm: NAA resonance consists predominantly of NAA but also contains smaller contributions from NAAG (Moore and Galloway, 2002). NAA constitutes approximately 3–4% of total brain osmolarity. NAA is synthesized from acetyl coenzyme A and aspartate in neurons by a mitochondrial enzyme (Baslow, 2000). Thus, NAA appears to be sensitive to mitochondrial oxidative phosphorylation (Bertolino et al., 2003). NAA is known to be an acetyl donor for acetyl coenzyme A and lipid biosynthesis such as myelin (Moore and Galloway, 2002). In some neurons a portion of NAA is converted into NAAG from NAA and glutamate (Baslow, 2000). NAA cycles between neurons and oligodendrocytes, among the only cells that contain large amounts of asparto acylase, the NAA catabolic enzyme in the brain. The NAAG appears to undergo a cycle similar to NAA, but with the catabolic enzyme in this case, NAAG peptidase, present on the surface of astrocytes only (Baslow, 2000).

Choline Compounds (Cho): 3.23 ppm: Cho resonance is predominantly composed of phosphorylcholine (PC) and glycerophosphorylcholine (GPC). Therefore, the Cho peak is considered as a potential biomarker for the status of membrane phospholipids metabolism (Moore and Galloway, 2002). Immobile, membrane bound Cho compounds are generally considered MRS invisible; however, phosphatidylcholine has a mobile head group that may be amenable to MR detection. Pathologies marked by membrane breakdown liberate bound Cho moieties into free Cho pool, thus contributing to an increase of this resonance in neurodegenerative states (Moore and Galloway, 2002). Cho peak is notably higher in white matter (Moore and Galloway, 2002).

Myo-inositol (mI): 3.56 ppm: The mI signal represents predominantly mI with minor contributions (< 5%) from glycine and inositol-1-phosphate (Moore and Galloway, 2002). It is a sugar involved in the regulation of neuronal osmolarity, the metabolism of membrane bound phospholipids, and in the phosphoinositide (PI) secondary messenger pathway.

Glutamate (Glu)/Glutamine (Gln)/Gamma-Aminobutyric Acid (GABA): Glu + Gln + GABA: Glutamix (Glx): 2.3 ppm: At low field strength the broad resonance centered at approximately 2.3 ppm contains overlapping resonances arising from Glu, Gln and GABA, which are often indistinguishable (Glx) (Glitz et al., 2002). Since the concentrations of Glu, Gln, and GABA are 9, 6, and 1 mmol/kg brain tissue, respectively, this resonance is often considered as an indicator of glutamatergic neurotransmission (Michael et al., 2003). Sustained elevated levels of glutamate are toxic (Glitz et al., 2002).

Creatine (Cr)/Phosphocreatine (PCr): 3.02 ppm: Cr peak reflects the presence of both Cr and PCr. The equilibrium maintained between Cr and PCr is determined by the cellular demand for the high energy phosphate stored as creatine phosphate (Moore and Galloway, 2002). As its level is considered to be relatively constant, it has often been used as an internal standard for comparison. The gray matter concentration of Cr is greater than the white matter.

This review presents a systematic inspection of the findings so far by addressing the following questions: 1. What are the main regions of interest for ¹H MRS studies in BD? In what anatomical regions have significant results been gained? 2. What was the power of the individual studies to detect the differences observed and what sample sizes should be aimed for in future studies? 3. What metabolites have been missed or under-reported? 4. Is there evidence that metabolic changes parallel the short term clinical status “mood states”? 5. Is there evidence of difference between the bipolar subtypes BDI and BDII in regard to metabolic profiles in the brain? 6. Is there any difference between the childhood and adult presentation of bipolar illness as reflected in the metabolic changes in the brain? 7. Is there evidence that medication changes the measurements within individuals? 8. How can the assumed functions of the metabolites of interest be linked to the pathophysiology of BD? 9. Is the neurochemical profile of the brain different in BD as compared to unipolar depressive disorder? 10. What are the technical implications for future studies?