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J Psychiatry Neurosci. Nov 2005; 30(6): 416–422.
PMCID: PMC1277024

Language: English |

Proton magnetic resonance spectroscopy of the anterior cingulate gyrus, insular cortex and thalamus in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome)

Abstract

Objective

To examine whether patients with schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome [GS]) have specific changes in brain metabolism.

Methods

We applied proton magnetic resonance spectroscopy (1H-MRS) to the anterior cingulate gyrus, insular cortex and thalamus of patients with schizophrenia and GS (n = 15) or without GS (n = 15), all diagnosed with schizophrenia according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and healthy subjects (n = 20).

Results

In the anterior cingulate gyrus, patients with schizophrenia and GS showed significant decreases in N-acetyl aspartate/creatine–phosphocreatinine (NAA/Cr), choline/creatine–phosphocreatinine (Cho/Cr) and myoinositol/ creatine–phosphocreatinine (mI/Cr) ratios compared with healthy subjects and compared with patients with schizophrenia without GS. Patients with schizophrenia without GS also showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects. In the insular cortex, patients with schizophrenia and GS showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects and compared with patients with schizophrenia without GS. Patients with schizophrenia without GS also showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects. In the thalamus, patients with schizophrenia and GS showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects, whereas patients with schizophrenia without GS only showed a significant decrease in ml/Cr compared with healthy subjects.

Conclusions

Our findings suggest that brain metabolism is more severely compromised in the subtype of schizophrenia with GS.

Medical subject headings: anterior cingulate gyrus, Gilbert disease, hyperbilirubinemia, insular cortex, proton magnetic resonance spectroscopy, schizophrenia, thalamus

Abstract

Objectif

Vérifier si les patients souffrant de schizophrénie associée à l'hyperbilirubinémie non conjuguée idiopathique (syndrome de Gilbert [SG]) présentent des changements particuliers dans le métabolisme du cerveau.

Méthodes

Nous avons fait une spectroscopie par résonance magnétique protonique (SRM-1H) du gyrus du cingulum, du cortex de l'insula et du thalamus de patients souffrant de schizophrénie avec SG (n = 15) ou sans SG (n = 15), tous diagnostiqués comme schizophrènes selon le quatrième édition du Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), et de sujets en santé (n = 20).

Résultats

Dans le gyrus du cingulum, les patients souffrant de schizophrénie avec SG ont enregistré des baisses notables des ratios N-acétyle aspartate/créatine acétamide-phosphocréatinine (NAA/Cr), choline/créatine-phosphocréatinine (Cho/Cr) et myoinositole/créatine-phosphocréatinine (mI/Cr) par rapport aux sujets en santé et aux patients souffrant de schizophrénie sans SG. Les patients affectés de schizophrénie sans SG ont aussi affiché des baisses marquées de NAA/Cr, Cho/Cr et mI/Cr comparativement aux sujets en santé. Dans le cortex de l'insula, les patients souffrant de schizophrénie avec SG ont révélé des baisses importantes de NAA/Cr, Cho/Cr et mI/Cr comparativement aux sujets en santé et aux patients souffrant de schizophrénie sans SG. Les patients souffrant de schizophrénie sans SG ont aussi révélé des baisses appréciables de NAA/Cr, Cho/Cr et mI/Cr comparativement aux sujets en santé. Dans le thalamus, les patients atteints de schizophrénie avec SG ont présenté des baisses marquées de NAA/Cr, Cho/Cr et mI/Cr comparativement aux sujets en santé, tandis que les patients souffrant de schizophrénie sans SG ont révélé seulement une baisse importante de mI/Cr comparativement aux sujets en santé.

Conclusions

Nos résultats laissent entendre que le métabolisme du cerveau est plus fortement atteint dans le sous-type de la schizophrénie avec SG.

Introduction

Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome [GS]) is a relatively common congenital hyperbilirubinemia that occurs in 3%–7% of the world's population.1 In Japan, the prevalence of this syndrome is 2.4% (3.3% in men, 1.6% in women) in the general healthy population.2 Since the condition was first described in 1901,3 it has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis and the plasma concentration of conjugated bilirubin is normal. This apparently benign, but chronic, disorder encompasses a heterogeneous group of biochemical defects. The precise mode of inheritance is still unclear, and this syndrome occurs sporadically in many people.

Recently, it was reported that unconjugated bilirubin may be associated with neurotoxicity in the developing nervous system.4 The evidence linking schizophrenia to neuropathological changes in the brain and to early brain development (the so-called neurodevelopmental hypothesis) consists of an increased frequency of minor physical anomalies and obstetric complications, an increased association with prenatal viral exposure, premorbid cognitive and neuromotor abnormalities, non-progressive morphological deviations in neuroimaging studies, morphometric deviations without gliosis in necropsy studies and cytoarchitectural abnormalities in histological studies.5 The neurodevelopmental hypothesis proposes that schizophrenia results from subtle neuropathological change occurring in utero or early postnatal life. Therefore, we proposed a relation between unconjugated bilirubin and the origin of and vulnerability to schizophrenia.

Individuals with schizophrenia show a significantly higher frequency of hyperbilirubinemia relative to patients with other psychiatric disorders and relative to the general healthy population.6 We also have observed that patients with schizophrenia frequently have an increased bilirubin plasma concentration when admitted to hospital.7,8 Moreover, patients with schizophrenia and GS showed significant enlargement of almost all cerebrospinal fluid spaces on brain computed tomographic study, compared with both patients with schizophrenia without GS and compared with healthy controls.9 Those findings suggest that there are significant anatomical differences between patients with schizophrenia and GS and those patients with schizophrenia without GS. Dalman and Cullberg reported that neonatal hyperbilirubinemia might be a vulnerability factor for mental disorder.10 Further, from the viewpoint of the heterogeneity of schizophrenia, there may be a poorer prognosis for the subtype of schizophrenia with GS.11

Proton magnetic resonance spectroscopy (1H-MRS), a recent development in MR technology, allows biochemical constituents to be directly assayed in vivo. N-acetyl aspartate (NAA), one of the prominent peaks on 1H-MRS, has been reported to exist mainly intraneuronally. A reduction of NAA is considered to reflect a loss of neurons and axons or neural dysfunction, or both.12 Choline (Cho), a marker of the membrane phospholipids, is increased in myelin breakdown. Creatine–phosphocreatine (Cr) is an energy marker of cells, and myoinositol (ml), a glial marker, is decreased with glial dysfunction. Patients with schizophrenia have been shown to have lower levels of NAA than healthy subjects.13,14,15,16,17,18,19,20,21,22It was reported that unconjugated bilirubin is toxic to astrocytes and neurons, damaging mitochondria and plasma membranes.23 Therefore, we hypothesized that unconjugated bilirubin would affect some metabolites in the brain. Our previous fluid-attenuated inversion recovery (FLAIR) MR imaging studies have suggested that the hippocampus, amygdala, thalamus, anterior cingulate gyrus, insular cortex and the cerebellar vermis have abnormalities within the brain in patients with schizophrenia and GS.24 Moreover, we previously reported that there are metabolic abnormalities in the hippocampus, the basal ganglia and the cerebellar vermis in schizophrenia with GS using 1H-MRS.22 In this study, in order to confirm this metabolic alteration, we studied levels of NAA, Cho and myoinositol in the anterior cingulate gyrus, insular cortex and thalamus of patients with schizophrenia and GS, because many previous brain imaging studies have suggested that the anterior cingulate gyrus,25 insular cortex26 and thalamus27 are the sites of abnormalities of structure and function in schizophrenia.

Methods

Patients with schizophrenia and GS (n = 15) and those without GS (n = 15), all diagnosed with schizophrenia according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),28 were recruited. They were outpatients or inpatients without acute psychiatric symptoms from the Department of Psychiatry of Shimane University School of Medicine Hospital, Izumo, Japan. Diagnoses were determined by the consensus of 3 senior psychiatrists based on extended interviews and medical chart review. Psychiatric symptoms were rated by a senior psychiatrist (T.M.), blind to the MRS findings and diagnosis (with or without GS), on the same day that the MRS examination was conducted using the Brief Psychiatric Rating Scale (BPRS)29 and the Positive and Negative Syndrome Scale (PANSS).30 The patients were matched with healthy subjects (n = 20) for age and sex. The psychiatric symptoms (BPRS, PANSS) were matched with schizophrenia with GS and without GS. None of the controls had any lifetime history of psychiatric disorders as evaluated by the Diagnostic Interview Schedule,31 organic illness, alcoholism or drug abuse. All the patients were treated with neuroleptic agents: risperidone (n = 7), perospirone (n = 2), quetiapine (n = 2), olanzapine (n = 1) and haloperidol (n = 3) in schizophrenia with GS, and risperidone (n = 6), quetiapine (n = 3), olanzapine (n = 2) and haloperidol (n = 4) in schizophrenia without GS. All subjects were right-handed. The handedness was defined by the Edinburgh inventory.32 After the subjects received a complete description of the study, written informed consent was obtained. All subjects gave informed consent according to institutional guidelines and the recommendations of the Declaration of Helsinki. The study was approved by the Ethical Committee (institutional review board) of Shimane University School of Medicine for the patients and the healthy control subjects.

MRI and spectroscopy were performed on a General Electric (GE) Signa 1.5-T MR Imaging system (GE Medical systems, Milwaukee, Wis.) using a standard head coil. T2-weighted fast spin-echo images were used to obtain sagittal and axial views of the brain (Fig. 1). The mean voxel size studied was 8 mL3 in the left anterior cingulate gyrus, insular cortex and thalamus.33 Imaging parameters were echo time (TE) 4700 ms, TEeffective 102 ms, with echo train length 12, 256 matrix over a 24 cm х 18 cm field of view and 6-mm contiguous slice. 1H-spectra were acquired with PROBE (Proton Brain Exam), the manufacturer's automated MRI protocol,34 using a point-resolved spectroscopy sequence (PRESS) localization (TE 30 ms, repetition time [TR] 1500 ms). Metabolite spectra suppressed by water were obtained with 64 averages and the water signal with 8 averages within each PROBE acquisition. Using the coregistered axial T2-weighted MR images to identify anatomy, an individual 1H-MRS voxel was selected within each of the following structures (in left hemispheres): anterior cingulate gyrus, thalamus and insular cortex.

figure 4FF1
Fig. 1: Voxel placement of the left anterior cingulate gyrus (A), left insular cortex (B) and left thalamus (C) in patients with schizophrenia.

Metabolite concentrations were calculated with the brain-tissue water signal as reference, using methods and analysis protocols similar to those described previously.35 For postprocessing of the MRS data, an automated spectral fitting program was used. This program uses a parametric spectral model with acquisition-specific a priori information, in combination with a wavelet-based, nonparametric characterization of baseline signals. Spectral phasing was also performed automatically. The signals of NAA, Cr and Cho were curve fit, and voxels from the anterior cingulate gyrus, insular cortex and thalamus were manually selected. Absolute integral values for NAA, Cr and Cho were corrected for differential head coil loading by multiplication by the transmitter reference voltage.36,37 The area ratios of each peak were expressed as relative ratio to Cr in each spectrum (Fig. 2). Almost all previous MRS studies reported their data as ratio to Cr rather than as absolute metabolite levels. Therefore, we also used results as ratio to Cr. Voxel placements for spectroscopy and all data analysis were carried out by a trained radiologist who was blind to each subject's diagnosis.

figure 4FF2
Fig. 2: A representative proton magnetic resonance spectroscopy spectrum of a control subject. NAA = N-acetyl aspartate; Cr = creatine; Cho = choline-containing compounds; ml = myoinositol.

All data are expressed as mean (and standard devision [SD]). Analysis of variance (ANOVA) with post-hoc Bonferronis's protected least-significance difference (PLSD) was used to test for group differences in NAA/Cr, Cho/Cr and ml/Cr, mean age, BPRS score, PANSS score, duration of illness and neuroleptic therapy, and mean dosage of neuroleptics. χ2 tests were used for the ratio of sex, subtype of schizophrenia and use of atypical antipsychotics. The level of statistical significance was set at p < 0.05.

Results

The general features of the patients with schizophrenia with and without GS and of healthy controls are shown in Table 1. There were no significant differences in sex, age and dosage of antipsychotics (chlorpromazine equivalents) by χ2 test or ANOVA with post-hoc Bonferroni's PLSD. There were no significant differences in the severity of psychotic symptoms (BPRS and PANSS), duration of illness, duration of drug therapy and use of atypical antipsychotics. In patients with GS, catatonic (n = 8) and hebephrenic (n = 3) were the most common schizophrenic subtypes, whereas in those without GS, paranoid (n = 10) and hebephrenic (n = 3) were common.

Table thumbnail
Table 1

In the anterior cingulate gyrus, patients with schizophrenia and GS showed significant decreases of NAA/Cr (p < 0.001), Cho/Cr (p < 0.001) and ml/Cr (p < 0.001) compared with healthy subjects. Compared with patients with schizophrenia, but without GS, those with GS showed significant decreases of NAA/Cr (p = 0.007), Cho/Cr (p = 0.001) and ml/Cr (p < 0.001) (Table 2. Patients with schizophrenia without GS showed significant decreases of NAA/Cr (p < 0.001), Cho/Cr (p < 0.001) and ml/Cr (p < 0.001) compared with healthy subjects.

Table thumbnail
Table 2

In the insular cortex, patients with schizophrenia with GS showed significant decreases in NAA/Cr (p < 0.001), Cho/Cr (p < 0.001) and ml/Cr (p < 0.001) compared with healthy subjects. Compared with patients with schizophrenia, but without GS, those with GS showed significant decreases in NAA/Cr (p = 0.005), Cho/Cr (p = 0.028) and ml/Cr (p = 0.043) (Table 3). Patients with schizophrenia without GS, compared with healthy subjects, showed significant decreases of NAA/Cr (p < 0.001), Cho/Cr (p < 0.001) and ml/Cr (p < 0.001).

Table thumbnail
Table 3

In the thalamus, patients with schizophrenia with GS showed significant decreases in NAA/Cr (p < 0.001), Cho/Cr (p = 0.001) and ml/Cr (p < 0.001) compared with healthy subjects (Table 4). Compared with patients with schizophrenia without GS, those with GS showed significant decreases of NAA/Cr (p = 0.003), and ml/Cr (p = 0.047). Patients with schizophrenia without GS showed a significant decrease in ml/Cr (p = 0.016) compared with healthy subjects.

Table thumbnail
Table 4

Discussion

Recently, significant differences in some metabolite ratios, including decreases in NAA/Cr and ml/Cr, have been observed between patients with schizophrenia and healthy subjects.13,14,15,16,17,18,22,23 Indeed, in a 1H-MRS study, Omori et al18 showed a reduced level of NAA in the postmortem brain tissues of patients with schizophrenia compared with healthy subjects. These results were consistent with those of a study by Pakkenberg,13 which found a reduction of the total number of neurons in the brain in schizophrenia. Moreover, in a recent 1H-MRS study, abnormalities in the left brain38 were found; therefore, in the present study, we observed the left brain in uniquely right-handed subjects.

We have previously reported that patients with schizophrenia and GS showed higher scores on the positive and general subscales of PANSS than patients without GS, although there were no differences in score on the negative subscales.8,11 In this study, there were no significant differences in the severity of psychotic symptoms (BPRS and PANSS), duration of illness and duration of drug therapy. All the patients were treated with single atypical antipsychotics. It is important to consider the role of antipsychotics on hyperbilirubinemia, and we have reported that most antipsychotics decreased serum unconjugated bilirubin levels.8

Hyperbilirubinemia has been considered to be a risk factor for brain injury. At autopsy it appears as a yellow stain, known as kernicterus. It has been reported that the Gunn rat, which is a model for hyperbilirubinemia, showed brain hypoplasia.39,40 McDonald et al reported the role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat.41 These reports suggest that bilirubin affects brain development or is neurotoxic and may play an important role in brain tissue changes, as seen in the changes shown through 1H-MRS in schizophrenia with GS.22,42

The major finding in this study is that schizophrenia accompanied by GS showed significant decreases of NAA/Cr, Cho/Cr and ml/Cr in the anterior cingulate gyrus and insular cortex. However, because all metabolite ratios are reduced in patients with schizophrenia compared with healthy subjects, we should consider the possibility that our results are consistent with atrophy of brain areas investigated in the patients. In the thalamus, only patients with schizophrenia and GS showed significant decreases of NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects and, compared with patients with schizophrenia without GS, showed significant decreases of only NAA/Cr and ml/Cr. Assuming that NAA is a neuron number or viability marker, or both,12 decreases of NAA/Cr in patients with schizophrenia and GS suggest the effect of unconjugated bilirubin on the structure and/or function of the anterior cingulate gyrus, insular cortex and thalamus. Cho is a marker of the membrane phospholipid state, and decreases of Cho/Cr in patients with schizophrenia and GS suggest the effects of unconjugated bilirubin on the phospholipid state of each region. A decrease in ml/Cr, as a glial marker and/or viability marker, in patients with schizophrenia and GS suggests the effect of unconjugated bilirubin also on the glial structure and/or function of each region. However, this study has limitations in that we reached our conclusions from metabolite ratios rather than absolute concentrations.

Our findings should stimulate further prospective and laboratory studies on hyperbilirubinemia in patients with schizophrenia to evaluate this well-known phenomenon.

Acknowledgments

Part of this work was supported by Grants-in-Aid for Scientific Research on Priority Areas No. 13770544 and 15790622 from the Ministry of Education, Science, Sports and Culture of Japan.

Footnotes

Contributors: Drs. Yasukawa, Miyaoka, Horiguchi and Kitagaki contributed to the conception and design of the study. Drs. Yasukawa, Miyaoka, Mizuno, Inagaki and Oda contributed to the acquisition of data. Drs. Yasukawa and Miyaoka contributed to the analysis and interpretation of the data. Dr. Yasukawa wrote the article. Drs. Miyaoka, Mizuno, Inagaki, Horiguchi, Oda and Kitagaki critically reviewed the article. All authors gave final approval of the article.

Competing interests: None declared.

Correspondence to: Dr. Rei Yasukawa, Department of Psychiatry, Shimane University School of Medicine, 89-1 Enyacho, Izumo 693-8501, Japan; fax 853-20-2260; pj.ca.u-enamihs.dem@ier

Submitted Nov. 16, 2004; Revised Mar. 24, 2005; Accepted May 30, 2005

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