Investigation of Heschl's gyrus and planum temporale in patients with schizophrenia and bipolar disorder: A proton magnetic resonance spectroscopy study

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Abstract

Background

Superior temporal cortices include brain regions dedicated to auditory processing and several lines of evidence suggest structural and functional abnormalities in both schizophrenia and bipolar disorder within this brain region. However, possible glutamatergic dysfunction within this region has not been investigated in adult patients.

Methods

Thirty patients with schizophrenia (38.67 ± 12.46 years of age), 28 euthymic patients with bipolar I disorder (35.32 ± 9.12 years of age), and 30 age-, gender- and education-matched healthy controls were enrolled. Proton magnetic resonance spectroscopy data were acquired using a 3.0 T Siemens MAGNETOM TIM Trio MR system and single voxel Point REsolved Spectroscopy Sequence (PRESS) in order to quantify brain metabolites within the left and right Heschl's gyrus and planum temporale of superior temporal cortices.

Results

There were significant abnormalities in glutamate (Glu) (F(2,78) = 8.52, p < 0.0001), N-acetyl aspartate (tNAA) (F(2,81) = 5.73, p = 0.005), creatine (tCr) (F(2,83) = 5.91, p = 0.004) and inositol (Ins) (F(2,82) = 8.49, p < 0.0001) concentrations in the left superior temporal cortex. In general, metabolite levels were lower for bipolar disorder patients when compared to healthy participants. Moreover, patients with bipolar disorder exhibited significantly lower tCr and Ins concentrations when compared to schizophrenia patients. In addition, we have found significant correlations between the superior temporal cortex metabolites and clinical measures.

Conclusion

As the left auditory cortices are associated with language and speech, left hemisphere specific abnormalities may have clinical significance. Our findings are suggestive of shared glutamatergic abnormalities in schizophrenia and bipolar disorder.

Introduction

Emil Kraepelin's dichotomous approach to discriminate schizophrenia and bipolar disorder relies on their different clinical courses. However, there has been discrepancy between Kraepelin's approach and studies showing co-aggregation of schizophrenia and bipolar disorder in families as well as shared susceptibility genes (Bramon and Sham, 2001, Craddock and Owen, 2005). The challenge arises due to the presence of overlapping symptoms between schizophrenia and bipolar disorder, but yet the desire for clear diagnostic categorization. Dimensional concepts suggest focusing on symptom domains rather than diagnostic categories (Cuthbert, 2014, Keshavan and Ongur, 2014). These symptom domains in conjunction with biological findings may provide insight for shared and distinct mechanisms underlying the disorders.

Superior temporal cortices host primary, secondary and association auditory cortices and have been implicated in the pathophysiology of schizophrenia. Both postmortem and in vivo measurements have shown reductions in volume, thickness and gray matter content of the superior temporal cortex in schizophrenia (Vita et al., 2012, Modinos et al., 2013). Longitudinal studies report progressive gray matter loss in the superior temporal gyrus and more precisely the Heschl's gyrus and planum temporale with progression to psychosis and development of delusions (Vita et al., 2012). Moreover, left superior temporal cortices have been associated with symptom domains such as auditory hallucinations (Dierks et al., 1999, Jardri et al., 2011, Kuhn and Gallinat, 2012, Modinos et al., 2013, Shinn et al., 2013) and thought disorder (Seese et al., 2011, Shenton et al., 1992) in psychosis. These findings suggest the superior temporal gyrus as a highly relevant location for the neurobiology and development of psychosis (Shenton et al., 1992, Rajarethinam et al., 2000, Takahashi et al., 2006, Seese et al., 2011). On the other hand, two meta-analyses of volumetric studies of superior temporal cortices did not report any significant differences between patients with bipolar disorder and healthy participants (Kempton et al., 2008, Arnone et al., 2009). However, primary and secondary auditory cortices are located in the region and functional studies consistently reported auditory processing disturbances in both schizophrenia (Dierks et al., 1999, Umbricht and Krljes, 2005, Domjan et al., 2012) and bipolar disorder (Hall et al., 2009, Oribe et al., 2010).

Since glutamate is the major excitatory neurotransmitter and since the EEG signal consists of excitatory end synaptic potentials, auditory processing deficits detected in both schizophrenia (Umbricht and Krljes, 2005, Oribe et al., 2010) and bipolar disorder (Hall et al., 2009, Ethridge et al., 2012, Atagun et al., 2014) could potentially be due to glutamatergic dysfunction in the auditory cortices (Javitt, 2009). Glutamate-modulating agents have been found to be efficacious in the treatment of mood disorders both in pre-clinical (Skolnick et al., 2009) and clinical studies (Sanacora et al., 2008, Machado-Vieira et al., 2012). Current psychotomimetics also modulate different components of the glutamatergic system (for reviews: (Machado-Vieira et al., 2012, Sanacora et al., 2008)). Chronic treatment with lamotrigine, valproate or lithium is likely to effect glutamatergic system through a variety of mechanisms (for reviews: (Colla et al., 2009, Gigante et al., 2012, Schifitto et al., 2009, Soeiro-de-Souza et al., 2013, Yatham et al., 2009)). Therefore, the nature and extent of the glutamatergic system abnormalities in patients with schizophrenia and mood disorders require further clarification.

Proton magnetic resonance spectroscopy (1H MRS) is a non-invasive neuroimaging technique that can quantify in vivo neurochemical metabolites, including those related to the glutamatergic system. Glutamatergic neurotransmission is thought to be disturbed in both schizophrenia (Goff and Coyle, 2001, Paz et al., 2008, Javitt, 2009, Javitt, 2010) and bipolar disorder (Sanacora et al., 2008, Machado-Vieira et al., 2012). Moreover, altered glutamatergic metabolites have been reported both in schizophrenia (Brugger et al., 2011, Marsman et al., 2013, Poels et al., 2014a, Poels et al., 2014b) and bipolar disorder (Yildiz-Yesiloglu and Ankerst, 2006, Moore et al., 2007, Yuksel and Ongur, 2010, Ongur et al., 2011). Frontal, anterior cingulate and hippocampal regions are the most frequently studied brain regions and the findings were consistent across these brain regions. Only one study has investigated brain metabolites within the superior temporal gyrus (Seese et al., 2011) and reported a correlation between N-acetyl aspartate (NAA) concentrations and thought disorder in children with schizophrenia. However, to our knowledge, no single 1H MRS study has investigated the superior temporal region and compared the findings in adult patients with schizophrenia and patients with bipolar disorder.

Hence, in this study, we utilized 1H MRS to examine neurometabolic changes within superior temporal cortices of adults with schizophrenia or bipolar disorder. Studies by different research modalities consistently report structural and functional abnormalities of auditory cortices, thus we expected to see abnormalities within the neurochemical profile of this region in schizophrenia and/or bipolar disorder.

Section snippets

Participants and study procedures

Thirty-five stable patients with paranoid schizophrenia (male or female; between ages of 18–59 years old) and 37 euthymic patients with bipolar disorder (male or female; between ages of 20–54 years old) were recruited for the study from the outpatient unit of Ankara Ataturk Training and Education Hospital, Ankara, Turkey. Five of the schizophrenia and 3 of the bipolar patients could not attend the MRI session and hence were excluded. Moreover, 5 of the bipolar patients had bipolar disorder II and

Participant demographics

Thirty remitted patients with paranoid schizophrenia (18 male; average age: 38.7 ± 12.5 years) and 28 euthymic patients with bipolar disorder (13 male; average age: 35.3 ± 9.1 years) and 30 healthy participants (13 male; average age: 32.8 ± 10.7 years) were included in the study. There were no significant differences in any of the demographic variables across the groups (p > 0.05). Age of onset varied between the ages of 10 and 38 years for schizophrenia patients (average age of onset: 22.5 ± 6.4 years), and

Discussion

In this study, we observed decreased Glu concentrations within the left Heschl's gyrus and planum temporale of the superior temporal gyrus of patients with schizophrenia and bipolar disorder when compared to healthy participants. On the other hand, Glu, tNAA, tCr and Ins concentrations of the bipolar disorder group were lower when compared to schizophrenia patients and healthy participants. Moreover, tCr and Ins concentrations in the left superior temporal gyrus of schizophrenia patients were

Limitations

The current study had several limitations. First, our patients were patients with chronic disease and all were medicated. Although there was no statistically significant medication effect, small numbers of patients were taking each individual medication; therefore we cannot exclude medication effects conclusively. It is still possible that some of the metabolites were altered due to medications. Second, at 3 T magnetic field strength, some of the metabolite peaks in the 1H-MRS spectrum cannot be

Conclusion

Overlapping symptoms and intermediate diagnoses suggest that schizophrenia and bipolar disorder are disorders on a continuum. Genome wide association studies have identified shared risk genes in schizophrenia and bipolar disorder involving glutamatergic metabolism and cascades (see review; Coyle, 2006), which are in line with the glutamatergic abnormalities we have observed. Given that neurotransmission and intracellular functions are two major functions of glutamatergic metabolites, future

Role of funding source

The study was funded by the Scientific Research Projects Committee of the Yıldırım Beyazıt University (project #803) and NIMH grants to CMM (MH073998) and to DÖ (MH094594).

Contributions

MİA: Conceptualized and designed the study, prepared the initial protocol, conducted the psychiatric assessments of the participants, acquired the MRI data with support from MR technicians, helped with the statistical analysis, interpreted the data and wrote the manuscript.

EMS: Aided the design of the study, analyzed the MRS data, performed the statistical analysis, prepared figures and tables, helped with interpretation of the data and writing the manuscript.

SSC: Referred patients and helped

Conflict of interest

The author DÖ participated in the Scientific Advisory Board for Lilly Inc. in 2013. Other authors do not report any conflict of interest.

Acknowledgment

MRI scans were conducted at the National Magnetic Resonance Research Center (UMRAM) of the Bilkent University (Ankara, Turkey) with support from the staff led by Prof. Dr. Ergin Atalar. In addition, we also appreciate technical help regarding voxel segmentation provided by Dinesh Deelchand, Dr. Uzay Emir and Dr. Gulin Oz from the Center for Magnetic Resonance Research, Minneapolis, MN, USA.

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