N-acetylaspartate reductions in the mediodorsal and anterior thalamus in men with schizophrenia verified by tissue volume corrected proton MRSI

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Abstract

Objective

Deficits in the mediodorsal and anterior nuclei of the thalamus may contribute to the psychopathological symptoms of schizophrenia. These thalamic nuclei have been found to be abnormal in schizophrenia and have close connections with other brain structures implicated in the disorder. We therefore examined schizophrenia-related alterations in brain metabolite levels specifically in the mediodorsal and anterior thalamic subregions.

Method

We used in vivo proton magnetic resonance spectroscopic imaging (1H MRSI) to measure N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine + phosphocreatine (Cr) in the mediodorsal and anterior thalamus in 22 male patients with schizophrenia and 22 male controls. Magnetic resonance imaging (MRI) tissue segmentation and thalamic volume mask techniques were performed to distinguish the thalamus, extrathalamic gray and white matter, and CSF within the spectroscopic voxels.

Results

Compared to healthy subjects, patients with schizophrenia had significantly lower NAA in the mediodorsal and anterior thalamus bilaterally. No significant differences in Cho or Cr levels were seen. NAA was significantly higher in the left thalamus relative to the right in both groups. We found a strong negative correlation between left thalamic NAA and duration of illness, even after partialling out the effect of age. Tissue segmentation and thalamic volume mask techniques detected no group or lateralized differences in tissue type or CSF percentages, demonstrating that the metabolite reductions were not an artifact of spectroscopic voxel heterogeneity.

Conclusions

These findings suggest diminished function and/or structure in the mediodorsal and anterior thalamus in male patients with schizophrenia and support earlier research demonstrating schizophrenia-related abnormalities in the thalamus and its circuitry.

Introduction

Structural and functional neuroimaging studies of the thalamus in schizophrenia have been inconsistent, which most likely reflects the structural and functional heterogeneity of the thalamus. This has prompted investigators to examine specific thalamic subregions such as the anterior and mediodorsal nuclei, which have close connections to the dorsolateral prefrontal cortex and other limbic structures implicated in the pathophysiology of schizophrenia. Postmortem studies have detected significant reductions in neuronal number and volume in the mediodorsal, anteroventral, and anteromedial nuclei of the thalamus in patients with schizophrenia (Popken et al., 2000, Young et al., 2000). Studies of the whole thalamus may obscure schizophrenia-related deficits that are localized to these important thalamic subregions.

For example, many structural magnetic resonance imaging (MRI) investigations have reported lower total thalamic volume in patients with schizophrenia compared to controls (Danos et al., 2003, Gilbert et al., 2001, Staal et al., 1998, Staal et al., 2001, Volz et al., 2000) whereas other neuroimaging (Arciniegas et al., 1999, Bridle et al., 2002) and neuropathological (Cullen et al., 2003) studies have not found such differences. More precisely localized MRI and postmortem investigations have, however, detected significant schizophrenia-related volume deficits in the mediodorsal nucleus in the absence of differences in the volume of the thalamus as a whole (Byne et al., 2001, Byne et al., 2002). In addition, Hazlett et al. (1999) found significant morphological abnormalities in the anterior region of the thalamus despite normal total thalamic volume in patients with schizophrenia. Reduced anterior thalamic area without significant changes in overall thalamic area has also been reported (Buchsbaum et al., 1996).

Similarly, positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies of patients with schizophrenia have shown thalamic metabolism or blood flow to be increased (Andreasen et al., 1997, Rubia et al., 2001) as well as decreased (Braus et al., 2002, Crespo-Facorro et al., 1999). Given that many functional studies take measurements broadly from the center of the thalamus rather than from specific nuclei (see Hazlett et al., 1999), it is not surprising that the results of such studies are contradictory. Diminished thalamic metabolism could result from altered thalamic glutamate receptor expression in the mediodorsal, anterior, and other limbic nuclei (Ibrahim et al., 2000), or from volume and neuronal loss in the mediodorsal nucleus (Byne et al., 2001). Indeed, a recent study combining PET with fMRI found that schizophrenia-related changes in thalamic metabolism varied within the thalamus, with the most pronounced deficits occurring in the area of the mediodorsal nucleus (Hazlett et al., 1999). Two investigations have also reported diminished thalamic metabolism in the anterior region of the thalamus (Buchsbaum et al., 1996, Katz et al., 1996).

In recent years, in vivo proton magnetic resonance spectroscopy (1H MRS) has been used to measure thalamic concentrations of N-acetylaspartate (NAA), an amino acid found in neuronal cell bodies and their dendritic and axonal extensions (Urenjak et al., 1992) and a potential indicator of neuronal integrity. Emerging evidence appears to point to decreased NAA or NAA/creatine (Cr) concentrations in the thalamus in patients with schizophrenia (Auer et al., 2001, Deicken et al., 2000, Ende et al., 2001, Heimberg et al., 1998, Omori et al., 2000). Several authors, however, have found no differences in the thalamic NAA/Cr or NAA of patients with schizophrenia compared to healthy controls (Bertolino et al., 1996, Bertolino et al., 1998, Delamillieure et al., 2000, Hagino et al., 2002, Theberge et al., 2002, Theberge et al., 2003). The heterogeneity of the thalamus may again help to explain such discrepancies, as most spectroscopic research has sampled either the entire thalamus or wide-ranging thalamic regions. Two spectroscopic studies with more localized voxel placement have detected decreased NAA in the mediodorsal region of the thalamus in patients with schizophrenia (Deicken et al., 2000, Ende et al., 2001).

Those two studies did not, however, analyze the tissue content of the 1H MRS voxels. Because metabolite concentrations are not homogenous across tissue types (Noworolski et al., 1999, Wang and Li, 1998), the varying mixtures of gray and white matter within spectroscopic voxels may contribute to the discrepant findings of studies to date. Patients with schizophrenia may also have increased CSF-filled spaces and lack of correction for CSF concentrations may underestimate metabolite levels in this population (see Bustillo et al., 2002). Only one previous spectroscopic investigation of thalamic NAA in schizophrenia applied tissue segmentation methods to account for regional partial volume effects, and that study found genuine NAA reductions in the thalamic voxels of the patient group (Auer et al., 2001). However, thalamic tissue was not identified as a separate tissue category distinct from gray and white matter surrounding the thalamus, making it impossible to determine how the NAA alterations varied with the amount of thalamic tissue within the spectroscopic voxels.

Therefore, this study of male patients with schizophrenia used proton magnetic resonance spectroscopic imaging (1H MRSI) co-registered with MRI tissue segmentation information to obtain NAA, choline (Cho), and Cr concentration estimates specifically in the mediodorsal and anterior thalamus. More importantly, in order to adjust metabolite alterations to the amount of actual thalamic tissue within the spectroscopic voxels, thalamic tissue volume masks were created to allow the MRI tissue segmentation program to differentiate thalamic tissue from the gray and white matter surrounding the thalamus.

Section snippets

Subjects

Twenty-two male patients who met the DSM-IV criteria for schizophrenia (mean ± S.D. age = 34.5 ± 9.4 years) and 22 male comparison subjects (mean ± S.D. age = 36.4 ± 11.3 years) gave written informed consent for study participation after being fully informed of the procedures. The procedures were approved by the University of California, San Francisco, Committee on Human Research. Subjects were recruited from the San Francisco Veterans Affairs Medical Center, outpatient mental health clinics, and the local

Results

The values for NAA, Cho, Cr, MRSI voxel tissue % thalamus, MRSI voxel tissue % extrathalamic WM, and MRSI voxel tissue % extrathalamic GM for the two groups are shown in Table 1. Relative to the comparison subjects, the patients with schizophrenia showed significantly diminished NAA bilaterally. A lateralized asymmetry was seen in both groups, with NAA significantly greater on the left side compared to the right. The asymmetry index was not significantly different between groups (p > 0.05). No

Discussion

Our primary finding of decreased NAA in the mediodorsal and anterior thalamus in patients with schizophrenia is consistent with some (Auer et al., 2001, Deicken et al., 2000, Ende et al., 2001, Heimberg et al., 1998, Omori et al., 2000) but not all (Bertolino et al., 1996, Bertolino et al., 1998, Delamillieure et al., 2000, Hagino et al., 2002, Theberge et al., 2002, Theberge et al., 2003) previous spectroscopic investigations of the thalamus. Explanations for the mixed results of studies to

Acknowledgement

This research was supported by a 1997 Stanley Foundation Research Award.

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