Focal and lateralized subcortical abnormalities in unipolar major depressive disorder: an automated multivoxel proton magnetic resonance spectroscopy study
Introduction
The basal ganglia mediate important brain processes other than motor function and are increasingly implicated in the pathophysiology of major depressive disorder (MDD). Smaller caudate and putamen volumes have been reported in magnetic resonance imaging (MRI) studies of MDD Husain et al 1991, Krishnan et al 1992, Parashos et al 1998. Functional abnormalities, including reduced cerebral blood flow and metabolism, have also been reported in the caudate nucleus of depressed patients compared with healthy control subjects Baxter et al 1985, Drevets et al 1992. Recent postmortem data confirmed a reduction in the volume of the external pallidum and the right putamen in MDD (Baumann et al 1999), structural or functional abnormalities in the amygdala, prefrontal cortex, or the striatum result in the disruption of the limbic-cortical-striatal-pallidal-thalamic (LCSPT) circuit and are associated with an increased risk for developing MDD (Drevets 2000).
Magnetic resonance spectroscopy (MRS) is a recently developed neuroimaging tool that has significantly changed the understanding of in vivo brain neurochemical abnormalities in psychiatric disorders (Lyoo and Renshaw 2002). The capacity to measure concentrations of brain choline (Cho), creatine (Cr), and N-acetyl-L-aspartate (NAA) using proton MRS (1H-MRS) has further clarified and confirmed neurochemical abnormalities in the basal ganglia of subjects with affective disorders. Nevertheless, 1H-MRS findings in the basal ganglia of patients with unipolar MDD are mixed. Renshaw et al (unpublished data) reported an elevated Cho/Cr ratio in unipolar depressed patients, suggesting an altered membrane phospholipid metabolism in MDD. A later report by the same group, however, found a reduced Cho/Cr ratio (Renshaw et al 1997). Charles et al (1994) demonstrated an elevated Cho/Cr ratio in elderly medication-free depressed patients, but other groups have not reported significant differences in subcortical Cho/Cr ratio or absolute Cho levels in MDD patients compared with healthy subjects Hamakawa et al 1998, Steingard et al 2000.
N-acetyl-L-aspartate (NAA) resonance as measured by 1H-MRS has been used as a marker of neuronal viability and dysfunction Tsai and Coyle 1995, Urenjak et al 1993, Valenzuela and Sachdev 2001. The existing structural and functional imaging and postmortem evidence supports the likelihood that NAA will be reduced in the basal ganglia of patients with MDD; however, at least three studies that evaluated NAA/Cr found no significant differences between MDD patients and healthy subjects Charles et al 1994, Hamakawa et al 1998, Renshaw et al 1997. The inconsistent and contradictory findings for Cho and NAA resonances using 1H-MRS in unipolar MDD might be attributed to the limitations of using single-voxel, one-dimensional chemical-shift imaging (CSI) nonautomated techniques. The application of a single voxel to a specific region makes it difficult to evaluate diffuse or global cortical abnormalities proposed to occur in unipolar depression (Nikolaus et al 2000). Sampling from multiple voxels placed bilaterally on the caudate, putamen, globus pallidus, and thalamus should help resolve contradictory data regarding subcortical membrane phospholipid metabolism in MDD and should also confirm impaired versus intact neuronal structure and function in the basal ganglia.
Automated multiple-voxel two-dimensional CSI 1H-MRS was used to evaluate global and focal abnormalities in MDD compared with control subjects. We hypothesized that patients with MDD would demonstrate focal alterations of Cho in subcortical regions in the absence of global abnormalities. We also hypothesized that NAA, as a marker of neuronal viability and function, would be reduced in the caudate and putamen, consistent with prior MRI, positron emission tomography (PET), and postmortem reports of focal abnormalities of the basal ganglia in MDD. Because reduced levels of frontal myo-inositol (mI) have been reported in MDD, consistent with an abnormal second-messenger system (Frey et al 1998), we proposed that mI levels would be reduced in the basal ganglia of MDD patients.
Section snippets
Subjects
The study was approved by the Institutional Review Board of Duke University Medical Center. All subjects gave written informed consent before participation in the research. Eighteen inpatients (14 women and 4 men, mean age 37 ± 11 years) who met criteria for current unipolar MDD according to DSM-III-R were recruited. At the time of the study, 12 patients were on a selective serotonin reuptake inhibitor (SSRI), 1 on a tricyclic antidepressant, and 1 on nefazodone. Six of the MDD patients had
Whole brain
An extracted single spectrum from a representative patient is shown in Figure 3. The mean (± SD) global metabolite ratios in depressed patients and control subjects are presented in Table 1. No significant findings were observed for Cho/Cr, NAA/Cr, or mI/Cr.
Caudate
Only 8 patients (36 ± 9 years; 7 women, 1 man) and 12 control subjects (32 ± 8 years; 6 women, 6 men) had voxels corresponding to the caudate nuclei, and insufficient numbers had both left- and right-hemisphere measurements. Means (± SD)
Discussion
Using improved 1H-MRS techniques, we found abnormalities in specific subcortical regions, particularly in the caudate and putamen, in patients with unipolar MDD compared with normal control subjects. The NAA/Cr metabolite ratio was reduced in the caudate nuclei of MDD patients, and Cho/Cr was elevated in the putamen. These focal putaminal abnormalities, including lower NAA/Cr ratios, were most prominent on the right side in depressed subjects compared with control subjects. To our knowledge,
Acknowledgements
This work was supported in part by a grant to LAT (National Institutes of Mental Health Grant No. K08-MH01460). We thank Sanjay Mathew, M.D. and Dietmar Plenz, Ph.D. for valuable comments on an earlier version of the paper and Holly Giesen, B.A. for editorial assistance.
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