IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy

Abstract

Cytokine effects on behavior may be related to alterations in glutamate metabolism. We therefore measured glutamate concentrations in brain regions shown to be affected by inflammatory stimuli including the cytokine interferon (IFN)-alpha. IFN-alpha is known to alter neural activity in the dorsal anterior cingulate cortex (dACC) and basal ganglia in association with symptoms of depression and increases in peripheral cytokines including the tumor necrosis factor (TNF) and its soluble receptor. Single-voxel magnetic resonance spectroscopy (MRS) was employed to measure glutamate concentrations normalized to creatine (Glu/Cr) in dACC and basal ganglia of 31 patients with hepatitis C before and after ∼ 1 month of either no treatment (n = 14) or treatment with IFN-alpha (n = 17). Depressive symptoms were measured at each visit using the Inventory of Depressive Symptoms-Clinician Rating (IDS-C) and the Multidimensional Fatigue Inventory. IFN-alpha was associated with a significant increase in Glu/Cr in dACC and left basal ganglia. Increases in dACC Glu/Cr were positively correlated with scores on the IDS-C in the group as a whole, but not in either group alone. Glu/Cr increases in left basal ganglia were correlated with decreased motivation in the group as a whole and in IFN-alpha-treated subjects alone. No Glu/Cr changes were found in the right basal ganglia, and no significant correlations were found between Glu/Cr and the inflammatory markers. IFN-alpha-induced increases in glutamate in dACC and basal ganglia are consistent with MRS findings in bipolar depression and suggest that inflammatory cytokines may contribute to glutamate alterations in patients with mood disorders and increased inflammation.

Figure 1

Placement of MRS voxels and representative spectrum: MRS voxels were placed as indicated: a 2 × 3 × 1-cm³ voxel in the dorsal anterior cingulate region (dACC)(BA24) and two 1.7 × 3 × 1.7-cm³ voxels in the left and right basal ganglia. A representative spectrum from the dACC is depicted.

Figure 2

IFN-alpha increases Glu/Cr in dACC and left basal ganglia region. Regional changes in glutamate concentrations normalized to creatine (delta Glu/Cr) between visit 1 and 2 in the dorsal anterior cingulate cortex (dACC), left and right basal ganglia regions are depicted in interferon (IFN)-alpha-treated (closed circles) and control subjects (open circles). Delta Glu/Cr (visit 2−visit 1) was significantly increased in IFN-alpha-treated patients compared with controls in the dACC and left basal ganglia (t=3.91, df=28, p<0.001 and t=2.10, df=27, p=0.046, respectively). No changes were seen in the right basal ganglia. *p<0.05, ***p<0.001.

Figure 3

Correlations between changes in behavior and Glu/Cr in control and IFN-alpha-treated subjects. (a) Change in depression scores (delta IDS-C) from visit 1 (baseline) to visit 2 (after the 4th dose of IFN-alpha) were correlated in the total sample of 31 IFN-alpha-treated (n=17) and untreated (n=14) subjects with changes in glutamate concentrations normalized to creatine (delta Glu/Cr) in the dorsal anterior cingulate cortex (dACC)(Spearman r=0.54, df=28, p=0.002, p_corr=0.024). Of note, no significant correlations were found between dACC Glu/Cr and IDS-C in the groups individually. (b) Change in motivation scores (delta reduced motivation on the MFI) was significantly correlated with delta Glu/Cr in the left basal ganglia (r_s=.60, df=27, p=0.001, p_corr=0.012) in the group as a whole and in IFN-alpha-treated patients only (r_s=0.68, df=13, p=0.006).