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 B1 month of either no treatment (n ¼ 14) or treatment with IFN-alpha (n ¼ 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-alphainduced 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.

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Another emerging neurotransmitter target relative to the effects of inflammation on the brain is glutamate. As noted previously, inflammatory cytokines can have marked effects on glutamate metabolism, especially in the basal ganglia as documented by MRS (Haroon et al, 2014. Nevertheless, although there are drugs currently available and in development that block glutamate receptors (eg, memantine) or influence glutamate reuptake (eg, riluzole), there have been no studies examining the ability of glutamate antagonists to reverse inflammation-induced alterations in the CNS and the associated changes in motivation and motor activity in patients with depression or other psychiatric disorders.…”

“…However, increasing data suggest that these two pathophysiologic pathways may be intimately interrelated. For example, patients treated with IFN-α exhibit significant increases in basal ganglia and dorsal anterior cingulate cortex (dACC) glutamate concentrations as measured by magnetic resonance spectroscopy (MRS) (Haroon et al, 2014). Increases in glutamate as measured by MRS were in turn associated with IFN-α-induced depressive symptoms.…”

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

“…One biological mechanism by which inflammation influences neural networks critical for the regulation of emotional behavior and fear processes is by altering central neurotransmitter systems (reviewed in Dunn et al (1999)). For instance, administration of IFN-α for the treatment of hepatitis C increases glutamate to creatinine levels in the dACC that correlate with anhedonia and fatigue (Haroon et al, 2014). Increased CRP in depression is also associated with heightened glutamate levels within the basal ganglia .…”

Inflammatory cytokine-associated depression

“…91 (viii) Various stress-induction paradigms result in behavioral changes along with activation of inflammatory cytokines 92, 93 and subsequent suppression of neurogenesis and neuroplasticity. 94-99 (ix) Inflammatory cytokines such as IFN-α can affect systems that are likely key in depressogenesis, including frontal lobe and anterior cingulate function, 100, 101 dopaminergic activity, 87 serotonergic activity, 102-105 glutamatergic activity, 106 and growth factors such as brain-derived neurotrophic factor (BDNF). 107, 108 …”