IFN-Alpha-Induced Cortical and Subcortical Glutamate Changes Assessed by Magnetic Resonance Spectroscopy, 2014, Haroon et al

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IFN-Alpha-Induced Cortical and Subcortical Glutamate Changes Assessed by Magnetic Resonance Spectroscopy

Spoiler: Authors

Haroon, Ebrahim; Woolwine, Bobbi J; Chen, Xiangchuan; Pace, Thaddeus W; Parekh, Samir; Spivey, James R; Hu, Xiaoping P; Miller, Andrew H

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.

Web | DOI | PMC | PDF | Neuropsychopharmacology

 

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Effect of interferon-αon cortical glutamate in patients with hepatitis C: a proton magnetic resonance spectroscopy study 2013, Taylor et al

Spoiler: Authors

Taylor, M. J.; Godlewska, B.; Near, J.; Christmas, D.; Potokar, J.; Collier, J.; Klenerman, P.; Barnes, E.; Cowen, P. J.

Abstract
Background
The development of depressive symptomatology is a recognized complication of treatment with the cytokine interferon-α(IFN-α) and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of IFN-induced depression have implicated neurotoxic influences that could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure glutamate and its major metabolite glutamine in patients with hepatitis C who received treatment with pegylated IFN-αand ribavirin.

Method
MRS measurements of glutamate and glutamine were taken from a 25 × 20 × 20 mm voxel including the pregenual anterior cingulate cortex in 12 patients before and after 4–6 weeks of treatment with IFN.ResultsIFN treatment led to an increase in cortical levels of glutamine (p = 0.02) and a significant elevation in the ratio of glutamine to glutamate (p < 0.01). Furthermore, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan.

Conclusions
We conclude that treatment with IFN-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression, which suggests that the pathophysiology of IFN-induced depression may be distinct from that of major depression more generally.

Web | DOI | PMC | PDF | Psychological Medicine

 

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Interferon-β1a modulates glutamate neurotransmission in the CNS through CaMKII and GluN2A-containing NMDA receptors 2016, Di Filippo et al

Spoiler: Authors

Di Filippo, Massimiliano; Tozzi, Alessandro; Arcangeli, Sara; de Iure, Antonio; Durante, Valentina; Di Gregorio, Maria; Gardoni, Fabrizio; Calabresi, Paolo

Abstract
Interferons (IFNs) are widely expressed cytokines with antiviral and immune-modulating effects and have been utilised for the treatment of several human pathological conditions. In particular, the immune-modulatory drug IFN-β is utilized in the treatment of multiple sclerosis (MS), a chronic autoimmune and neurodegenerative disorder of the central nervous system (CNS).

Although the effects of IFN-β on immune cells functions have been widely investigated, information about the ability of the drug to modulate neuronal transmission in the CNS is still largely lacking. The aim of this study was to investigate the ability of IFN-β1a to modulate excitatory synaptic transmission in the CNS. Whole cell patch-clamp electrophysiological recordings were performed in the nucleus striatum, one of the CNS grey matter structures that is prone to degenerate during the course of MS.

We demonstrate that the drug IFN-β1a, independently from its known peripheral immune-modulating action, is able to directly modulate synaptic transmission. In particular, we demonstrated that IFN-β1a reduces the amplitude of striatal excitatory post-synaptic currents, indicating an inhibitory effect on glutamate neurotransmission, and in particular on its NMDA component. The inhibitory effect of IFN-β1a on striatal glutamate neurotransmission was found to be mediated by a novel post-synaptic mechanism requiring Ca(2+), CaMKII and the GluN2A subunit of the NMDA receptor, without the involvement of the classic STAT1 pathway.

The evidence of a novel neuro-modulating effect of IFN-β shed light on the mechanisms of action of the drug and on the complex bidirectional interaction occurring between the immune and the nervous system. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

Web | DOI | Neuropharmacology

 

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Hypothalamic damage in multiple sclerosis correlates with disease activity, disability, depression, and fatigue 2017, Kantorová et al

Spoiler: Authors

Kantorová, E.; Poláček, H.; Bittšanský, M.; Baranovičová, E.; Hnilicová, P.; Čierny, D.; Sivák, Š.; Nosáľ, V.; Zeleňák, K.; Kurča, E.

Abstract
Objectives: Disturbances in the hypothalamo-pituitary axis are supposed to modulate activity of multiple sclerosis (MS). We hypothesised that the extent of HYP damage may determine severity of MS and may be associated with the disease evolution. We suggested fatigue and depression may depend on the degree of damage of the area.

Method: 33 MS patients with relapsing-remitting and secondary progressive disease, and 24 age and sex-related healthy individuals (CON) underwent 1H-MR spectroscopy (1H-MRS) of the hypothalamus. Concentrations of glutamate + glutamin (Glx), cholin (Cho), myoinositol (mIns), N-acetyl aspartate (NAA) expressed as ratio with creatine (Cr) and NAA were correlated with markers of disease activity (RIO score), Multiple Sclerosis Severity Scale (MSSS), Depressive-Severity Status Scale and Simple Numerical Fatigue Scale.

Results: Cho/Cr and NAA/Cr ratios were decreased and Glx/NAA ratio increased in MS patients vs CON. Glx/NAA, Glx/Cr, and mIns/NAA were significantly higher in active (RIO 1–2) vs non-active MS patients (RIO 0). Glx/NAA and Glx/Cr correlated with MSSS and fatigue score, and Glx/Cr with depressive score of MS patients. In CON, relationships between Glx/Cr and age, and Glx/NAA and fatigue score were inverse.

Conclusion: Our study provides the first evidence about significant hypothalamic alterations correlating with clinical outcomes of MS, using 1H-MRS. The combination of increased Glu or mIns with reduced NAA in HYP reflects whole-brain activity of MS. In addition, excess of Glu is linked to severe disease course, depressive mood and fatigue in MS patients, suggesting superiority of Glu over other metabolites in determining MS burden.

Web | DOI | PDF | Neurological Research

 

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I posted these altogether as it’s all part of the same sort or chain of thought, inspired by some of the ideas @jnmaciuch has around type I interferon and also wider discussions of sickness behaviour, fatigue, and some hunches I have after looking at PrecisionLife and DecodeMe data.

So there seems to be some evidence of type I interferon treatment causing increased glutumate within certain parts of the brain (including the basal ganglia and the dorsal anterior cingulate cortex). These changes also correlate with increases in measures of physical and mental fatigue and reduced activity as well as mood changes.

Then looking at MS, excess glutamate measured within the hypothalamus correlates with severity of fatigue and wider clinical outcomes.

This seems to tie into with lots of ideas and questions I’ve had and things we’ve discussed on the forum particularly around how fatigue (mental and physical). So I’d be interested in others thoughts.

Maybe a couple of jumps but I can see there being a problem in the brain around glutumate/glutamate receptors/glutamatergic synapses which perhaps exists somewhat independently but is exacerbated by activity and interferon release in PEM. I’m drawn to the idea of interferon upsetting astrocytes so the clean up at the synapses and recycling of glutamine/glutamate goes awry.

Then there’s this one here which touches on the same areas in the context of ME/CFS but obviously had a bit of context and controversy…
https://www.s4me.info/threads/persi...ic-fatigue-syndrome-2018-pariante-et-al.7050/

Also of note is the description of depressive life symptoms being distinct from clinical depression. Having had both clinical depression and ME/CFS I9ve noticed similarities in mood changes but they are also very distinct to me.

Often when I’m in PEM or any sort of flare up I have mood changes. Particularly waves of feeling sad, sometimes anxiety like (quite fluctuating rather than persistent as I had when depressed earlier in life, but there is a recognisable pattern for me).

I’m not so sure about the motivation side of things, that is something I’ve not heard people speak about. But speaking to my Mum and her PD and how it can be harder to do things, that sounds familiar. So maybe it’s either a matter of language used and interpretation or perhaps of different bits of the brain or neurotransmitters being involved?