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

[hotblack]

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

 

[hotblack]

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

 

[hotblack]

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?

 

[ScoutB]

I really appreciate you putting this together @hotblack as I have a lot of the same questions. Looking over these papers reminded me that maybe I should try to lean some neurology. Do we have anything like your 'Learning about the immune system' thread, for neurology?

For instance, a couple of the questions that always come up when I try to look at papers like this:

1. When we say a certain brain region is involved in a certain process, how confident are we in that?
2. As seen above, some studies seem to look at concentrations and others look at ratios of concentrations (e.g. glutamate concentrations normalized to creatine). I can imagine how it could make sense to do one or the other depending on how things normally fluctuate, if they fluctuate together etc. but since I don't know anything I am always just relying on the authors to get it right and never really know how to interpret anything. I guess this isn't really a question just a complaint haha

What you're saying about depression, anxiety and mood swings aligns with my experiences.

On motivation: agree our language for these things might be confusing things, and also it's hard to talk about it when medicine/society views motivation as something largely under our control rather than just a part of biology like everything else. At times (esp when feeling worse overall) I feel like I am pushing through a strong force of something like 'anti-motivation' to do the smallest thing. If I understood neurology better I'd try to learn more about the causes and brain regions involved in the various kinds of Disorders of diminished motivation.

 

[AliceLily]

The mood change is a really concerning part of PEM for some. I went through over 10 years of severe PEM and I wish I could have understood more about this part and why it made PEM so much more difficult to get through. The physical symptoms were bad enough and to have the mental decline on top made it very difficult to get through. Looking back I can see why I called coming out of PEM a breather. It was like coming up for air, after nearly drowning.

 

[AliceLily]

On motivation: agree our language for these things might be confusing things, and also it's hard to talk about it when medicine/society views motivation as something largely under our control rather than just a part of biology like everything else. At times (esp when feeling worse overall) I feel like I am pushing through a strong force of something like 'anti-motivation' to do the smallest thing. If I understood neurology better I'd try to learn more about the causes and brain regions involved in the various kinds of Disorders of diminished motivation.

Yes, the anti-motivation part of ME/CFS is a symptom sign, it is a feeling in the body the ME produces to warn that you now have limitations on how much you can do and it most likely means you are already experiencing a level of PEM. This is my read on how it felt to me.

I remember in my early years of ME not knowing I had ME and I wanted to make some biscuits but just the thought of the process and effort to do the job was too much. I could feel my body was not up to it. I knew something was very wrong.

It is hard to explain. I have a hundred and ten jobs that I need and want to get done but I can't because I have to consider the ME/CFS and not push and then deteriorate. The anti-motivation (ME/CFS produced) when it appears is also a reminder to be careful.

 

[hotblack]

I’m glad talking about the mood changes is of help to people. And thanks for sharing your experiences @AliceLily it certainly can be a rollercoaster at times, clinging on while you ride it out but not knowing how long it’ll go on. I’ve ended up in predictable fluctuations throughout the day in some crashes or PEM (not sure if that’s linked to hormones, meds or what) and knowing that has helped a bit but it’s still tough.

It’s a tricky one given all the connotations and history. But the comparison with things like MS/PD is perhaps useful and to me the distinction with clinical depression.

The findings on physical and mental fatigue seem really clear here too and that was what drew me in to these papers (along with some theories about astrocyte involvement). So seeing it as all part of the same biological process, triggered by interferon could be helpful.

Do we have anything like your 'Learning about the immune system' thread, for neurology?

We don’t and I agree could be useful. I can try to put some stuff together, but I feel even less confident than with immunology. I’ve mainly just been through khan academy stuff on synapses, etc. We have some great immunology knowledge and expertise on the forum to help push those of us learning in the right direction, I’m not sure if we have the same for neurology?

For instance, a couple of the questions that always come up when I try to look at papers like this:

1. When we say a certain brain region is involved in a certain process, how confident are we in that?
2. As seen above, some studies seem to look at concentrations and others look at ratios of concentrations (e.g. glutamate concentrations normalized to creatine). I can imagine how it could make sense to do one or the other depending on how things normally fluctuate, if they fluctuate together etc. but since I don't know anything I am always just relying on the authors to get it right and never really know how to interpret anything. I guess this isn't really a question just a complaint haha

Good questions. The studies seem pretty specific in that they looked at levels of neurotransmitters in specific sections of the brain. But yeah, I don’t know if that means they onky looked at those sections, or looked at the whole brain and these sections ‘lit up’ or what would happen if they looked st a different section, or different neurotransmitter, etc. Maybe someone more knowledgeable can chime in. I’m with you in having ti rely on the authors to have got things right!

Anyone got a spare MRI machine to do some MRS studies of people in PEM?