• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of, and finding treatments for, complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia, long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Central fatigue in MS and altered GABA /glutamate levels 2021


Senior Member
, April 2021, 109610

Research article

Altered in vivo brain GABA and glutamate levels are associated with multiple sclerosis central fatigue

https://doi.org/10.1016/j.ejrad.2021.109610Get rights and content



Fatigue is a common symptom in patients with multiple sclerosis (MS) with unknown pathophysiology. Dysfunction of the GABAergic/glutamatergic pathways involving inhibitory and excitatory neurotransmitters such as  γ-aminobutyric acid (GABA) and glutamine + glutamate pool (Glx) have been implicated in several neurological disorders. This study is aimed to evaluate the potential role of GABA and Glx in the origin of central fatigue in relapse remitting MS (RRMS) patients.


24 RRMS patients and 16 age- and sex-matched healthy controls (HC) were scanned using Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) with a 3 T system to quantify GABA+ and Glx from prefrontal (PFC) and sensorimotor (SMC) cortices.

Self-reported fatigue status was measured on all participants using the Modified Fatigue Impact Scale (MFIS).

RRMS patients had higher fatigue scores relative to HC (p ≤  0.05).

Compared to HC, Glx levels in RRMS patients were significantly decreased in SMC (p =  0.04).

Significant correlations were found between fatigue scores and GABA+ (r = -0.531, p =  0.008) and Glx (r = 0.511, p =  0.018) in PFC.

Physical fatigue was negatively correlated with GABA+ in SMC and PFC (r = -0.428 and -0.472 respectively, p ≤  0.04) and positively with PFC Glx (r = 0.480, p =  0.028).

The associations between fatigue and GABA + and Glx suggest that there might be dysregulation of GABAergic/glutamatergic neurotransmission in the pathophysiological mechanism of central fatigue in MS.


Senior Member
I've been looking a lot at the potential effects of glutamate levels. I guess the question is how to fix that dysregulation - lower glutamate, raise GABA, etc? Through diet, or herbs and vitamins, or pharmaceuticals?


Senior Member
I've been looking a lot at the potential effects of glutamate levels. I guess the question is how to fix that dysregulation - lower glutamate, raise GABA, etc? Through diet, or herbs and vitamins, or pharmaceuticals?
central dysregulation in Central fatigue is much more than just GABA and Glutamate, it can involve also Dopamine/Orexin/Histamine and Melatonine or acetylcholine dysregulation.

Furthermore, the dysregulation is not the same across the brain, it changes from an area to another.

This is why it is very hard to fix the issue, whatever the way you try. Many PR members try many things and some find their own way to a better balance,.

Here another new study on fatigue in MS:

Microstructural Changes in the Left Mesocorticolimbic Pathway are Associated with the Comorbid Development of Fatigue and Depression in Multiple Sclerosis
Miklos Palotai ....

First published: 01 February 2021


Depressed (CES‐D ≥ 16) SF /Sustained Fatigue patients showed significantly higher Mean Diffusivity (MD), and Radial Diffusivity (RD) than non-depressed SF and RF/Reversible Fatigue , and depressed RF patients, and significantly lower FA/Fractional Anisotropy than non-depressed SF and depressed RF patients in their left slMFB/ superolateral medial forebrain bundle.

Depressed SF patients showed significantly higher left slMFB/ superolateral medial forebrain bundle MD and AD/axial Diffusivity than healthy controls.

Microstructural changes to the left slMFB may play a role in the comorbid development of fatigue and depression in MS.


Senior Member
Association of Central Hypersomnia and Fatigue in Patients With Multiple Sclerosis: A Polysomnographic Study
View ORCID ProfileAnne-Laure Dubessy, View ORCID ProfileSophie Tezenas du Montcel, Frederique Viala, View ORCID ProfileRana ASSOUAD, Michel Tiberge, View ORCID Profilecaroline papeix, View ORCID Profilecatherine Lubetzki, Michel Clanet, View ORCID ProfileIsabelle Arnulf, View ORCID ProfileBruno Stankoff

First published April 30, 2021,
DOI: https://doi.org/10.1212/WNL.0000000000012120


To evaluate sleepiness and central hypersomnia in multiple sclerosis (MS) associated fatigue, we performed long term polysomnography in MS patients and healthy controls.


Patients with MS and healthy controls completed questionnaires on sleep, fatigue, sleepiness, and depression. They underwent nocturnal polysomnography, multiple sleep latency tests and bed rest 24-hour polysomnography.

Patients were divided into 3 groups (fatigue and sleepiness; fatigue and no sleepiness; neither fatigue nor sleepiness).


Among 44 patients with MS, 19 (43.2%) had fatigue and sleepiness, 15 (34%) had only fatigue, and 10 (22.7%) had neither fatigue nor sleepiness.

Compared to 24 controls, patients with fatigue and sleepiness had higher REM sleep percentages (median [interquartile range]: 20.5% [19.6-24.7] vs. 18.1% [12.6-20.6]), lower arousal indexes (12.7 [7.5-17.0] vs. 22.4 [14.3-34.4]) and shorter daytime mean sleep latencies (8.6 [6.3-14.3] vs. 16.6 [12.6-19.5] min).

Restless leg syndrome, periodic leg movements and sleep apnea had similar frequencies between groups.

Central hypersomnia was found in 10 (53%) patients with fatigue and sleepiness (narcolepsy type 2, N=2), in 2 (13%) patients with fatigue only, and in 3 (30%) patients with neither fatigue nor sleepiness.

Patients with central hypersomnia were younger and sleepier than those without hypersomnia, but had similar levels of fatigue, disability, depression, cognitive performance and frequencies of the human leukocyte antigen DQB1*0602 genotype.

The severity of fatigue increased with higher depression scores, higher sleepiness severity, and lower sleep efficacy.


Central hypersomnias are frequent in MS when fatigue and sleepiness are present.

Screening them through polysomnography studies is recommended.