Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms. These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.

Exercise-induced changes in gene expression do not mediate post exertional malaise in Gulf War illness

“…In contrast to these ME/CFS studies, our investigation found that Veterans with GWI had decreased gene expression in similar genes (COMT and TLR4). Although sex differences of the participants sampled in these studies are an obvious potential explanation, our results suggest that gene expression responses to exercise in GWI are unique to those observed in ME/CFS and are supportive of differences in pathophysiology found in previous investigations ( Baraniuk, 2022 ).…”

Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controls

“…Likewise, individuals experiencing Gulf War Illness have symptom overlap with both Long COVID and ME/CFS [ 7 ]. However, a number of assays, such as neuroimaging [ 8 ], distinguish Gulf War Illness and ME/CFS. Whether Long COVID and ME/CFS not associated with SARS-CoV-2 infection will likewise be differentiated through imaging or other measures is not yet known.…”

Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Association with Symptom Severity

“…The last factor has long been considered as increasing the risk of ME/CFS [30]. An imbalance between excitatory and inhibitory neurotransmission has been linked to ME/CFS and FM [31]. Interestingly, pregabalin, which is one of the three FDA-approved drugs for the treatment of FM, is a lipophilic analogue of GABA.…”

“…Interestingly, pregabalin, which is one of the three FDA-approved drugs for the treatment of FM, is a lipophilic analogue of GABA. At the same time, it neither acts like GABA nor binds to GABA receptors, but strongly to the auxiliary alpha-2 delta subunit of the presynaptic voltage-gated calcium channel receptor to reduce the activation of postsynaptic neurotransmitter release [31]. Regarding some potential substances for future clinical research in ME/CFS and FM, it should be mentioned that a number of complementary dietary supplements have been reported to rebalance glutamate:GABA neurotransmission, namely Omega-3 PUFAs, CoQ10, Withania Somnifera (Ashwagandha, Indian Ginseng), N-acetylcysteine, vitamin B12, curcumin (contained in turmeric), zinc, magnesium, 2-aminoethanesulfonic acid (L-Taurine), and carnitine (L-Carnitine) [32].…”