Neurometabolic Modelling of PEM and Central Sensitisation

Dr Graham Exelby May 2025

Abstract

Post-exertional malaise (PEM) and central sensitization are defining features of POTS, ME/CFS, Long COVID, and fibromyalgia-spectrum disorders, reflecting a breakdown in neurometabolic and neuroimmune homeostasis.

This paper presents a systems-level model in which mitochondrial dysfunction, amino acid imbalance, brainstem hypoperfusion, and neuroinflammation interact to perpetuate exertional intolerance, sensory amplification, and cognitive dysfunction. Clinical and biochemical profiling reveals a reproducible triad of low aspartate, elevated glutamate, and low GABA, which disrupts the malate-aspartate shuttle, promotes glutamate excitotoxicity, and impairs autonomic inhibitory tone.

Aspartate depletion emerges as a key bottleneck in post-exertional recovery, impeding ATP regeneration and lactate clearance. Glutamate accumulation overstimulates NMDA receptors, activates microglia, and drives neuroinflammation. GABA deficiency removes the brake on sympathetic output and pain amplification, compounding postural and sensory instability. Brainstem hypoperfusion exacerbates mitochondrial inefficiency and sustains oxidative stress.

This model reframes PEM as a metabolic collapse triggered by exertion but sustained by intertwined energy, neurotransmitter, and inflammatory deficits.

Therapeutic targets include SIRT4 activation (nicotinamide riboside), restoration of MAS function (L-aspartate + magnesium), glutamate modulation and microglial stabilization.

Clinical observations suggest early normalization of GABA and ethanolamine with treatment, while aspartate recovery lags—supporting its role as the rate-limiting substrate in exertional resilience.

This neurometabolic framework not only clarifies the pathophysiology of PEM and central sensitization but offers mechanistically informed strategies for personalized intervention across post-viral and autonomic syndromes.

Introduction

Post-exertional malaise (PEM) and central sensitization represent interconnected pathological phenomena underlying POTS, Chronic Fatigue Syndrome (CFS) long COVID, fibromyalgia (FMS), and related conditions.

The NICE guidelines define CFS as a condition characterized by debilitating fatigue that worsens with activity, post-exertional malaise (PEM), unrefreshing sleep, and cognitive dysfunction ('brain fog'), which are often disproportionate to exertion and not significantly relieved by rest.

This section integrates these clinical features with emerging findings on brainstem hypoperfusion, amino acid imbalances, mitochondrial dysfunction, immune dysregulation, and metabolic impairment. Specifically, clinic Amino Acid profiling based on research by Fluge et al 2016, 2021 (1)(2) in CFS consistently demonstrates pattern of impaired amino acid function, most commonly with low GABA, low aspartate, and elevated glutamate which can disrupt neurovascular stability, impair energy metabolism, and perpetuate central sensitization.

These biochemical and neuroimmune disruptions contribute to prolonged fatigue, pain hypersensitivity, autonomic dysfunction, and cognitive impairment, forming a self-sustaining cycle of sensitization and exertion intolerance. Understanding these mechanisms provides a foundation for targeted metabolic, autonomic, and neuroimmune interventions to mitigate PEM and central sensitization in POTS, CFS, and long COVID.

Pathophysiology of PEM and Central Sensitization in CFS

Chronic fatigue syndrome (CFS) is a debilitating condition defined by the NICE guidelines (3) as including:

• Debilitating fatigue worsened by activity, not relieved by rest

• Post-exertional malaise (PEM) with delayed onset, disproportionate severity, and prolonged recovery

• Unrefreshing sleep and altered sleep patterns

• Cognitive dysfunction ('brain fog'), including impaired memory, slowed processing, and difficulty multitasking

Emerging research indicates that PEM and central sensitization in CFS share common biochemical and neuroimmune disturbances, particularly in amino acid metabolism, mitochondrial function, and brainstem perfusion.

Clinical Breakthrough: Manual Lymphatic Drainage (MLD) and ECM Detoxification

Clinical studies using Vodder manual lymphatic therapy, as part of a multi-system approach to POTS have found resolution of PEM symptoms as the various mechanical and vascular obstruction with lymphatic obstruction are targeted.  This implies:

• The extracellular matrix (ECM) acts as a reservoir for hypoxic and inflammatory metabolites (likely including lactate, glutamate, oxidized proteins, and DAMPs such as HMGB1 and S100s).

• Resolution of PEM appears linked not merely to metabolic restoration, but physical clearance of these endproducts via lymphatic flow restoration.

• This aligns with growing recognition that brain glymphatic and peripheral lymphatic stagnation contribute to neuroimmune sensitization 

  
  

Amino Acid Dysregulation: The Core Metabolic Deficit

1.     Aspartate Depletion and ATP Crisis in PEM

• Aspartate depletion impairs mitochondrial ATP synthesis, delaying post-exertional recovery.

• Low aspartate disrupts the malate-aspartate shuttle (MAS), reducing NADH transport into mitochondria and worsening energy deficits. (Chambers. 2023 (4))

• Aspartate is required for nitrogenous end product clearance in the urea cycle, and its depletion contributes to metabolic stress and neuroinflammation.

2.     Glutamate Dysregulation and Excitotoxicity in PEM and Sensitization

• Elevated glutamate levels lead to NMDA receptor overactivation, driving excitotoxicity and prolonged neuroinflammation.

• Impaired glutamate clearance worsens sensory hypersensitivity, autonomic dysfunction, and cognitive dysfunction ('brain fog').

3.     Low GABA and the Breakdown of Inhibitory Control

• GABAergic inhibition regulates autonomic balance, pain modulation, and cognitive function.

• Low GABA fails to counteract glutamate-driven neuroexcitation, amplifying fatigue, dysautonomia, and central pain sensitization.

Mitochondrial Dysfunction and ATP Depletion

• CFS is characterized by mitochondrial energy failure, forcing reliance on inefficient anaerobic pathways.

• Aspartate depletion limits mitochondrial NADH transport, increasing lactate accumulation and prolonging post-exertional crashes.

• Neurovascular hypoxia and ATP shortages in brainstem autonomic centres worsen dysautonomia, fatigue, and cognitive impairment.

Brainstem Hypoperfusion and Neurovascular Dysfunction in CFS

• Positional and sympathetic-driven vasoconstriction blood flow reductions impair mitochondrial ATP synthesis in the brainstem, worsening PEM and cognitive dysfunction.   Studies by Wirth et al. (5) show a 24.5% reduction in brainstem perfusion in CFS upon orthostatic challenge, correlating with autonomic instability.

• Hypoxia-driven neuroinflammation amplifies microglial activation, worsening neuroimmune dysregulation.(Blitshteyn. 2022 (6))

RAGE Activation as a Central Amplifier of Neuroinflammation in PEM

RAGE is a multi-ligand receptor upregulated in response to oxidative stress, tissue damage, and advanced glycation. In the context of PEM and central sensitization, RAGE ligands—particularly HMGB1 and S100 proteins—are released during exertion, hypoxia, and cellular stress.

Upon binding to RAGE on endothelial, microglial, and neuronal cells, a feedforward loop is triggered involving NF-κB, ROS generation, and mitochondrial dysfunction. This perpetuates microglial activation, glutamate excitotoxicity, and suppression of inhibitory GABAergic tone.

Brainstem hypoperfusion and neurovascular congestion further promote local hypoxia, a known driver of RAGE ligand expression. Simultaneously, impaired glymphatic clearance and ECM toxin accumulation enhance RAGE ligand persistence. This convergence establishes a self-sustaining immunometabolic circuit—critically involving the RAGE–NF-κB–ROS axis—which underlies PEM prolongation and central sensitization.

RAGE activation sustains PEM not merely via transient exertional damage, but through the chronic presence of retained ligands in the interstitial matrix. Without lymphatic mobilization, these ligands—including AGEs, HMGB1, and S100 proteins—accumulate and perpetuate NF-κB signalling, microglial excitation, and autonomic destabilization. Thus, therapeutic suppression of RAGE (e.g., with ALA, telmisartan) may be potentiated by concurrent ECM drainage to eliminate the upstream ligands.

The Self-Sustaining Cycle of PEM, Central Sensitization, and Metabolic Dysfunction in CFS

• Exertion depletes aspartate, impairing ATP production and metabolic efficiency.

• Aspartate depletion impairs glutamate clearance, increasing excitotoxicity and neuroimmune activation.

• Low GABA fails to counteract excitotoxicity, amplifying dysautonomia and sensory hypersensitivity.

• Mitochondrial dysfunction prolongs ATP shortages, worsening PEM.

• Brainstem hypoperfusion sustains neurovascular dysregulation, exacerbating autonomic dysfunction and cognitive fatigue.

• Chronic neuroimmune activation reinforces PEM, prolonging the post-exertional recovery period.

Potential Therapeutic Strategies for PEM and Central Sensitization in CFS

Various pathways are becoming apparent for potential targeted metabolic solutions depending on amino acid profiles and responses. Described in Targeting the Perfect Storm. (7) For many the introduction of Liposomal Nicotinamide Riboside restores ethanolamine, GABA and other amino acids, but seldom aspartate.

1.     Restoring Aspartate Availability and Mitochondrial Recovery

• Nicotinamide Riboside (NR) + SIRT1/SIRT4 Modulation → Improves mitochondrial NADH transport and oxidative phosphorylation- in clinic studies, this provides significant improvements in most, then dose might be increased or addition of:

  • L-Aspartate + Magnesium → Supports MAS function, ATP synthesis, and metabolic recovery. This restoration is a subject of current research

  • More complicated amino acid patterns, or failure to improve may require targeted metabolic solutions

2.     Reducing Glutamate Excitotoxicity and Neuroimmune Stress

• Low-Dose Naltrexone (LDN) → Modulates neuroimmune overactivation and reduces PEM severity.(Bonilla et al 2023 (25))

  • Case studies suggest potential benefits of LDN in managing chronic fatigue syndrome (CFS), indicating its role as an immune modulator, (Bolton et al 2020 (26)) and explored at Griffith University, where researchers have demonstrated that LDN can restore the function of ion channels, specifically TRPM3, in natural killer (NK) cells from ME/CFS patients. (Cabanas et al 2021(27)) This restoration is crucial for calcium signalling and immune function.   

  • The study suggests that LDN acts by antagonizing opioid receptors, which are involved in inhibiting TRPM3 channels. By blocking these receptors, LDN enhances calcium signalling and NK cell function. 

  • Their researchers have noted similarities in ion channel dysfunction between Long COVID and ME/CFS patients, suggesting that treatments effective for ME/CFS might also benefit Long COVID patients, so it has become a valuable tool in Long COVID management at a clinical level.

• Magnesium L-Threonate → NMDA receptor inhibition to prevent glutamate-induced excitotoxicity.   While specific studies on Magnesium L-Threonate's role in NMDA receptor inhibition are limited, magnesium in general is known to block NMDA receptors, thereby reducing excitotoxicity.

• L-Theanine + Taurine → Enhances GABAergic tone and astrocytic glutamate clearance.  L-Theanine has been shown to increase GABA levels and exhibit neuroprotective effects by modulating glutamate transporters. Taurine also plays a role in supporting GABAergic neurotransmission and regulating glutamate levels.

3.     Restoring GABAergic Inhibition and Autonomic Stability

• GABA + Magnesium Support → Supports autonomic tone and sensory inhibition.  Supplementation with GABA and magnesium has been associated with improved relaxation and stress reduction, potentially supporting autonomic function. However, direct evidence linking this combination to autonomic tone and sensory inhibition is limited and requiring further study. Many GABA levels are improved with addition of nicotinamide.

• Vagus Nerve Stimulation (VNS) → Enhances parasympathetic balance, reducing PEM severity. Studies have shown that transcutaneous auricular vagus nerve stimulation can improve symptoms such as post-exertional malaise, pain, and gut problems in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),(11) although in clinic trials have been less than convincing, but warranting continuing studies.

• Phosphatidylcholine (PC) + Ethanolamine → Maintains neuronal membrane integrity and neurotransmitter balance.    Phosphatidylcholine is a key component of cell membranes and supports neuronal health. Ethanolamine is a precursor in the biosynthesis of phospholipids, contributing to membrane integrity. However, specific studies on their combined effect on neurotransmitter balance and autonomic stability are limited, and as the preliminary studies show ethanolamine returning to normal in most with just nicotinamide riboside, it is probably only appropriate as part of a targeted metabolic solution.

Post-exertional malaise (PEM) is a hallmark of CFS, Long COVID, and severe POTS. This model proposes that:

• Mitochondrial dysfunction leads to metabolic inflexibility, with impaired pyruvate and amino acid metabolism (low aspartate, high glutamate), worsening energy depletion and oxidative stress.

• Microglial activation leads to increased glutamatergic signalling, amplifying central sensitization and neuroinflammation.

• Hypoxia and oxidative stress sustain persistent neuroinflammatory states, reducing cellular recovery after exertion and leading to PEM crashes believed to be associated with depleted aspartate stores, with the PEM recovering as the stores are rebuilt.

• Dysregulated malate-aspartate shuttling impairs lactate clearance, leading to a metabolic bottleneck that further worsens fatigue and neuroinflammation. The inability to efficiently cycle aspartate, coupled with low NAD+ bioavailability, contributes to energy depletion and autonomic dysregulation.

Biomarker Correlation – Aspartate and GABA

 A temporal pattern of recovery has emerged: GABA and ethanolamine levels improve early with SIRT4/NAD+ repletion, while aspartate remains persistently low until lymphatic clearance is optimized. This suggests that aspartate depletion reflects ongoing metabolic detoxification demands from ECM-stored hypoxic metabolites, and its restoration signals effective resolution of PEM-inducing toxic load.

I propose that aspartate normalization may indicate effective ECM clearance, as it is otherwise diverted for detoxification and urea cycling. Simultaneously, GABA improvement (earlier than aspartate) may reflect reduced microglial and excitotoxic burden.

This introduces a dynamic metabolic timeline of recovery:

• Early markers: GABA and ethanolamine restoration with NAD+ elevation.

• Delayed marker: Aspartate normalization—correlating with PEM recovery

Conclusion

Post-exertional malaise (PEM) and central sensitization reflect a systems-level collapse in energy metabolism, neurotransmitter regulation, and neuroimmune control across conditions such as POTS, ME/CFS, and Long COVID. While mitochondrial insufficiency, brainstem hypoxia, and amino acid dysfunction have been long recognized as central contributors, emerging clinical evidence now redefines the extracellular matrix (ECM) as an active pathological compartment—sequestering hypoxic waste and inflammatory ligands that perpetuate RAGE-mediated neuroinflammation.

Resolution of PEM via targeted manual lymphatic drainage (MLD) marks a critical clinical breakthrough, revealing that mechanical clearance of ECM-bound metabolites—such as HMGB1, S100 proteins, and oxidized glutamate derivatives—can rapidly attenuate neuroimmune loops and restore exertional tolerance. This supports a revised pathophysiological model in which the ECM functions not only as a sink for metabolic debris but as a potent driver of sustained RAGE–NF-κB activation, autonomic dysfunction, and delayed bioenergetic recovery.

Within this framework, aspartate emerges as a key metabolic bottleneck: its persistent depletion reflects both impaired mitochondrial NADH shuttling and ongoing urea cycle demand from ECM-derived nitrogenous waste. In contrast, early normalization of GABA and ethanolamine with SIRT4 activation suggests partial neurochemical stabilization precedes full metabolic restoration. The delayed rebound of aspartate correlates with PEM resolution, identifying it as a critical biomarker of exertional resilience.

This unified model—integrating ECM congestion, neurovascular hypoxia, mitochondrial dysfunction, and immune sensitization—provides new therapeutic targets and sequencing strategies:

• Metabolic rescue: SIRT4 activation with Nicotinamide riboside + Magnesium

• Neuroimmune modulation: inhibition of the RAGE–NF-κB axis using agents like ALA, low-dose naltrexone, or telmisartan;

• Neurotransmitter rebalancing: GABAergic support via taurine, magnesium and L-theanine;

• Mechanical detoxification: manual lymphatic drainage and enhancement of glymphatic–lymphatic flow.

These findings reconceptualize PEM as a dynamic and reversible immunometabolic state, not a static failure of energy production. Crucially, the persistence of PEM appears to depend on the retention of immune-stimulatory ligands in the ECM, which sustain pathological signalling loops until cleared. MLD may therefore represent a pivotal adjunct to biochemical and pharmacological therapies, enabling physical detoxification to accelerate metabolic recovery.

This paradigm shift has profound implications for clinical management, biomarker tracking, and research design in fatigue-spectrum disorders, and warrants urgent validation through controlled trials. If replicated, it may finally explain the protracted and unpredictable nature of PEM—and offer a tractable, multi-modal pathway toward its resolution.

References

1.     Fluge Ø, Mella O, Bruland O, Risa K, Dyrstad SE, Alme K, Rekeland IG, Sapkota D, Røsland GV, Fosså A, Ktoridou-Valen I, Lunde S, Sørland K, Lien K, Herder I, Thürmer H, Gotaas ME, Baranowska KA, Bohnen LM, Schäfer C, McCann A, Sommerfelt K, Helgeland L, Ueland PM, Dahl O, Tronstad KJ. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016 Dec 22;1(21):e89376. doi: 10.1172/jci.insight.89376. PMID: 28018972; PMCID: PMC5161229.

2.     Hoel F, Hoel A, Pettersen IK, Rekeland IG, Risa K, Alme K, Sørland K, Fosså A, Lien K, Herder I, Thürmer HL, Gotaas ME, Schäfer C, Berge RK, Sommerfelt K, Marti HP, Dahl O, Mella O, Fluge Ø, Tronstad KJ. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2021 Aug 23;6(16):e149217. doi: 10.1172/jci.insight.149217. PMID: 34423789; PMCID: PMC8409979.

3.     Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. NICE. 2021. https://www.nice.org.uk/guidance/ng206

4.     Chambers, P. Long COVID, POTS, CFS and MTHFRE: Linked by Biochemistry and Nutrition. J Orthomol Med 38(2) 2023. https://isom.ca/article/long-covid-pots-cfs-and-mthfr-linked-by-biochemistry-and-nutrition/

5.     Wirth, K.J., Scheibenbogen, C. & Paul, F. An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Transl Med 19, 471 (2021). https://doi.org/10.1186/s12967-021-03143-3 

6.     Blitshteyn S. Is postural orthostatic tachycardia syndrome (POTS) a central nervous system disorder?. J Neurol. 2022;269(2):725-732. doi:10.1007/s00415-021-10502-z

7.     Exelby, G. Targeting the Perfect Storm -Amino Acid dysfunction from Post Exertional Malaise. MCMC-Research.com. 2024. https://www.mcmc-research.com/post/amino-acid-dysfunction-from-post-exertional-malaise-targetting-the-perfect-storm

8.     Bonilla H, Tian L, Marconi VC, Shafer R, McComsey GA, Miglis M, Yang P, Bonilla A, Eggert L, Geng LN. Low-dose naltrexone use for the management of post-acute sequelae of COVID-19. Int Immunopharmacol. 2023 Nov;124(Pt B):110966. doi: 10.1016/j.intimp.2023.110966. Epub 2023 Oct 5. PMID: 37804660; PMCID: PMC11028858.

9.     Bolton MJ, Chapman BP, Van Marwijk H. Low-dose naltrexone as a treatment for chronic fatigue syndrome. BMJ Case Rep. 2020 Jan 6;13(1):e232502. doi: 10.1136/bcr-2019-232502. PMID: 31911410; PMCID: PMC6954765.

10.  Cabanas H, Muraki K, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S. Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment. Front Immunol. 2021 Jul 13;12:687806. doi: 10.3389/fimmu.2021.687806. PMID: 34326841; PMCID: PMC8313851.

11.  Clague-Baker N, Davenport TE, Madi M, Dickinson K, Leslie K, Bull M, Hilliard N. An international survey of experiences and attitudes towards pacing using a heart rate monitor for people with myalgic encephalomyelitis/chronic fatigue syndrome. Work. 2023;74(4):1225-1234. doi: 10.3233/WOR-220512. PMID: 36938766.