Neurotransmitter and Neurochemical Findings

1 Yamamoto et al. 2004 β€” Serotonin Transporter Reduction in CFS

Full Citation:: Yamamoto S, Ouchi Y, Onoe H, et al. Reduction of serotonin transporters of patients with chronic fatigue syndrome. NeuroReport. 2004;15(17):2571–2574. DOI:: 10.1097/00001756-200412030-00002 PMID:: 15570154 Key Findings::

- PET imaging (DASB ligand) showed significantly reduced serotonin transporter density in CFS
- Reduction was most pronounced in the rostral subdivision of the anterior cingulate cortex (ACC)
- Demonstrates in vivo serotonergic dysfunction in ME/CFS using direct neuroimaging
- Provides neurobiological basis for sleep, mood, and cognitive symptoms in ME/CFS

2 Miller et al. 2014 β€” Basal Ganglia Activation and Dopamine in CFS

Full Citation:: Miller AH, Jones JF, Drake DF, Tian H, Unger ER, Pagnoni G@. Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue. PLoS One. 2014;9(5):e98156. DOI:: 10.1371/journal.pone.0098156 PMID:: 24858857 Sample Size:: 18 CFS patients, 41 healthy controls Key Findings::

- Significantly reduced right caudate nucleus and globus pallidus activation during reward tasks
- Diminished globus pallidus responsivity correlated with mental fatigue ($r^2 = 0.49$, $p = 0.001$)
- Proposes inflammatory cytokine-mediated disruption of basal ganglia dopamine availability
- Supports dopaminergic dysfunction as a contributor to ME/CFS fatigue

3 Dehhaghi et al. 2022 β€” Kynurenine Pathway and NAD+ in ME/CFS

Full Citation:: Dehhaghi M, Panahi HKS, Kavyani B, et al. The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Aging and Disease. 2022;13(3):698–711. DOI:: 10.14336/AD.2021.0824 PMID:: 35656104 Key Findings::

- Under inflammatory/IDO-1 activation, up to 90% of tryptophan is catabolized through the kynurenine pathway
- Pro-inflammatory cytokines (IFN-$\gamma$, TNF-$\alpha$) documented in ME/CFS drive IDO-1 activity
- Kynurenine pathway overactivation depletes NAD+ and produces neurotoxic quinolinic acid accumulation
- Mechanistic explanation for reduced serotonin precursor availability and neurotransmitter imbalances in ME/CFS

4 Murrough et al. 2010 β€” Increased Ventricular Lactate in CFS vs Major Depressive Disorder

Full Citation:: Murrough JW, Mao X, Collins KA, et al. Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR in Biomedicine. 2010;23(6):643–650. DOI:: 10.1002/nbm.1512 PMID:: 20661876 Sample Size:: n=17 CFS, n=21 MDD, n=19 healthy controls Key Findings::

- Ventricular CSF lactate significantly elevated in CFS vs healthy controls, replicating a prior Shungu-group study
- Ventricular lactate in major depressive disorder did not differ from healthy controls
- Lactate correlated with severity of mental fatigue specific to the CFS group

Conclusion:: Brain MRS lactate distinguishes CFS from major depressive disorder despite symptom overlap, supporting lactate as a differential biomarker. Limitations:: Single center; modest sample; ventricular CSF (global) rather than tissue-specific measurement.

5 Jones et al. 2025 β€” Neurometabolite Alterations in Gulf War Illness (Whole-Brain MRS)

Full Citation:: Jones C, Haskin O, Younger J. Neurometabolite alterations in Gulf War Illness: a whole-brain magnetic resonance spectroscopy study. Experimental Brain Research. 2025;243(11):237. DOI:: 10.1007/s00221-025-07174-w PMID:: 41137912 Sample Size:: n=20 GWI veterans, n=20 healthy veterans Key Findings::

- Widespread decreases in brain choline, N-acetylaspartate, and creatine in GWI vs healthy veterans
- Regional elevations in lactate and brain temperature
- No group difference in cerebral perfusion

Conclusion:: Chronic fatigue syndromes can share a brain metabolite signature (choline decrease, lactate increase); cross-disease parallel to ME/CFS lactate and long-COVID choline findings. Limitations:: Small sample; same UAB (Younger) methodology as the ME/CFS Mueller study, so not an independent methodological replication.

6 Sklinda et al. 2021 β€” Ischaemic Background of Brain Fog in Long-Haul COVID (MRS)

Full Citation:: Sklinda K, GΓ³recki A, Dorobek M, et al. Ischaemic background of brain fog in long-haul COVID-19 β€” a nuclear magnetic resonance spectroscopy-based metabonomic analysis. Preliminary results. Polish Journal of Radiology. 2021;86:e654–e660. DOI:: 10.5114/pjr.2021.111100 PMID:: 35059058 Sample Size:: n=11 brain-fog long COVID, n=14 healthy controls Key Findings::

- Routine MRI showed no macroscopic changes, but 1H MRS showed Glx and Lac concentration changes in brain fog patients
- Authors infer a probable ischaemic background to symptomatic brain fog

Conclusion:: Supports brain energy-metabolite alteration in long COVID, concordant with a hypoperfusion/ischaemia mechanism rather than a primary structural lesion. Limitations:: Pilot, very small sample, preliminary.

7 Pajuelo et al. 2024 β€” Choline in the Corpus Callosum of Post-COVID Patients

Full Citation:: Pajuelo D, Dezortova M, Hajek M, et al. Metabolic changes assessed by 1H MR spectroscopy in the corpus callosum of post-COVID patients. MAGMA. 2024;37(5):937–946. DOI:: 10.1007/s10334-024-01171-w PMID:: 38865058 Sample Size:: n=58 post-COVID, n=23 healthy controls Key Findings::

- Choline INCREASED in the splenium of the corpus callosum in OLDER (>40y) post-COVID patients only (p=0.02)
- No difference between symptomatic and asymptomatic patients

Conclusion:: Contrasts with the Godlewska dACC choline DECREASE; choline direction is region- and age-dependent, not a uniform reduction across the long-COVID brain. Limitations:: Single region (corpus callosum splenium); age-dependent effects limit generalizability.

8 Bravi et al. 2025 β€” Long-Term Effect of COVID-19 on Brain Metabolism and Connectivity

Full Citation:: Bravi B, Paolini M, Colombo F, et al. Long term effect of COVID-19 on brain metabolism and connectivity. Neuroscience. 2025;580:1–8. DOI:: 10.1016/j.neuroscience.2025.06.015 PMID:: 40516783 Sample Size:: n=64 COVID-19 survivors, n=33 healthy controls Key Findings::

- Higher glutamate and N-acetylaspartate in COVID-19 survivors vs controls, with a positive association with cognitive complaints
- Higher fractional anisotropy, lower diffusivity

Conclusion:: Offers a competing interpretation to an energy-deficit reading: brain metabolites may reflect repair/remyelination after SARS-CoV-2 infection. Limitations:: Cross-sectional at 3 years; interpretation of NAA/glutamate as cumulative repair is indirect.