Glossary of Medical and Scientific Terms

This glossary defines medical, biochemical, immunological, and statistical terms used throughout this document. Terms are organized alphabetically. Where a term is used in a specialized sense specific to ME/CFS research, the ME/CFS-specific usage is indicated.

1

2-Arachidonoylglycerol (2-AG): The most abundant endocannabinoid, acting as a full agonist at CB₁ and CB₂ receptors. Produced from PIP₂-derived DAG by DAG lipase. 2-AG is the primary retrograde signaling messenger at synapses, suppressing neurotransmitter release. Dysregulated 2-AG signaling impacts pain, inflammation, and neuroplasticity.

3β-HSD: 3β-Hydroxysteroid Dehydrogenase: an enzyme converting pregnenolone to progesterone and DHEA to androstenedione in steroidogenesis. Impaired 3β-HSD activity may alter neurosteroid balance in ME/CFS.

4-Hydroxynonenal (4-HNE): A major product of lipid peroxidation and a biomarker of ferroptosis (iron-dependent cell death). Elevated 4-HNE indicates oxidative damage to cell membranes. Measured in research settings to assess ferroptosis activity.

4-PBA: 4-phenylbutyrate (sodium phenylbutyrate): a chemical chaperone that reduces endoplasmic reticulum stress by facilitating protein folding and attenuating the unfolded protein response (UPR). Used experimentally for ER stress-related pathologies.

5-HT: 5-Hydroxytryptamine (Serotonin): a monoamine neurotransmitter involved in mood, sleep, appetite, pain perception, and GI function. Serotonergic dysfunction is implicated in multiple ME/CFS symptom domains.

5-HT3: 5-HT3 receptor: the only ligand-gated ion channel among serotonin receptors. Mediates nausea and vomiting; 5-HT3 antagonists (ondansetron) are used for ME/CFS-related nausea.

5-HT4: A serotonin receptor subtype on gut-nerve cells; stimulating it (with drugs such as prucalopride) increases gastric and intestinal motility, making it a prokinetic target.

2 A

AADC: Aromatic L-Amino Acid Decarboxylase: the enzyme that converts L-DOPA to dopamine and 5-HTP to serotonin. AADC requires pyridoxal phosphate (vitamin B6) as a cofactor; AADC dysfunction would impair both dopaminergic and serotonergic neurotransmission.

AAI: Atlantoaxial Instability: excessive movement between the first and second cervical vertebrae (C1–C2). Often coexists with CCI in ME/CFS patients with connective tissue disorders.

ACE: Angiotensin-Converting Enzyme: converts angiotensin I to angiotensin II in the RAAS. ACE dysregulation may contribute to vascular and autonomic dysfunction in ME/CFS.

acetyl-CoA: Acetyl Coenzyme A: the central metabolic intermediate, feeding the TCA cycle from carbohydrate (via PDH), fat (via β-oxidation), and protein (via amino acid degradation) metabolism. Acetyl-CoA availability limits TCA cycle flux; may be reduced in ME/CFS.

Acetylcholine (ACh): The primary neurotransmitter of the parasympathetic nervous system, also used at the neuromuscular junction and in central circuits governing attention, learning, and memory. Synthesized from choline and acetyl-CoA by choline acetyltransferase (ChAT). Reduced cholinergic tone is a hallmark of autonomic dysfunction in ME/CFS, contributing to tachycardia, GI dysmotility, and cognitive impairment.

Acetylcholinesterase (AChE): The enzyme that rapidly hydrolyzes acetylcholine in the synaptic cleft, terminating cholinergic signaling. Found at neuromuscular junctions and central cholinergic synapses. Acetylcholinesterase inhibitors (pyridostigmine, donepezil) prolong acetylcholine action and are used therapeutically in myasthenia gravis, Alzheimer’s disease, and experimentally in ME/CFS to enhance vagal tone and cognitive function.

ACh: Acetylcholine: the primary parasympathetic neurotransmitter. Reduced cholinergic (vagal) tone contributes to autonomic imbalance in ME/CFS.

AChE: Acetylcholinesterase: the enzyme that rapidly hydrolyzes acetylcholine in the synaptic cleft, terminating cholinergic signaling. Inhibited by pyridostigmine (Mestinon) to enhance parasympathetic vagal tone in ME/CFS/POTS.

Aconitase: A Krebs cycle enzyme that converts citrate to isocitrate. Its Fe-S cluster makes it sensitive to oxidative stress and iron availability. Aconitase exists in two cellular forms: mitochondrial (ACO2, Krebs cycle) and cytosolic (ACO1/IRP1, which doubles as an iron regulatory protein).

ACTH: Adrenocorticotropic Hormone: pituitary hormone stimulating cortisol release from the adrenal glands. Blunted ACTH responses contribute to low cortisol output in ME/CFS.

AD: Alzheimer’s Disease: the most common neurodegenerative dementia. Not a comorbidity of ME/CFS, but relevant to glymphatic clearance research.

ADCC (Antibody-Dependent Cellular Cytotoxicity): An immune mechanism where Fc receptor-bearing effector cells (NK cells, macrophages) recognize and kill antibody-coated target cells. Mediated by CD16 (FcγRIII) engagement. Reduced NK cell ADCC has been reported in ME/CFS.

Adenosine: A purine nucleoside structural component of ATP, ADP, AMP, and RNA. Acts as a signaling molecule through four GPCR subtypes (A₁, A₂A, A₂B, A₃), regulating sleep, inflammation, vasodilation, and immune function. Extracellular adenosine increases during cellular stress. Adenosine signaling dysregulation is relevant to ME/CFS through purinergic signaling, sleep dysfunction, and immune modulation.

ADHD: Attention-Deficit/Hyperactivity Disorder: a neurodevelopmental condition of inattention, hyperactivity, and impulsivity. Associated with ME/CFS via shared dopaminergic dysfunction and increased prevalence.

ADP: Adenosine Diphosphate: the product of ATP hydrolysis. Elevated ADP/ATP ratios in ME/CFS indicate impaired energy metabolism.

Adrenal: The adrenal glands sit atop the kidneys and produce cortisol (zona fasciculata), aldosterone (zona glomerulosa), DHEA (zona reticularis), and catecholamines (adrenal medulla). Adrenal dysfunction in ME/CFS includes blunted cortisol output, low DHEA-S, and altered catecholamine secretion — reflecting HPA axis dysregulation.

Aerobic glycolysis: Glycolysis occurring in the presence of oxygen, with pyruvate entering the Krebs cycle rather than being converted to lactate. Distinct from anaerobic glycolysis.

AHR: Aryl Hydrocarbon Receptor: a ligand-activated transcription factor sensing environmental toxins and tryptophan metabolites (kynurenine). AHR activation by kynurenine shifts T-cell differentiation toward Treg vs Th17; the IDO-KYN-AHR axis links tryptophan metabolism to immune regulation in ME/CFS.

AHRQ: Agency for Healthcare Research and Quality — US federal agency that produces evidence to improve healthcare safety and quality through systematic reviews.

AIMM: Acquired Ischemic Mitochondrial Myopathy: mitochondrial damage in muscle tissue caused by impaired microvascular oxygen delivery rather than a primary mitochondrial defect. AIMM links endothelial dysfunction → tissue hypoxia → mitochondrial dysfunction in ME/CFS, suggesting the primary lesion may be vascular, not mitochondrial.

AIP: Autoimmune Protocol diet: an elimination diet removing potentially immunogenic foods (grains, legumes, nightshades, dairy, eggs, nuts, seeds) followed by structured reintroduction. Used experimentally in ME/CFS patients with suspected autoimmune or food-sensitivity components.

AKT: AKT (Protein Kinase B): a serine/threonine kinase downstream of PI3K that regulates metabolism, cell survival, and protein synthesis via mTOR and FOXO. Reduced AKT signaling may contribute to ME/CFS metabolic inflexibility and immune dysfunction.

aldosterone: A mineralocorticoid hormone regulating sodium retention, potassium excretion, and blood volume. Low aldosterone or aldosterone resistance may contribute to hypovolemia and orthostatic intolerance in ME/CFS/POTS.

allodynia: Pain caused by a stimulus that does not normally provoke pain (e.g., light touch, clothing, breeze). Allodynia in ME/CFS reflects central sensitization of pain pathways and is a hallmark of comorbid fibromyalgia.

allostatic load: The cumulative physiological wear and tear from chronic stress or repeated adaptive responses. ME/CFS can be framed as a state of decompensated allostatic overload where the body’s regulatory systems (HPA axis, ANS, immune) lose their adaptive capacity.

ALP: Alkaline Phosphatase: an enzyme from liver, bone, and placenta. Elevated ALP requires differential diagnosis (liver disease, bone disease). Generally normal in ME/CFS.

ALS: Amyotrophic Lateral Sclerosis: a progressive neurodegenerative disease of motor neurons. Severe fatigue can be a prodromal feature.

ALT: Alanine Aminotransferase: liver enzyme measured in standard blood panels. Normal in ME/CFS despite fatigue and malaise.

AMH: Anti-Müllerian hormone: a blood marker of ovarian reserve; higher levels indicate more remaining egg follicles, and it is stable across the menstrual cycle.

AMP: Adenosine Monophosphate: a nucleotide and energy-sensing molecule. Elevated AMP activates AMPK, the cellular energy sensor frequently implicated in ME/CFS metabolic dysfunction.

AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: the main fast-acting receptor for the excitatory neurotransmitter glutamate at most synapses. Its trafficking into and out of the postsynaptic membrane is a key mechanism of synaptic plasticity.

AMPK: AMP-Activated Protein Kinase: the cellular energy sensor activated by rising AMP/ATP ratios. Impaired AMPK activation may prevent appropriate energy-conservation responses in ME/CFS.

amygdala: An almond-shaped structure in the temporal lobe mediating fear, anxiety, and emotional salience. Amygdala hyperactivity in ME/CFS may drive hypervigilance, anxiety, and exaggerated stress responses.

ANA: Anti-Nuclear Antibody — an autoantibody targeting components of the cell nucleus, used as a screening test for autoimmune diseases.

Anaerobic threshold (AT): The exercise intensity above which lactate production exceeds clearance, causing blood lactate to rise. Reduced in ME/CFS.

Anandamide (AEA): An endocannabinoid neurotransmitter (N-arachidonoylethanolamine) that activates CB₁ and CB₂ receptors, modulating pain, mood, appetite, and memory. Anandamide is degraded by fatty acid amide hydrolase (FAAH). Dysregulated endocannabinoid signaling may contribute to ME/CFS pain amplification and sleep disturbance.

ANC: Absolute Neutrophil Count: the number of neutrophils per microliter of blood. Neutropenia (low ANC) can occur with certain ME/CFS treatments (valacyclovir, rituximab) or as a drug side effect requiring monitoring.

ANCOVA: Analysis of Covariance: ANOVA adjusted for covariates (e.g., age, sex, BMI). Important in ME/CFS studies to control for confounding variables.

Anelloviruses: A large family of small single-stranded DNA viruses (family Anelloviridae, including Torque teno virus, TTV) found in 80–90% of the human population. They establish lifelong, generally harmless infection and are increasingly interpreted as markers of immune competence or dysregulation rather than as disease-causing agents.

angiogenesis: The formation of new blood vessels from existing vasculature. Dysregulated angiogenesis via VEGF may contribute to microvascular abnormalities observed in ME/CFS.

ANOVA: Analysis of Variance: a statistical test comparing means across multiple groups. Widely used in ME/CFS biomarker studies to compare patient subgroups vs controls.

ANP: Atrial Natriuretic Peptide: heart-derived hormone promoting sodium excretion and vasodilation. ANP levels may be altered in ME/CFS-related dysautonomia.

ANS: Autonomic Nervous System: the branch of the nervous system controlling involuntary functions (heart rate, blood pressure, digestion, temperature). Dysfunction of the ANS is central to ME/CFS pathophysiology.

ANT: Adenine Nucleotide Translocator: the mitochondrial inner membrane transporter exchanging matrix ATP for cytosolic ADP. ANT is a core component of the mPTP and its function is impaired by oxidative stress; ANT dysfunction locks ATP inside failing mitochondria in ME/CFS.

anterior cingulate cortex: The ACC is a cortical region involved in error detection, conflict monitoring, pain processing, and autonomic regulation. ACC dysfunction in ME/CFS links to cognitive effort intolerance and altered pain perception.

anti-neuronal antibodies: Autoantibodies that bind proteins or receptors on neuronal cell surfaces, including dopamine D1/D2 receptors, tubulin, lysosomal-associated proteins, and CaMKII. In PANS/PANDAS, anti-neuronal antibodies generated by molecular mimicry disrupt dopamine signaling in the basal ganglia, producing obsessive-compulsive and motor symptoms. Parallel anti-neuronal antibody mechanisms (e.g., anti-GPCR antibodies) are documented in ME/CFS, suggesting shared pathophysiology.

AP-1: Activator Protein 1: a dimeric transcription factor (c-Fos/c-Jun) activated by MAPK signaling (JNK, ERK). AP-1 drives pro-inflammatory and stress-response genes; AP-1 activation links MAPK dysregulation to inflammation in ME/CFS.

apathy: A reduction in motivation, interest, and goal-directed behaviour that is distinct from depression. In long COVID and post-infectious illness, apathy has been linked to reduced dopaminergic terminals in the ventral striatum.

apoptosis: Programmed cell death — a controlled, non-inflammatory form of cellular suicide. Increased lymphocyte apoptosis has been reported in ME/CFS; failure to clear apoptotic debris may contribute to autoimmunity.

aPTT: Activated Partial Thromboplastin Time: a coagulation test measuring the intrinsic and common pathways. Used to screen for bleeding disorders and monitor heparin therapy.

AQP2: Aquaporin-2: the vasopressin-regulated water channel in renal collecting ducts controlling water reabsorption. AQP2 dysfunction or impaired vasopressin signaling may contribute to the nocturia and fluid dysregulation frequently reported in ME/CFS/POTS.

AQP4: Aquaporin-4: a water-channel protein highly expressed on astrocyte end-feet, essential for glymphatic clearance of brain waste products. Inhibited by sustained norepinephrine, linking sympathetic overactivation to impaired brain waste removal in ME/CFS.

area postrema: A brainstem sensory circumventricular organ that senses circulating inflammatory signals and nausea/vomiting triggers and, in animal models, is the origin of a neural circuit that suppresses eating, drinking, and movement (sickness behavior).

arterial spin labelling (ASL): A non-invasive MRI technique that measures cerebral blood flow by magnetically tagging arterial blood and detecting its arrival in brain tissue, without contrast dye. Used in ME/CFS research to quantify regional brain perfusion and its response to challenges such as hypoxia.

ASD: Autism Spectrum Disorder: a neurodevelopmental condition of social communication differences and restricted/repetitive behaviors. Higher prevalence in ME/CFS cohorts; both conditions share sensory sensitivities and autonomic dysregulation.

Aspartate (Asp): An amino acid involved in the malate-aspartate shuttle, urea cycle, and purine nucleotide synthesis. Aspartate is also an excitatory neurotransmitter acting on NMDA receptors. The malate-aspartate shuttle is critical for transferring reducing equivalents into mitochondria.

Aspiration: Breathing foreign material (food, fluid, or saliva) into the lungs, which can cause pneumonia; in bedbound or severely deconditioned patients it may be silent and present as confusion or low-grade fever rather than choking.

AST: Aspartate Aminotransferase: liver enzyme commonly measured in blood panels. Generally normal in ME/CFS; elevated AST suggests other pathology.

astrocyte: Star-shaped glial cells that support neurons metabolically, regulate extracellular ion and neurotransmitter levels, form the blood-brain barrier, and mediate glymphatic clearance via AQP4 channels. Astrocyte dysfunction in ME/CFS impairs brain energy metabolism and waste clearance.

AT1R: Angiotensin II Type 1 Receptor: the primary receptor mediating angiotensin II effects (vasoconstriction, aldosterone release, inflammation). AT1R overactivation contributes to oxidative stress and vascular dysfunction in ME/CFS.

ATAC-seq (Assay for Transposase-Accessible Chromatin): A technique measuring chromatin accessibility genome-wide, used to detect whether a gene’s regulatory region is open (active) or closed; distinguishes transcriptionally-active from epigenetically-fixed (locked) cell states.

ATF4: Activating Transcription Factor 4: a stress-responsive transcription factor whose translation is selectively upregulated when eIF2α is phosphorylated. ATF4 controls amino acid metabolism, antioxidant genes, and autophagy; chronic ATF4 activation in ME/CFS may drive metabolic reprogramming.

ATF6: Activating Transcription Factor 6: the third UPR sensor, a transmembrane protein that traffics to the Golgi upon ER stress, where it is cleaved to release an active transcription factor that induces ER chaperones.

ATP: Adenosine Triphosphate: the primary energy currency of cells. Impaired ATP production via mitochondrial dysfunction is a central hypothesis in ME/CFS energy failure.

ATP Synthase (Complex V): The mitochondrial enzyme complex that synthesizes ATP from ADP and inorganic phosphate using the proton gradient generated by the electron transport chain. Consists of F₁ (catalytic) and F₀ (proton channel) domains. ATP synthase dysfunction reduces cellular energy production in ME/CFS.

AUC: Area Under the receiver operating characteristic Curve: a measure of diagnostic test performance (0.5 = random; 1.0 = perfect). ME/CFS biomarker panels aim for AUC > 0.80 for clinical utility.

autoantibody: An antibody directed against the body’s own proteins or receptors. Functional autoantibodies against GPCRs (adrenergic, muscarinic, angiotensin receptors) have been identified in subsets of ME/CFS and POTS, potentially explaining autonomic and vascular symptoms.

autophagy: The cellular self-digestion process that degrades damaged organelles, protein aggregates, and pathogens, recycling components for reuse. Impaired autophagy in ME/CFS may accumulate mitochondrial damage and protein aggregates, perpetuating cellular dysfunction.

AYUSH: Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy — India’s Ministry of AYUSH promotes integration of these traditional medicine systems with conventional healthcare. Acupuncture and traditional medicine access in India is partly structured through AYUSH.

3 B

B cell: B lymphocytes: antibody-producing immune cells. B cell dysregulation in ME/CFS includes expanded autoreactive clones, altered subset distribution, and abnormal response to EBV-infected cells. The negative RituxME trial does not preclude B cell involvement in a subset.

Babesia: A tick-borne protozoan parasite (Babesia microti, B. divergens) infecting red blood cells, causing babesiosis (fever, hemolytic anemia, fatigue). A known co-infection with Lyme disease; chronic babesiosis can produce ME/CFS-like fatigue and must be considered in the differential diagnosis.

BAFF (B-cell Activating Factor): A TNF family cytokine (BLyS) essential for B cell survival, maturation, and antibody production. Overexpression of BAFF promotes autoreactive B cell survival and autoantibody production. Elevated BAFF may contribute to the B cell abnormalities and autoantibody generation in ME/CFS.

BALT: Bronchus-Associated Lymphoid Tissue: organized immune structures in the respiratory tract containing B cells, T cells, and plasma cells capable of local antibody production.

Baroreceptor: Stretch-sensitive nerve endings in the carotid sinus and aortic arch that detect blood pressure changes, forming the afferent limb of the baroreflex. Baroreflex dysfunction in ME/CFS impairs the ability to maintain blood pressure when upright, directly contributing to orthostatic intolerance.

Baroreflex: The reflex arc that maintains blood pressure by adjusting heart rate and vascular tone in response to changes detected by arterial baroreceptors.

Bartonella: A genus of intracellular bacteria causing cat-scratch disease (B. henselae) and trench fever (B. quintana). Tick-borne Bartonella co-infections are common in Lyme disease; chronic Bartonella may cause neuropsychiatric symptoms, fatigue, and vasculitis that overlap with ME/CFS.

basal ganglia: A group of interconnected subcortical nuclei (caudate, putamen, globus pallidus, substantia nigra, subthalamic nucleus) that coordinate motor control, habit learning, and executive function. The basal ganglia are the primary target of anti-neuronal antibodies in PANS/PANDAS/Sydenham chorea; basal ganglia dysfunction also contributes to movement abnormalities and cognitive inflexibility in ME/CFS.

basophil: A type of white blood cell that, like mast cells, stores and releases histamine. A comparatively minor blood cell in number, but it contributes to allergic responses; mast cells and basophils together are the main histamine stores.

BAX: BCL-2-Associated X protein: a pro-apoptotic BCL-2 family protein that forms pores in the mitochondrial outer membrane during apoptosis, releasing cytochrome c. BAX activation may be increased in ME/CFS metabolic stress.

BBB: Blood-Brain Barrier: the highly selective semipermeable border separating circulating blood from the brain. BBB dysfunction/permeability is implicated in ME/CFS neuroinflammation.

BCL-2: B-Cell Lymphoma 2: the prototypical anti-apoptotic protein that inhibits BAX/BAK pore formation. Reduced BCL-2/BAX ratios indicate a pro-apoptotic shift; may be altered in ME/CFS lymphocytes.

BDNF: Brain-Derived Neurotrophic Factor: a protein supporting neuronal survival, growth, and synaptic plasticity. Altered BDNF levels have been reported in ME/CFS.

Bell Disability Scale: A 0–100 rating scale for functional capacity in ME/CFS, where 100 represents normal function and 0 represents bedridden and dependent.

Benzoate: A carboxylate compound from dietary sources (e.g., benzoic acid preservatives, plant foods) and microbial metabolism. In ME/CFS, BioMapAI reports an increased benzoate-to-hippurate transformation, which the model attributes to sleep, emotional, and fatigue symptoms — though this is model output, not held-out validated.

Beta-amyloid (Aβ): β-Amyloid (Aβ): a 36–43 amino-acid peptide cleaved from the amyloid precursor protein (APP) by β- and γ-secretase. Aβ is cleared from the brain chiefly by the glymphatic system during slow-wave sleep. Its accumulation is a hallmark of Alzheimer’s disease. In ME/CFS, chronic glymphatic-impairment risk raises a hypothetical (untested) question about long-term Aβ accumulation; no ME/CFS Aβ data exist. The hypothesis that the sleep drug daridorexant (a dual orexin receptor antagonist) could reduce Aβ is mechanistic speculation with no primary evidence.

Beta-hydroxybutyrate: β-Hydroxybutyrate (BHB): the primary ketone body, serving as an alternative brain fuel during carbohydrate restriction or fasting. BHB also functions as a signaling molecule — it inhibits HDACs (epigenetic regulation) and activates HCA2/GPR109A (anti-inflammatory). Ketone metabolism may bypass the PDH gate that is impaired in ME/CFS.

Beta2-adrenergic autoantibodies (β2-Abs): Autoantibodies targeting the β2-adrenergic receptor, identified in ME/CFS subsets. May contribute to vascular and autonomic dysfunction.

BH4: Tetrahydrobiopterin: an essential cofactor for nitric oxide synthase, tyrosine hydroxylase, tryptophan hydroxylase, and phenylalanine hydroxylase. BH4 depletion is a convergent mechanism linking vascular, neurotransmitter, and inflammatory dysfunction in ME/CFS.

bioavailability: The fraction of an administered drug dose that reaches systemic circulation unchanged. Oral bioavailability may be altered in ME/CFS due to GI dysmotility, SIBO, or altered first-pass metabolism.

BioMapAI: A supervised deep neural network trained on a 4-year longitudinal multi-omics dataset (n=249) to integrate gut metagenomics, plasma metabolomics, immune profiling, blood labs, and clinical symptoms for ME/CFS. It classified ME/CFS from controls (AUC=0.99) and built an explainable microbiome-immune-metabolome connectivity map, though the headline AUC is partly inflated by the model learning its diagnostic symptoms (symptom circularity).

biomarker: A measurable biological indicator of a disease state, severity, or treatment response. No validated diagnostic biomarker exists for ME/CFS, though candidates include 2-day CPET, cytokine panels, metabolomic signatures, EEG alpha-delta sleep, and microRNA profiles.

Bistability: A dynamical system property in which two stable steady states coexist for the same parameter values, separated by an unstable equilibrium (separatrix). Transition between states requires a perturbation exceeding a threshold. In ME/CFS, bistability models propose that metabolic or immune networks can switch between healthy and disease states and become ‘trapped’ in the disease state.

blood volume: The total volume of blood in the circulatory system. ME/CFS patients often have reduced blood volume (by 10–30%), driven by low renin-aldosterone, autonomic dysfunction, and possible venous pooling, contributing substantially to orthostatic intolerance.

BMAL1: Brain and muscle ARNT-like 1 — core clock gene that forms the CLOCK-BMAL1 heterodimer driving circadian transcription of PER, CRY, and clock-controlled output genes.

BMI: Body Mass Index: weight-to-height ratio. Not a diagnostic tool for ME/CFS; however, weight changes (gain or loss) can occur due to reduced activity, metabolic shifts, or comorbid conditions.

BNP: B-Type Natriuretic Peptide: ventricular hormone responding to cardiac stretch. Used clinically to assess heart failure; generally normal in ME/CFS.

boom-bust cycle: A self-reinforcing pattern where a patient overexerts on good days (‘boom’), triggering PEM, forcing prolonged rest (‘bust’), then overexerts again when feeling marginally better. Pacing aims to break this cycle.

Borg RPE: Borg Rating of Perceived Exertion: a validated scale (6–20 or 0–10) for quantifying subjective exercise intensity. ME/CFS patients consistently rate perceived exertion higher than healthy controls at the same absolute workload, reflecting the amplified effort cost of physical activity.

BP: Blood Pressure: the pressure of circulating blood on vessel walls. Orthostatic BP changes are central to ME/CFS autonomic assessment; many patients show either orthostatic hypotension or a blunted/nocturnal BP dip.

bradykinin: A potent vasodilatory and pro-inflammatory peptide of the kallikrein-kinin system that increases vascular permeability and stimulates pain nerve endings. Bradykinin-mediated angioedema overlaps with MCAS histamine-mediated swelling, and bradykinin may contribute to vascular leak and pain in ME/CFS.

brain fog: A colloquial term for the cognitive dysfunction of ME/CFS: impaired working memory, attention, word-finding, processing speed, and executive function. Not a formal medical term, but universally recognized by patients and now used in research literature.

brainstem: The stalk connecting the brain to the spinal cord, containing vital autonomic, cardiovascular, and respiratory control centers. Brainstem hypoperfusion and neuroinflammation are consistently reported in ME/CFS and may underpin orthostatic intolerance and autonomic failure.

BRANDO: Blinding-Relevant Assessment of Non-specific effects and Demand characteristics in Outcome — a framework for evaluating whether unblinding bias explains positive trial results.

brown adipose tissue: A type of fat tissue rich in mitochondria and the protein UCP1 that generates heat (non-shivering thermogenesis) to raise body temperature and drive arousal from torpor/hypothermia.

BUN: Blood Urea Nitrogen: a marker of kidney function and protein metabolism. BUN may be elevated in dehydration (common in ME/CFS with POTS due to low fluid intake) or kidney disease.

Butyrate: A short-chain fatty acid produced by gut bacteria from dietary fiber. Maintains intestinal barrier integrity and exerts anti-inflammatory effects.

4 C

CAD: Coronary Artery Disease: atherosclerotic narrowing of coronary arteries. ME/CFS is not a risk factor, but overlapping chest pain/fatigue symptoms require differential diagnosis.

Calcitonin: A peptide hormone from thyroid C-cells that lowers blood calcium by inhibiting osteoclast activity. Calcitonin belongs to the calcitonin gene-related peptide (CGRP) family, which includes potent vasodilators implicated in migraine — relevant to ME/CFS headache and vascular symptoms.

Calcium (Ca²⁺): The most abundant mineral in the human body and a universal intracellular second messenger. Cytosolic calcium concentration is tightly regulated by channels, pumps (SERCA, PMCA), and exchangers (NCX). Dysregulated calcium signaling contributes to mitochondrial dysfunction, excitotoxicity, and immune dysregulation — each relevant to ME/CFS pathophysiology.

Calcium Channel: A transmembrane ion channel selectively permeable to calcium ions (Ca²⁺). Includes voltage-gated calcium channels (Cav1–Cav3 subtypes) that open in response to membrane depolarization, and ligand-gated channels (e.g., NMDA receptors, TRP channels). Calcium influx through these channels triggers neurotransmitter release, muscle contraction, gene expression, and metabolic regulation.

Calmodulin (CaM): A ubiquitous calcium-binding messenger protein that mediates intracellular calcium signaling. Upon binding Ca²⁺, calmodulin undergoes a conformational change enabling it to activate target proteins including CaMKII, calcineurin, and MLCK. Links calcium influx to gene expression, neurotransmitter release, and cytoskeletal dynamics.

Calprotectin (S100A8/S100A9): A heterodimeric calcium- and zinc-binding protein complex released by neutrophils and monocytes during inflammation. Fecal calprotectin is a clinical biomarker for intestinal inflammation (IBD). Elevated fecal calprotectin in ME/CFS may indicate low-grade gut inflammation and barrier dysfunction.

CaMK: Calcium/Calmodulin-dependent Kinase: a family of serine/threonine kinases activated by calcium-bound calmodulin. CaMKII is critical for learning, memory, and cardiac function; calcium signaling dysfunction in ME/CFS may impair CaMK-dependent processes.

CaMKII: Calcium/calmodulin-dependent protein kinase II: a multifunctional serine/threonine kinase highly expressed in brain and heart, where it regulates synaptic plasticity, learning, memory, and cardiac calcium handling. CaMKII overactivation in PANS/PANDAS links anti-neuronal antibodies to disrupted dopamine and glutamate signaling in the basal ganglia — a signaling node relevant to neuroimmune dysfunction in ME/CFS.

cAMP: Cyclic Adenosine Monophosphate: a ubiquitous second messenger produced by adenylyl cyclase (AC) from ATP, degraded by phosphodiesterases (PDEs). cAMP/PKA signaling regulates energy metabolism, immune function, and synaptic plasticity; cAMP dysregulation is reported in ME/CFS.

Campylobacter: A bacterial genus (primarily C. jejuni) causing gastroenteritis and a major trigger of Guillain-Barré syndrome via molecular mimicry between bacterial ganglioside-like structures and peripheral nerve antigens. Campylobacter is a model organism for infection-triggered autoimmunity — directly relevant to the post-infectious ME/CFS paradigm.

CAP: Cholinergic Anti-inflammatory Pathway: a vagus nerve-mediated reflex where efferent vagal signals release acetylcholine, which binds α7 nicotinic receptors on splenic macrophages, suppressing TNF-α and other pro-inflammatory cytokines. Impaired CAP (low vagal tone) may permit unchecked peripheral inflammation in ME/CFS.

Capillary-to-fibre ratio: The number of capillaries supplying each muscle fibre — a structural measure of oxygen delivery capacity at the tissue level.

CAR: Cortisol Awakening Response: the natural rise in cortisol levels in the first 30-45 minutes after waking, a marker of HPA axis integrity. Blunted CAR is one of the most consistent neuroendocrine findings in ME/CFS.

CAR-T (Chimeric Antigen Receptor T cell): A cancer immunotherapy in which a patient’s T cells are modified in the lab to recognize a specific molecular target, then reinfused. No evidence base supports CAR-T for ME/CFS.

Cardiolipin (CL): A unique dimeric phospholipid found almost exclusively in the inner mitochondrial membrane. Essential for maintaining mitochondrial cristae structure, stabilizing electron transport chain supercomplexes, and facilitating ATP synthesis. Cardiolipin peroxidation triggers ferroptosis. Autoantibodies against cardiolipin are found in antiphospholipid syndrome and some ME/CFS patients.

Carotid body: A small cluster of chemoreceptor cells at the carotid artery bifurcation that senses blood oxygen, CO₂, and pH, driving ventilatory responses to hypoxia. Carotid body dysfunction has been proposed in ME/CFS dysautonomia — inappropriate chemoreflex activation could drive hyperventilation and sympathetic overactivation.

case-control: A study design comparing individuals with a disease (cases) to those without (controls), looking retrospectively at exposures or biomarkers. The most common ME/CFS study design; limited by selection bias and reverse causation.

Caspase: A family of cysteine-aspartic proteases that execute programmed cell death (apoptosis) and mediate inflammation. Initiator caspases (caspase-8, -9) activate executioner caspases (caspase-3, -6, -7). Caspase-1 (part of the NLRP3 inflammasome) cleaves pro-IL-1β and pro-IL-18.

CASS: Composite Autonomic Severity Score. A standardized scoring system that quantifies the severity of autonomic failure based on sudomotor, cardiovagal, and adrenergic function test results.

caudate: A dorsal-striatum structure involved in motor control, learning, and memory/executive function. Dopaminergic loss in the caudate is associated with cognitive decline and word-finding difficulty in long COVID.

Cav2.x: Voltage-gated calcium channel family type 2 (P/Q-type Cav2.1, N-type Cav2.2, R-type Cav2.3). These channels are primarily expressed in neurons where they control neurotransmitter release at presynaptic terminals. Cav2.x dysfunction can impair synaptic transmission, contributing to cognitive dysfunction and autonomic dysregulation. Autoantibodies against Cav2.1 are implicated in Lambert-Eaton syndrome and some cerebellar ataxias.

CBC: Complete Blood Count — a routine blood test measuring red blood cells, white blood cells, hemoglobin, hematocrit, and platelets. Used in ME/CFS diagnostic workup to exclude anaemia as a cause of fatigue.

CBF: Cerebral Blood Flow. The volume of blood perfusing brain tissue per unit time, typically measured by Doppler ultrasound (transcranial), MRI (arterial spin labeling), or SPECT. Reduced CBF during orthostatic challenge is a hallmark of ME/CFS dysautonomia.

CBT: Cognitive-Behavioral Therapy: a psychological intervention. No longer recommended by NICE as a curative treatment for ME/CFS; may have supportive role for coping with chronic illness but does not address underlying pathophysiology.

CCC: Canadian Consensus Criteria (2003): ME/CFS diagnostic criteria requiring PEM plus multiple symptom domains (fatigue, sleep, pain, neurological/cognitive, autonomic, neuroendocrine, immune). Widely used in research.

CCI: Craniocervical Instability: abnormal movement at the junction of the skull and upper cervical spine, potentially compressing the brainstem and causing neurological symptoms. A controversial but recognized finding in a subset of severe ME/CFS patients.

CCL11: Eotaxin-1: a chemokine (immune signalling molecule) that rises after some viral infections, promotes microglial reactivity, and has been linked to impaired hippocampal neurogenesis and cognitive symptoms.

CCR4: C-C chemokine receptor type 4 — a cell-surface protein on T cells that directs migration toward CCL17/CCL22 chemokines.

CCR6: C-C chemokine receptor type 6 — a cell-surface protein on T cells and dendritic cells that binds CCL20 and directs immune cell homing to mucosal tissues.

CD8+ TEM: CD8+ Effector Memory T Cells: a T-cell subset (CD3+CD8+CD45RA-CCR7-) capable of rapid effector function upon antigen re-encounter. The most severely dysregulated T-cell population in ME/CFS, showing metabolic dysfunction, mitochondrial membrane potential loss, and exhaustion transcription factor upregulation.

CDC: Centers for Disease Control and Prevention (US): the US public health agency responsible for ME/CFS surveillance, research funding, and clinical guidance (Fukuda 1994 criteria).

CDE: Common Data Element — a standardized data collection field used across clinical research studies to enable comparison and pooling of data.

Cell danger response (CDR): A conserved metabolic response to cellular threat, characterized by reduced mitochondrial function and extracellular ATP/ADP signaling. Proposed as a unifying mechanism in ME/CFS by Naviaux.

Central motor drive: The output signal from the brain (motor cortex and connected subcortical circuits) that drives muscles to contract. A failure to increase central motor drive under sustained effort means the brain does not push the muscle harder as it tires, even though the muscle itself can produce maximum force.

central sensitization: Increased responsiveness of nociceptive neurons in the CNS to normal or subthreshold afferent input. Explains widespread pain, allodynia, and hyperalgesia in ME/CFS and fibromyalgia beyond what peripheral pathology would predict.

cerebral hypoperfusion: Reduced blood flow to the brain. SPECT and MRI studies consistently demonstrate cerebral hypoperfusion in ME/CFS, particularly in the brainstem, frontal lobes, and temporal lobes, correlating with cognitive symptom severity.

Ceruloplasmin: A copper-containing ferroxidase enzyme that converts Fe²⁺ to Fe³⁺, enabling iron to bind to transferrin after export from cells via ferroportin. Without functional ceruloplasmin, exported iron cannot be loaded onto transferrin and is lost to non-specific reuptake.

CFS/ME: An alternative ordering of the combined term Chronic Fatigue Syndrome / Myalgic Encephalomyelitis.

cGAS: Cyclic GMP-AMP Synthase: a cytosolic DNA sensor producing cGAMP upon detecting double-stranded DNA. cGAS activation by leaked mitochondrial DNA is a candidate mechanism linking mitochondrial damage to innate immune activation in ME/CFS.

cGMP: Cyclic Guanosine Monophosphate: a second messenger produced by guanylyl cyclase (soluble sGC activated by NO, or particulate pGC activated by natriuretic peptides). cGMP mediates vasodilation via PKG; NO-sGC-cGMP signaling dysfunction may contribute to impaired endothelial vasodilation in ME/CFS.

CGRP (Calcitonin Gene-Related Peptide): A 37-amino-acid neuropeptide released from sensory nerve endings that mediates vasodilation and pain signaling. CGRP is implicated in migraine and may contribute to headache, allodynia, and neurogenic inflammation in ME/CFS. CGRP receptor antagonists (gepants) and monoclonal antibodies are used for migraine prevention.

Chemoreceptor: Sensory receptors detecting chemical changes in blood or interstitial fluid. Peripheral chemoreceptors in the carotid and aortic bodies sense O₂/CO₂/pH; central chemoreceptors in the brainstem sense CO₂/pH. Chemoreflex hypersensitivity may contribute to hyperventilation and dyspnea in ME/CFS.

Chloride (Cl⁻): The primary extracellular anion, essential for maintaining osmotic balance and electrical neutrality. Chloride channels (GABA-A, CFTR, CLC family) regulate neuronal excitability, fluid secretion, and pH homeostasis. GABA-A receptor-mediated Cl⁻ influx underlies inhibitory neurotransmission.

Cholesterol: A sterol lipid essential for cell membrane fluidity, lipid raft formation, and the precursor for all steroid hormones, vitamin D, and bile acids. Dysregulated cholesterol metabolism, including altered LDL/HDL ratios, has been reported in ME/CFS.

Cholinergic: Pertaining to the neurotransmitter acetylcholine or its signaling pathways. Cholinergic neurons include preganglionic autonomic fibers, postganglionic parasympathetic fibers, and basal forebrain projections regulating attention and memory. The cholinergic anti-inflammatory pathway (vagus nerve → α7 nAChR → splenic macrophage TNF suppression) is impaired in ME/CFS due to reduced vagal tone.

CHOP: C/EBP Homologous Protein (also GADD153): a pro-apoptotic transcription factor induced by severe/prolonged ER stress via ATF4. CHOP promotes cell death when UPR adaptation fails; elevated CHOP in ME/CFS may indicate unresolved ER stress.

choroid plexus: A network of cells in the brain’s ventricles that produces cerebrospinal fluid and forms the blood-CSF barrier; also functions as a metabolic sensor that may help initiate arousal from torpor.

chromatin: The complex of DNA and proteins (histones) that packages the genome; its 3D folding state regulates gene expression and is measured by chromosome-conformation platforms such as EpiSwitch.

Chronic Fatigue Syndrome: An older diagnostic term for ME/CFS, now largely superseded by more specific case definitions (CCC, ICC, IOM/SEID). Defined by unexplained fatigue plus 4 of 8 accessory symptoms. Does not require PEM, making it less specific than modern criteria.

Chronic Lyme disease: A controversial term for persistent symptoms after Lyme disease treatment. The IDSA defines post-treatment Lyme disease syndrome (PTLDS) as persistent fatigue, pain, and cognitive dysfunction after appropriate antibiotic treatment in confirmed Lyme. Chronic Lyme and ME/CFS share substantial symptom overlap; distinguishing them requires thorough infectious disease evaluation.

Chymase: A serine protease stored in mast cell secretory granules, released during degranulation. Converts angiotensin I to angiotensin II, activates IL-1β and MMP-9, and degrades extracellular matrix. Chymase contributes to tissue inflammation and fibrosis in MCAS and related conditions.

CI: Confidence Interval: a range of values likely to contain the true population parameter. 95% CI is the standard; wide CIs in ME/CFS studies often reflect small sample sizes.

Circadian rhythm: Endogenous biological oscillations with approximately 24-hour periodicity, governed by the suprachiasmatic nucleus and peripheral clock genes.

circumventricular organs: Brain regions lacking a blood-brain barrier, allowing direct sensing of circulating signals (cytokines, hormones, osmolality). CVOs are key entry points for peripheral inflammatory signals to reach the brain in ME/CFS sickness behavior.

Citrate: A tricarboxylic acid and the first intermediate of the Krebs (TCA) cycle, formed by condensation of acetyl-CoA with oxaloacetate via citrate synthase. Beyond the TCA cycle, citrate is exported to the cytoplasm for fatty acid synthesis and regulates glycolysis through inhibition of phosphofructokinase (PFK).

CK: Creatine Kinase: enzyme involved in ATP regeneration in muscle. Generally normal in ME/CFS despite severe fatigue, distinguishing it from primary muscle diseases.

CLOCK: Circadian Locomotor Output Cycles Kaput — core clock gene that heterodimerizes with BMAL1 to drive circadian transcription. CLOCK polymorphisms have been associated with circadian rhythm disorders and metabolic syndrome.

Clostridium: A genus of anaerobic bacteria including C. difficile (antibiotic-associated colitis), a major gut dysbiosis pathogen. Clostridium species produce short-chain fatty acids and secondary bile acids that regulate gut barrier function and immune tolerance — Clostridium depletion in ME/CFS gut dysbiosis may impair these protective functions.

Cmax: Maximum plasma concentration — the peak drug level achieved after a dose. Drug interactions that increase Cmax may cause toxicity even if the total drug exposure (AUC) remains within theraptic range.

CME: Continuing Medical Education — educational activities that maintain and develop the knowledge and skills of medical professionals after formal training.

CMV: Cytomegalovirus: a common herpesvirus. CMV seropositivity and reactivation have been investigated in ME/CFS cohorts.

CNS: Central Nervous System: the brain and spinal cord. ME/CFS involves CNS dysfunction including neuroinflammation, reduced cerebral blood flow, and cognitive impairment.

COMPASS-31: Composite Autonomic Symptom Score 31. A validated 31-item patient questionnaire assessing autonomic symptom severity across 6 domains — orthostatic intolerance, vasomotor, secretomotor (sweating), gastrointestinal, bladder, and pupillomotor function — with a 1-month recall period.

complement: A set of around 30 blood proteins that help the immune system fight infection and clear debris. Some complement fragments (notably C3a and C5a) can also activate mast cells directly, providing a non-allergen route to degranulation.

COMT: Catechol-O-Methyltransferase: enzyme degrading catecholamine neurotransmitters (dopamine, norepinephrine, epinephrine). COMT polymorphisms (e.g., Val158Met) may influence pain sensitivity and cognitive function in ME/CFS.

CONSORT: Consolidated Standards of Reporting Trials: a guideline for reporting RCTs. ME/CFS trials are assessed against CONSORT criteria for methodological quality.

contraindication: A condition or factor that makes a particular treatment inadvisable. Graded exercise therapy (GET) is contraindicated in ME/CFS per NICE 2021 guidelines due to risk of harm via PEM exacerbation.

Contrast-Enhanced Ultrasound (CEUS): An ultrasound imaging technique using microbubble contrast agents to visualize tissue microvascular perfusion in real time. Has been proposed as a non-invasive method to assess skeletal muscle microvascular dysfunction in ME/CFS.

Copper (Cu): An essential trace element serving as a cofactor for cytochrome c oxidase (Complex IV), superoxide dismutase (SOD1), dopamine β-hydroxylase, and ceruloplasmin. Copper dyshomeostasis contributes to mitochondrial dysfunction and oxidative stress; copper deficiency can mimic ME/CFS symptoms.

Corticomuscular coherence: A measure of how synchronized the electrical activity of the brain (motor cortex) is with the electrical activity of a muscle during a task. In ME/CFS, an absent rise in corticomuscular coherence during sustained effort suggests the brain is not adjusting its drive to muscle based on feedback from the fatiguing muscle.

cortisol: The primary glucocorticoid stress hormone produced by the adrenal cortex. Morning cortisol is typically low or low-normal in ME/CFS (blunted HPA axis), while evening cortisol may be inappropriately elevated, flattening the diurnal rhythm.

Cortisone: The inactive 11-keto form of cortisol, converted to active cortisol by 11β-HSD1 in tissues. Cortisone acetate is used therapeutically as a glucocorticoid. The cortisol/cortisone ratio reflects 11β-HSD activity, which may be altered in ME/CFS HPA axis dysfunction.

Cost-of-illness study: A type of health economics research that measures the total economic burden of a disease, including direct costs (medical care) and indirect costs (lost productivity, informal caregiver time).

COVID: Coronavirus Disease 2019: the illness caused by SARS-CoV-2. COVID-19 is a major infectious trigger for post-infectious ME/CFS (Long COVID/PASC), creating the largest-ever cohort of post-viral ME/CFS patients.

COVID/ME: Post-COVID ME/CFS — ME/CFS that develops following SARS-CoV-2 infection, also called post-COVID ME/CFS or Long COVID meeting ME/CFS diagnostic criteria.

COX: Cyclooxygenase: enzyme producing prostaglandins from arachidonic acid. COX-2 is induced by inflammation; implicated in ME/CFS neuroinflammation and pain.

COX-2: Cyclooxygenase-2: the inducible isoform of COX, upregulated by inflammatory stimuli (cytokines, NF-κB), producing prostaglandins (PGE2, PGI2) that mediate pain, fever, and inflammation. COX-2 is induced in ME/CFS neuroinflammation and is a therapeutic target of NSAIDs and celecoxib.

CO₂: Carbon Dioxide: the metabolic waste product of oxidative metabolism, exhaled via the lungs. End-tidal CO₂ and ventilatory equivalent for CO₂ (VE/VCO₂) are key CPET parameters; abnormal CO₂ handling in ME/CFS reflects ventilatory inefficiency and altered chemoreflex sensitivity.

CPAP: Continuous Positive Airway Pressure: a device delivering constant air pressure to keep the airway open during sleep. Used in ME/CFS patients with comorbid sleep apnea; treating OSA can improve sleep quality but does not resolve ME/CFS-specific unrefreshing sleep.

CPET: Cardiopulmonary Exercise Testing: a maximal exercise test measuring gas exchange (VO₂, VCO₂), heart rate, and ventilatory parameters. Two-day CPET (2-day CPET) uniquely demonstrates reduced VO₂ peak and anaerobic threshold on day 2 in ME/CFS — a physiological signature of PEM.

CPRD: Clinical Practice Research Datalink — UK primary care database containing anonymized electronic health records for approximately 20 million patients, used for epidemiological and health-services research.

CPT1: Carnitine Palmitoyltransferase 1: the rate-limiting enzyme for mitochondrial fatty acid oxidation, transporting long-chain fatty acyl-CoA into mitochondria. CPT1 dysfunction may impair fatty acid utilization in ME/CFS, forcing reliance on glycolysis.

CPT2: Carnitine Palmitoyltransferase 2: the inner mitochondrial membrane enzyme reconstituting fatty acyl-CoA from acylcarnitine. CPT2 deficiency/impaired activity may contribute to lipid metabolism abnormalities in ME/CFS.

Cr: Creatinine: a waste product of muscle metabolism, excreted by the kidneys. Serum creatinine is the most common kidney function marker; used with cystatin C for eGFR calculation. Low creatinine may indicate low muscle mass in severe ME/CFS.

Creatinine: A metabolic waste product of creatine phosphate breakdown in muscle. Produced at a relatively constant rate proportional to muscle mass. Serum creatinine is the most common clinical measure of renal function. Low creatinine in ME/CFS may reflect reduced muscle mass and metabolic rate.

CREB: cAMP Response Element-Binding protein: a transcription factor phosphorylated by PKA, CaMK, and MAPK pathways. CREB regulates synaptic plasticity, metabolism, and cell survival; altered CREB signaling may contribute to ME/CFS cognitive dysfunction.

CRF: Cancer-Related Fatigue. A distressing, persistent subjective sense of physical, emotional, and cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.

CRH: Corticotropin-Releasing Hormone: hypothalamic hormone triggering ACTH release from the pituitary. CRH dysregulation is part of the blunted HPA axis in ME/CFS.

CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats: a gene-editing technology using Cas9 nuclease guided by a single guide RNA. Used experimentally to study ME/CFS-associated gene variants in cell models.

cristae: Folded inner mitochondrial membrane structures where the electron transport chain and ATP synthase are concentrated. Cristae architecture regulates OXPHOS efficiency; disorganized cristae are a hallmark of mitochondrial dysfunction.

Crocetin: An apocarotenoid metabolite of saffron (Crocus sativus). It inhibits SERT and NMDA receptor signaling; studied for antioxidant and neuroprotective effects.

Crocin: The main active carotenoid glycoside of saffron (Crocus sativus) responsible for its color. It inhibits the serotonin transporter (SERT) and, with safranal, inhibits monoamine oxidase, contributing to saffron’s serotonergic and potential kynurenine-modulating actions.

CRP: C-Reactive Protein: an acute-phase protein produced by the liver in response to inflammation. Often within normal range in ME/CFS despite chronic inflammation, limiting its diagnostic utility.

CRPS: Complex Regional Pain Syndrome — a chronic pain condition typically affecting a limb after injury, involving autonomic dysfunction and functional GPCR autoantibodies.

CSF: Cerebrospinal Fluid: the clear fluid surrounding the brain and spinal cord. ME/CFS CSF studies show elevated cytokines, lactate, and other metabolic abnormalities.

CSF:Blood Ratio: The concentration ratio of brain-derived proteins (neurofilament light chain, tau, S100B, GFAP) between cerebrospinal fluid and peripheral blood. Under normal clearance, these proteins drain via glymphatic-lymphatic pathways and are diluted in plasma. Under impaired clearance, CSF concentrations rise while plasma levels fall, producing a ratio that reflects glymphatic efficiency independently of absolute protein production rates. Not yet systematically measured in ME/CFS cohorts.

CT: Computed Tomography: X-ray based cross-sectional imaging. Generally normal in ME/CFS; used to exclude structural CNS pathology.

CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4): An immune checkpoint receptor expressed on T cells that outcompetes CD28 for B7 ligand binding (CD80/CD86), dampening T cell activation. CTLA-4 is critical for Treg function and maintaining self-tolerance. Polymorphisms in CTLA-4 are associated with autoimmune disease susceptibility.

Cunningham Panel: A commercially available blood test measuring anti-neuronal antibody activity against five targets (dopamine D1 receptor, dopamine D2 receptor, tubulin, lysosomal-associated membrane protein 1, and CaMKII), with results reported as percent activation of CaMKII in a cell-based assay. Originally developed for PANDAS diagnosis at the University of Oklahoma; controversial due to limited validation and lack of payer coverage. Relevant to ME/CFS as a precedent for anti-neuronal antibody testing in neuroimmune conditions.

CVD: Cardiovascular Disease: the umbrella term for diseases of the heart and blood vessels. ME/CFS autonomic dysfunction may mimic or exacerbate CVD symptoms.

CXCR3: C-X-C chemokine receptor type 3 — a receptor on T cells and NK cells that binds CXCL9/10/11 chemokines and directs migration to sites of inflammation.

CXCR5: C-X-C chemokine receptor type 5 — a receptor on B cells and T follicular helper cells that directs migration to lymphoid follicles.

CYP: Cytochrome P450: a superfamily of heme-containing enzymes responsible for Phase I metabolism of most drugs, steroid hormones, and xenobiotics. CYP polymorphisms (CYP2D6, CYP2C19, CYP3A4) explain variability in drug response and side-effect susceptibility in ME/CFS patients.

CYP450: Cytochrome P450 — family of liver enzymes that metabolize most drugs. Different CYP isoforms (1A2, 2D6, 3A4, 2C19) process different drug classes. Drug interactions often occur when one drug inhibits the CYP enzyme another drug needs for clearance, causing the second drug to accumulate to toxic levels.

CysLT1: Cysteinyl Leukotriene Receptor Type 1: the receptor mediating the bronchoconstrictor and pro-inflammatory effects of cysteinyl leukotrienes (LTC4, LTD4, LTE4) released by mast cells. CysLT1 is the target of montelukast (Singulair), used in ME/CFS/MCAS to block mast-cell-driven respiratory and systemic symptoms.

Cysteine (Cys): A sulfur-containing amino acid and the rate-limiting precursor for glutathione synthesis. Cysteine’s thiol group is essential for protein structure (disulfide bonds) and redox signaling. Cysteine availability limits glutathione production, linking oxidative stress to glutathione depletion in ME/CFS.

cytokine: Small signaling proteins secreted by immune cells that mediate inflammation, immune cell recruitment, and systemic responses. ME/CFS is characterized by a complex cytokine signature, not simple elevation: some are elevated (TNF-α, IL-6, IFN-γ in subsets), some are reduced (IL-10, TGF-β in subsets), and patterns vary by disease duration and severity.

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D-dimer: D-dimer: a fibrin degradation product indicating coagulation and fibrinolysis. Elevated in thrombosis, inflammation, and infection. Elevated D-dimer in Long COVID/ME/CFS may indicate persistent microvascular coagulation.

D1R: Dopamine D1 Receptor: a Gs-coupled receptor activating cAMP/PKA signaling. D1R in the prefrontal cortex supports working memory; D1R dysfunction may contribute to ME/CFS cognitive symptoms.

D2: Dopamine receptor D2: a G-protein-coupled receptor for dopamine, expressed in striatum, pituitary, and midbrain. D2 is the target of aripiprazole/LDA and is implicated in reward, motor control, and pituitary hormone regulation.

D3: Dopamine receptor D3: a G-protein-coupled receptor for dopamine, primarily expressed in limbic regions. D3 partial agonism contributes to aripiprazole’s therapeutic effects with lower motor side-effect liability than D2 antagonism.

DA: Dopamine: a catecholamine neurotransmitter involved in motivation, reward, motor control, and cognitive function. Dopaminergic dysfunction is implicated in ME/CFS fatigue and cognitive symptoms.

DAG: Diacylglycerol: a lipid second messenger produced by PLC, activating PKC. DAG is also a metabolic intermediate linking lipid metabolism to signaling.

DALY: Disability-Adjusted Life Year — a health economics metric combining years of life lost to premature death and years lived with disability; one DALY represents one lost year of healthy life.

DAMI: Dopaminergic Asymmetry Measurement Index: a composite biomarker integrating striatal FDG-PET asymmetry, COMPASS-31 autonomic symptom score, and aripiprazole response slope. DAMI aims to quantify the degree of lateralized dopaminergic dysfunction in ME/CFS — high asymmetry correlates with specific autonomic and motor symptom patterns.

DAMP: Damage-Associated Molecular Pattern: endogenous molecules (HMGB1, ATP, HSPs, mtDNA, S100 proteins) released from stressed or dying cells that activate innate immune receptors. Chronic DAMP release from cellular stress may sustain sterile inflammation in ME/CFS.

DAO: Diamine oxidase: the primary enzyme responsible for extracellular histamine degradation, predominantly produced in the intestinal mucosa. Reduced DAO activity contributes to histamine intolerance, which symptomatically overlaps with MCAS in ME/CFS.

DAT: Dopamine Transporter: protein reuptaking dopamine from synapses. Reduced DAT availability in the striatum has been reported in ME/CFS neuroimaging.

DBH: Dopamine-Beta-Hydroxylase: the enzyme that converts dopamine to norepinephrine inside synaptic vesicles. DBH is released with norepinephrine during sympathetic activation; serum DBH activity reflects sympathetic tone and may be elevated in hyperadrenergic ME/CFS/POTS subtypes.

DCX: Doublecortin: a microtubule-associated protein expressed by immature (newborn) neurons in the brain, widely used as a marker of adult neurogenesis in the hippocampus.

DDI: Drug-drug interaction — when two medications affect each other in the body, either by competing for the same receptor (pharmacodynamic), altering each other metabolism (pharmacokinetic), or opposing each other physiological goals.

DDR: Discoidin Domain Receptor: a family of collagen-activated receptor tyrosine kinases (DDR1, DDR2) regulating cell adhesion, migration, and ECM remodeling. DDR signaling is implicated in tissue fibrosis and may be relevant to connective tissue pathology in ME/CFS/EDS.

DecodeME: The largest genome-wide association study (GWAS) of ME/CFS to date (>15,000 participants, 8 million SNPs). Identified 8 genome-wide significant loci with brain tissue enrichment via MAGMA analysis (CA10, SHISA6, SOX6, LRRC7, DCC, UNC13C). Estimated SNP-based heritability at 9.5%. Published as a preprint in 2025 — the first molecular demonstration that ME/CFS has a polygenic genetic architecture with neurological tissue distribution.

DEGAM: Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin — German College of General Practitioners and Family Physicians.

degranulation: The process by which a mast cell (or other granulocyte) fuses its storage granules with the cell membrane and empties their contents — histamine, tryptase, prostaglandins, leukotrienes and more — into the surrounding tissue. The key event in allergic reactions and mast cell activation.

Deiodinase: An enzyme that removes iodine atoms from thyroid hormones. Three types: D1 (liver/kidney, produces circulating T₃ from T₄), D2 (brain, pituitary, brown fat, local T₃ production), D3 (inactivates T₃ and T₄ to reverse T₃ and T₂). Deiodinase dysfunction may contribute to the ‘low T₃ syndrome’ in ME/CFS.

Dementia: A syndrome of progressive cognitive decline (memory, reasoning, everyday function) resulting from multiple disorders that damage the brain over time, most commonly Alzheimer’s disease, vascular dementia, Lewy body dementia and frontotemporal dementia.

Dendritic Cell (DC): A professional antigen-presenting cell that captures, processes, and presents antigens to T cells via MHC molecules, initiating adaptive immune responses. Dendritic cell dysfunction may impair immune responses in ME/CFS and contribute to chronic viral reactivation.

dengue: A mosquito-borne flavivirus causing dengue fever (breakbone fever) characterized by severe myalgia, arthralgia, and fatigue. Post-dengue fatigue syndrome is well-documented and clinically overlaps with ME/CFS, providing another post-viral model for ME/CFS pathophysiology.

DHEA: Dehydroepiandrosterone: an adrenal steroid hormone precursor. Low DHEA-S levels have been reported in ME/CFS, reflecting adrenal dysfunction.

Digital twin: A patient-specific computational model continuously updated with real-time data to predict individual disease trajectory and treatment response.

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DLA: Disability Living Allowance — a UK benefit for people with disabilities who need help with personal care or mobility; replaced by Personal Independence Payment (PIP) for new adult claims since 2013.

DMH: Dorsomedial hypothalamus: a hypothalamic region involved in feeding, energy balance, body temperature, and circadian behaviour, containing neurons (including some that respond to the metabolic hormone leptin) that connect metabolic state to circadian timing.

DMT: Disease-Modifying Therapy — a treatment that alters the underlying disease course rather than merely managing symptoms; used in multiple sclerosis, rheumatoid arthritis, and other chronic conditions.

DMV: Dorsal Motor Nucleus of Vagus: a brainstem nucleus containing parasympathetic preganglionic neurons that project via the vagus nerve to the heart, lungs, and GI tract. DMV dysfunction may impair vagal parasympathetic output in ME/CFS, contributing to tachycardia, gastroparesis, and reduced anti-inflammatory cholinergic tone.

DNA methylation: The addition of methyl groups to cytosine bases in DNA (typically at CpG sites), generally silencing gene expression. Altered DNA methylation patterns in ME/CFS have been identified in immune, metabolic, and neurological pathways, including genes regulating the HPA axis and cellular energy metabolism.

Dopamine: A catecholamine neurotransmitter involved in motivation, reward, motor control, and cognitive function. Produced from tyrosine via tyrosine hydroxylase and DOPA decarboxylase. Dopamine dysregulation in ME/CFS may contribute to anhedonia, cognitive slowing, and reduced motivation.

DPP-4: Dipeptidyl Peptidase-4 (CD26): a serine protease that rapidly degrades incretin hormones (GLP-1, GIP), limiting their insulinotropic effects. DPP-4 also exists as soluble CD26, a T-cell activation marker elevated in some autoimmune conditions, and cleaves multiple chemokines. DPP-4 inhibitors (sitagliptin) are used in diabetes; DPP-4/CD26 dysregulation may link metabolic and immune dysfunction in ME/CFS.

DRD2: Gene encoding the dopamine D2 receptor, a G-protein-coupled receptor that inhibits adenylyl cyclase. Variants (Taq1A, C957T) influence receptor expression and are implicated in differential response to dopamine-modulating drugs including aripiprazole.

DRG: Dorsal Root Ganglion: a cluster of sensory neuron cell bodies along the spinal cord that transmit pain, temperature, and touch signals. DRG neurons express TRPV1, TRPA1, and PIEZO2; DRG sensitization is a key site of peripheral pain amplification in ME/CFS and fibromyalgia.

DRP1: Dynamin-Related Protein 1: a GTPase that mediates mitochondrial fission by constricting the outer mitochondrial membrane. Activated by phosphorylation at Ser616 (via ERK1/2); inhibited by phosphorylation at Ser637. Excessive DRP1 activity produces mitochondrial fragmentation, documented in ME/CFS PBMCs (Schreiner 2020).

DSM: Diagnostic and Statistical Manual of Mental Disorders — the American Psychiatric Association’s classification system for psychiatric diagnoses.

DSQ: DePaul Symptom Questionnaire — a validated patient-reported assessment tool for ME/CFS symptoms. The DSQ-PEM subscale measures post-exertional malaise frequency and severity using standardised items.

DTBZ: Dihydrotetrabenazine: a PET radioligand that binds to VMAT2 on presynaptic monoamine terminals, used to quantify dopaminergic neuron density. Reduced striatal DTBZ binding in ME/CFS would indicate dopaminergic terminal loss — a finding linking ME/CFS fatigue to Parkinsonian pathophysiology.

DTI-ALPS: Diffusion Tensor Imaging Analysis along the Perivascular Space: a non-invasive MRI technique that measures water diffusivity along perivascular spaces as a proxy for glymphatic function. DTI-ALPS has been used to demonstrate impaired glymphatic clearance in ME/CFS — lower ALPS index correlates with greater fatigue severity.

Dup15q: Duplication of chromosome 15q11-q13, the region containing the UBE3A gene. Extra copies cause a separate neurodevelopmental syndrome that overlaps Angelman syndrome in some features, illustrating that UBE3A-related outcomes depend on dosage rather than simply loss-of-function.

DVT: Deep Vein Thrombosis: a blood clot in a deep vein, typically in the leg. Immobility in severe ME/CFS increases DVT risk.

Dysautonomia: Dysfunction of the autonomic nervous system. In ME/CFS, manifests as orthostatic intolerance, POTS, temperature dysregulation, and gastrointestinal dysmotility.

dysbiosis: An imbalance in the composition, diversity, or function of the gut microbiome. Gut dysbiosis is consistently reported in ME/CFS, with reduced microbial diversity and shifts in short-chain fatty acid (SCFA) producers, linking to immune and metabolic dysfunction.

dysvirosis: A dysregulation of the human virome — the community of viruses that normally persist in the body without causing disease. In long COVID and ME/CFS research, dysvirosis refers to shifts in chronic viral (especially anellovirus) burden that reflect altered immune regulation rather than active viral infection.

E/L coupling: Electron-leak coupling efficiency — the ratio of maximal uncoupled respiration to leak respiration, measuring how tightly mitochondrial oxygen consumption is coupled to ATP production.

E6AP: E6-Associated Protein, the common name for the UBE3A gene product, an E3 ubiquitin ligase that marks proteins for proteasomal degradation. Loss of E6AP function underlies Angelman syndrome; referenced here as the mechanistic node of a cross-disease analogy with ME/CFS energy and GABAergic dysfunction.

EBNA (Epstein-Barr Nuclear Antigen): A family of EBV-encoded nuclear proteins (EBNA-1, -2, -3A, -3B, -3C, -LP) expressed in latently infected B cells. EBNA-1 maintains the viral episome; EBNA-2 transactivates viral and cellular genes. Antibodies against EBNAs serve as serological markers of EBV infection stage and reactivation.

EBNA1 (Epstein-Barr Nuclear Antigen 1): A key Epstein-Barr virus protein, expressed in latently infected cells, that maintains the viral genome. Antibody reactivity to specific EBNA1 epitopes is a marker used in post-infectious illness research.

EBV: Epstein-Barr Virus: a herpesvirus causing infectious mononucleosis. EBV reactivation is one of the most studied infectious triggers of ME/CFS onset.

EC cells: Enterochromaffin Cells: specialized gut epithelial cells that produce ~95% of the body’s serotonin via TPH1. EC cell serotonin regulates gut motility, secretion, and vagal afferent signaling. EC cell dysfunction may link gut dysbiosis to altered serotonergic signaling in ME/CFS.

ECG: Electrocardiogram: recording of the heart’s electrical activity. ECG may show tachycardia (resting sinus tachycardia), but structurally normal in ME/CFS. Used in POTS diagnosis via standing test or tilt table.

ECM: Extracellular Matrix: the network of collagen, elastin, proteoglycans, and glycoproteins that provides structural support to tissues. ECM abnormalities (collagen defects, MMP dysregulation) are central to hypermobility spectrum disorders (EDS/HSD) commonly comorbid with ME/CFS.

EDS: Ehlers-Danlos Syndrome: a group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Hypermobile EDS (hEDS) is the most common subtype co-occurring with ME/CFS.

EEG: Electroencephalogram: recording of brain electrical activity. EEG in ME/CFS may show alpha intrusion into delta sleep (the ‘alpha-delta anomaly’), correlating with unrefreshing sleep.

EHR: Electronic Health Record — digital version of a patient’s medical history maintained by healthcare providers, including diagnoses, medications, lab results, and clinical notes.

eIF2: Eukaryotic Initiation Factor 2: a translation initiation factor whose α-subunit phosphorylation by PERK, PKR, GCN2, or HRI halts general protein synthesis. Central to the ISR; eIF2α phosphorylation is a convergence point for multiple stress signals in ME/CFS.

Electron Microscopy (EM): A microscopy technique that uses electrons instead of light to visualize structures at nanometer resolution. Used in ME/CFS research to examine capillary basement membrane thickness, endothelial ultrastructure, and mitochondrial morphology in muscle biopsies.

ELISA: Enzyme-Linked Immunosorbent Assay: a plate-based immunoassay for detecting and quantifying soluble substances (antibodies, antigens, cytokines, hormones). Widely used in ME/CFS research to measure cytokine profiles, autoantibodies, and viral serologies.

ELISpot: Enzyme-Linked Immunospot — a laboratory assay measuring the frequency of cytokine-secreting cells (e.g., IFN-γ-producing T cells) at the single-cell level. Used to quantify antigen-specific T cell responses.

EMA: European Medicines Agency: the EU regulatory agency for medicines. Like the FDA, the EMA has no approved ME/CFS-specific treatments.

EMDR: Eye Movement Desensitization and Reprocessing: a psychotherapy for trauma/PTSD using bilateral stimulation. May benefit ME/CFS patients with comorbid PTSD, but does not treat core ME/CFS pathophysiology.

EMG: Electromyography: test of muscle electrical activity. Generally normal in ME/CFS despite severe fatigue, distinguishing it from primary neuromuscular disorders.

EMR: Electronic Medical Record — the digital system a clinic uses to store patient records; a specialist clinic may customize EMR fields to capture disease-specific measures such as head-up-angle and day-to-day symptom status.

Encephalitis: Inflammation of the brain parenchyma, typically caused by viral infection (HSV, enterovirus, arbovirus) or autoimmunity (anti-NMDAR encephalitis, limbic encephalitis). Post-encephalitic fatigue is a well-documented sequela that overlaps with ME/CFS; autoimmune encephalitis can mimic ME/CFS and must be excluded in atypical presentations.

Endorphin: An endogenous opioid peptide produced in the pituitary and hypothalamus. Endorphins bind μ-opioid receptors, producing analgesia and euphoria. Released during exercise (runner’s high), stress, and immune activation. Endorphin dysregulation may contribute to the pain amplification and reward-processing abnormalities in ME/CFS.

endothelial dysfunction: Impaired endothelium-dependent vasodilation due to reduced nitric oxide bioavailability, increased oxidative stress, and inflammation. Contributes to microvascular hypoperfusion and orthostatic intolerance in ME/CFS.

Endotheliopathy: A disease state of endothelial cell dysfunction encompassing impaired NO-mediated vasodilation, increased adhesion molecule expression, loss of glycocalyx, and a shift toward a pro-coagulant/pro-inflammatory phenotype. Endotheliopathy is proposed as a central mechanism in ME/CFS explaining microvascular hypoperfusion, exercise intolerance, and multisystem involvement.

endotype: A disease subtype defined by a distinct biological mechanism (rather than symptoms alone). ME/CFS is increasingly conceptualized as a collection of endotypes: autoimmune, metabolic, neuroinflammatory, hyperadrenergic, hypovolemic, connective tissue — each requiring different treatment approaches.

energy envelope: The range of daily activity a person can sustain without triggering PEM. Staying within the energy envelope — pacing — is the primary management strategy; exceeding it triggers the boom-bust cycle.

enterovirus: A genus of single-stranded RNA viruses including coxsackievirus and echovirus. Enteroviruses are a leading candidate for persistent viral infection in ME/CFS — enteroviral RNA and VP1 protein have been detected in ME/CFS muscle and gut biopsies, suggesting chronic low-level infection or defective viral clearance.

EOMES: Eomesodermin: a T-box transcription factor that drives CD8+ T-cell effector differentiation and, together with TOX, the terminal exhaustion program. Elevated on CD8+ effector memory T cells in ME/CFS (Iu et al. 2024).

epigenetics: Heritable changes in gene expression without changes to the DNA sequence, including DNA methylation, histone modification, and non-coding RNA regulation. ME/CFS epigenetic studies reveal differential DNA methylation patterns that may explain how infections trigger persistent disease without ongoing infection.

Epinephrine: Adrenaline: the catecholamine hormone released from the adrenal medulla during stress, producing the classic fight-or-flight response. Epinephrine increases heart rate, dilates airways, and mobilizes glucose. Epinephrine surges from MCAS degranulation or POTS sympathetic overactivity may explain the panic-like episodes ME/CFS patients describe.

EpiSwitch: A proprietary blood-test platform that measures 3D chromosome-conformation (chromatin loop and folding) architecture as a diagnostic signature; investigated in ME/CFS as a candidate blood-based biomarker.

EQ-5D: EuroQol 5-Dimension — a standardized health-related quality of life questionnaire used in health economics to calculate quality-adjusted life years (QALYs); measures mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.

ER stress: Endoplasmic reticulum stress: the accumulation of misfolded proteins in the ER lumen that activates the unfolded protein response (UPR). Chronic ER stress is implicated in ME/CFS as a contributor to cellular dysfunction, inflammation, and impaired protein homeostasis.

ERK: Extracellular signal-Regulated Kinase: a MAPK subfamily involved in growth factor signaling. Abnormal ERK activation may contribute to immune dysfunction in ME/CFS.

ERP: Event-Related Potential: a measured brain electrical response time-locked to a specific stimulus or task event, extracted from EEG by averaging. ERPs index neural processing stages such as attention allocation (P3b) that cannot be observed in raw behavior alone.

Escherichia coli: A gram-negative enteric bacterium and the most common cause of urinary tract infections (via uropathogenic strains). E. coli LPS is a potent TLR4 agonist; LPS translocation from the gut (‘metabolic endotoxemia’) is proposed as a driver of low-grade immune activation in ME/CFS with leaky gut.

ESR: Erythrocyte Sedimentation Rate: a non-specific marker of inflammation measuring how quickly red blood cells settle. Typically normal in ME/CFS.

Estrogen: The primary female sex hormone (17β-estradiol, E2), produced mainly by the ovaries. Estrogen modulates immune function, mitochondrial biogenesis, and neurotransmitter systems. The high female-to-male ratio in ME/CFS (3–6:1) and perimenopausal onset suggest estrogen involvement in disease susceptibility and severity.

ET-1: Endothelin-1: a potent vasoconstrictor peptide produced by endothelial cells, acting on ETA (vasoconstriction) and ETB (vasodilation via NO) receptors. ET-1 is elevated in ME/CFS and may drive microvascular constriction, contributing to tissue hypoperfusion and exercise intolerance.

ETA: Endothelin Receptor Type A: mediates the vasoconstrictor effects of endothelin-1 on vascular smooth muscle. ETA overactivation may contribute to microvascular dysfunction and tissue ischemia in ME/CFS. ETA receptor autoantibodies have been identified in subsets of ME/CFS patients.

ETC: Electron Transport Chain: the series of mitochondrial complexes (I–IV) that transfer electrons from NADH/FADH₂ to oxygen, pumping protons to drive ATP synthesis. Complex I and IV dysfunction are reported in ME/CFS.

EUROMENE: European Network on ME/CFS — a COST Action-funded European research network coordinating diagnosis, service provision, and care guidance for ME/CFS.

excitotoxicity: Neuronal damage caused by excessive activation of glutamate receptors (NMDA, AMPA), leading to calcium overload, mitochondrial failure, and cell death. Driven by elevated quinolinic acid (QUIN) in the kynurenine pathway; implicated in ME/CFS cognitive dysfunction.

6 F–G

FAD: Flavin Adenine Dinucleotide: a redox cofactor in the electron transport chain (Complex II) and fatty acid oxidation. FAD-dependent enzymes are critical to mitochondrial energy production.

falsifiability: The capacity for a hypothesis to be proven wrong — a criterion of scientific rigor. ME/CFS research has often suffered from unfalsifiable psychological models; current biomedical research emphasizes testable mechanistic hypotheses.

FAO: Fatty Acid Oxidation (β-oxidation): the mitochondrial breakdown of fatty acids to acetyl-CoA for the TCA cycle. Impaired FAO in ME/CFS forces reliance on glycolysis, reducing ATP yield per substrate molecule and accelerating fatigue during prolonged activity.

Fatigability: The objective decline in physical or cognitive performance during sustained effort, as measured by performance tests (e.g., twitch interpolation, transcranial magnetic stimulation, sustained-force tasks). In ME/CFS it is formally distinct from fatigue (the subjective perception of exhaustion); ICF codes them separately (b1300 energy level vs b4552 fatigability). Evidence suggests a central (brain-level) failure of motor drive contributes to ME/CFS fatigability.

Fc Receptor (FcR): A cell-surface receptor that binds the Fc (fragment crystallizable) region of antibodies. Fcγ receptors (FcγRI/CD64, FcγRII/CD32, FcγRIII/CD16) bind IgG and mediate antibody-dependent cellular phagocytosis, ADCC, and immune complex clearance. FcRn (neonatal Fc receptor) regulates IgG half-life and transcytosis. Fc receptor engagement is central to autoantibody pathology in autoimmune conditions.

FDA: US Food and Drug Administration: the agency regulating medications and medical devices. No FDA-approved treatments exist specifically for ME/CFS; all pharmacological treatments are off-label.

FDG: Fluorodeoxyglucose (¹⁸F-FDG): a radioactive glucose analogue used in PET imaging to measure tissue metabolic activity. FDG-PET in ME/CFS reveals regional hypometabolism in the brainstem, frontal cortex, and striatum, correlating with cognitive and fatigue severity.

FDR: False Discovery Rate — a statistical correction for multiple comparisons that controls the expected proportion of false positives among significant results.

Ferritin: Ferritin: the primary intracellular iron storage protein; serum ferritin reflects body iron stores. Low ferritin indicates iron deficiency anemia. Ferritin can be falsely elevated in inflammation (acute phase reactant).

Ferritin:TSAT Ratio (FTR): The ratio of serum ferritin (µg/L) divided by transferrin saturation (%). FTR > 10 suggests functional iron deficiency (iron present but trapped); FTR < 5 suggests genuine iron deficiency. A proposed — but not yet validated — diagnostic tool for distinguishing iron phenotypes in post-viral fatigue.

Ferritinophagy: The selective degradation of ferritin (the iron storage protein) by autophagy, mediated by the cargo receptor NCOA4. Ferritinophagy releases stored iron from ferritin for cellular use. If blocked, iron remains trapped in ferritin and unavailable for export.

ferroptosis: An iron-dependent form of regulated cell death driven by lipid peroxidation. Ferroptosis is linked to neurodegenerative diseases and may contribute to neuronal loss in ME/CFS given the oxidative stress and iron dysregulation observed.

Ferroxidase: Enzymes that oxidise Fe²⁺ (ferrous iron) to Fe³⁺ (ferric iron), a necessary step for iron to bind transferrin. Ceruloplasmin and hephaestin are the two main ferroxidases. Impaired ferroxidase activity produces functional iron deficiency even when iron is exported from cells.

fibromyalgia: Fibromyalgia: a chronic pain syndrome characterized by widespread musculoskeletal pain, fatigue, unrefreshing sleep, and cognitive difficulty. Genetically a central-nervous-system (nociplastic) disorder; co-occurs with ME/CFS in 20-70% of cases.

FM: Fibromyalgia: a chronic condition of widespread pain, fatigue, cognitive dysfunction, and sleep disturbance. Shares substantial clinical overlap with ME/CFS; ~35–70% of ME/CFS patients also meet FM criteria.

fMRI: Functional MRI: brain imaging measuring activity via blood-oxygen-level-dependent (BOLD) signal. ME/CFS fMRI studies show altered connectivity and reduced cerebral blood flow during cognitive tasks.

FMT: Fecal Microbiota Transplantation: transfer of gut microbiota from a healthy donor to a patient. Investigated experimentally for ME/CFS gut microbiome dysfunction.

FND: Functional Neurological Disorder. A condition involving neurological symptoms (weakness, seizures, movement disorders) without structural damage visible on standard brain imaging, now understood as a disorder of nervous system functioning rather than structural pathology.

FODMAP: Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols: short-chain carbohydrates poorly absorbed in the small intestine, fermented by gut bacteria causing bloating and gas. Low-FODMAP diet is used in ME/CFS with IBS/SIBO comorbidity to reduce GI symptoms.

FOXO1: Forkhead Box O1: a transcription factor regulating metabolism, antioxidant defense, and autophagy. AKT phosphorylation excludes FOXO from the nucleus; impaired FOXO signaling may reduce stress-resistance programs in ME/CFS.

FOXO3: Forkhead Box O3: a longevity-associated transcription factor activating antioxidant, DNA repair, and autophagy genes. FOXO3 activity is regulated by AMPK and SIRT1; FOXO3 dysfunction may impair cellular resilience in ME/CFS.

FROM-16: Family Reported Outcome Measure — a validated 16-item questionnaire measuring the impact of a patient’s chronic disease on family members’ quality of life, covering emotional, personal/social, and financial domains.

FSH: Follicle-stimulating hormone: a pituitary hormone that drives egg-follicle development; rising FSH levels indicate declining ovarian function approaching menopause.

Fukuda criteria: The 1994 CDC diagnostic criteria for chronic fatigue syndrome (Fukuda et al.). Requires ≥6 months of unexplained fatigue plus ≥4 of 8 symptoms (impaired memory, sore throat, tender lymph nodes, muscle pain, joint pain, new headaches, unrefreshing sleep, post-exertional malaise). Does not require PEM as mandatory.

Fumarate: A Krebs cycle intermediate produced by succinate dehydrogenase (Complex II). Converted to malate by fumarase. Fumarate also functions as a signaling metabolite, inhibiting HIF-1α prolyl hydroxylases and thereby stabilizing HIF-1α under normoxic conditions.

FUNCAP: Functional Capacity scale for ME/CFS. A validated patient-reported outcome measure assessing functional status across daily living domains including personal hygiene, mobility, and household activities.

functional connectivity: A statistical measure of how correlated the fMRI (BOLD) activity of two brain regions is over time. Altered functional connectivity of dopaminergically targeting circuits indicates disrupted communication between brain regions, though it does not directly measure dopamine itself.

FXR: Farnesoid X Receptor: a nuclear bile acid receptor regulating bile acid synthesis, lipid metabolism, and gut-liver signaling. FXR dysfunction may link gut microbiome alterations to metabolic abnormalities in ME/CFS.

G-BA: Gemeinsamer Bundesausschuss — German Federal Joint Committee, the highest decision-making body of the joint self-government of physicians, hospitals, and health insurers in Germany. Issues binding directives for statutory health insurance.

G-CSF: Granulocyte Colony-Stimulating Factor: a cytokine stimulating neutrophil production and mobilization from bone marrow. G-CSF is elevated in some ME/CFS cohorts and may contribute to the low-grade inflammatory state.

GABA: Gamma-Aminobutyric Acid: the brain’s primary inhibitory neurotransmitter. GABAergic dysfunction may contribute to sleep disturbance, anxiety, and sensory hypersensitivity in ME/CFS.

GABA-A: Gamma-aminobutyric acid type A receptor — the major inhibitory neurotransmitter receptor in the brain. Activated by benzodiazepines, alcohol, and neurosteroid metabolites. Overactivation suppresses prefrontal cortex function.

GABA-A Receptor: An ionotropic GABA receptor and ligand-gated chloride channel. The primary inhibitory receptor in the CNS. A pentameric complex assembled from 19 subunit subtypes (α1-6, β1-3, γ1-3, δ, ε, θ, π, ρ1-3). Target of benzodiazepines, barbiturates, neurosteroids (allopregnanolone, pregnenolone), and ethanol.

GABAergic: Relating to GABA, the brain’s main inhibitory neurotransmitter. GABAergic signaling dampens neuronal excitation; reduced GABAergic (inhibitory) tone is an excitatory/inhibitory imbalance proposed in both Angelman syndrome and ME/CFS.

GAD: Generalized Anxiety Disorder: chronic excessive worry and anxiety. Higher prevalence in ME/CFS; may be secondary to autonomic hyperarousal.

GALT: Gut-Associated Lymphoid Tissue: organized immune structures in the gastrointestinal tract (Peyer’s patches, isolated lymphoid follicles) that produce antibodies and maintain gut immune homeostasis.

Gamma-delta T cell: A T cell subtype (gamma-delta / γδ T cell) that acts at the interface of innate and adaptive immunity, recognizing stressed and infected cells without MHC restriction. BioMapAI multi-omics analysis reports heightened gamma-delta T-cell inflammatory activity (IFN-gamma, granzyme A) in ME/CFS, while some single-cell studies report reduced gamma-delta cell frequencies — an unresolved activation-versus-depletion question.

GAPDH: Glyceraldehyde-3-Phosphate Dehydrogenase: a glycolytic enzyme also functioning as an RNA-binding protein and redox sensor. GAPDH is oxidatively modified in ME/CFS, potentially impairing both glycolysis and its signaling functions.

Gastric emptying scintigraphy: A standard imaging test (abbreviated GES) that tracks the movement of a labelled meal through the stomach to measure how quickly it empties, used to diagnose gastroparesis.

Gastroparesis: Delayed emptying of the stomach, causing early satiety, nausea, vomiting, bloating, and abdominal discomfort. In ME/CFS it is thought to reflect autonomic (vagal) dysfunction of gastric motility and can threaten nutrition in severe cases.

GCN2: General Control Nonderepressible 2: an eIF2α kinase activated by uncharged tRNAs during amino acid deprivation. GCN2 activation may link branched-chain amino acid depletion in ME/CFS to the ISR.

GDP: Gross Domestic Product — the total value of goods and services produced in a country; used as a metric for comparing disease economic burden as a percentage of national economic output.

GERD: Gastroesophageal Reflux Disease: chronic acid reflux from the stomach into the esophagus. Common comorbidity in ME/CFS.

GES: Gastric emptying scintigraphy: a standard imaging test that measures how quickly food empties from the stomach, used to confirm or rule out gastroparesis.

GET: Graded Exercise Therapy: a progressive exercise program. Contraindicated in ME/CFS — NICE (2021) explicitly recommends against GET due to risk of harm (PEM exacerbation). Distinct from pacing/energy management.

GFAP: Glial fibrillary acidic protein: an intermediate-filament protein expressed by astrocytes. Its levels in blood or cerebrospinal fluid rise with astrocyte activation/injury and serve as a marker of reactive gliosis and neuroinflammatory damage.

GFR: Glomerular Filtration Rate: measure of kidney function. eGFR (estimated GFR) is typically normal in ME/CFS.

GGT: Gamma-Glutamyl Transferase: a liver enzyme elevated in biliary disease, alcohol use, and oxidative stress. GGT may also serve as a marker of glutathione depletion; elevated GGT in ME/CFS could reflect oxidative stress.

GH: Growth Hormone: pituitary hormone supporting tissue repair, metabolism, and immune function. Altered GH secretion, especially nocturnal GH, has been reported in ME/CFS.

GI: Gastrointestinal: pertaining to the digestive tract. GI symptoms (bloating, pain, nausea, altered motility, SIBO, GERD) are among the most common and disabling non-core symptoms in ME/CFS.

GLP-1: Glucagon-Like Peptide-1: an incretin hormone released from intestinal L-cells after meals, enhancing insulin secretion, slowing gastric emptying, and promoting satiety. GLP-1 receptor agonists (semaglutide) are diabetes/obesity drugs; GLP-1 has neuroprotective and anti-inflammatory properties that may be relevant to ME/CFS metabolic dysfunction.

Glucagon: A pancreatic α-cell hormone that raises blood glucose by stimulating hepatic glycogenolysis and gluconeogenesis. Counterregulatory to insulin. Glucagon signaling intersects with the cAMP/PKA pathway and may be dysregulated in ME/CFS metabolic dysfunction.

gluconeogenesis: The synthesis of glucose from non-carbohydrate precursors (lactate, amino acids, glycerol) in the liver and kidneys. Critical for maintaining blood glucose during fasting; may be dysregulated in ME/CFS contributing to hypoglycemia-like symptoms.

Glucose: The primary monosaccharide used for cellular energy production via glycolysis. Glucose is metabolized to pyruvate, then enters the TCA cycle under aerobic conditions or is converted to lactate anaerobically. Impaired glucose metabolism is documented in ME/CFS, with reduced glycolytic flux and a shift toward ketone body utilization.

GLUT1: Glucose Transporter 1: the primary glucose transporter at the blood-brain barrier and in erythrocytes. Reduced GLUT1 expression or function could limit cerebral glucose availability in ME/CFS, contributing to brain fog.

GLUT1 deficiency syndrome: A monogenic disorder caused by SLC2A1 mutations impairing glucose transport across the blood-brain barrier (via GLUT1), causing seizures, developmental delay, and movement disorders. GLUT1 deficiency serves as a model for brain energy failure: if glucose can’t enter the brain, symptoms mimic severe ME/CFS including exercise-induced worsening. Relevant to ME/CFS cerebral hypometabolism.

GLUT3: Glucose Transporter 3: the primary neuronal glucose transporter with high affinity (low Km). Essential for maintaining neuronal energy; GLUT3 dysfunction could contribute to ME/CFS neurocognitive symptoms.

GLUT4: Glucose Transporter 4: the insulin-responsive glucose transporter in muscle and adipose tissue. Insulin resistance or impaired GLUT4 translocation may reduce muscle glucose uptake in ME/CFS.

Glutamate: The primary excitatory neurotransmitter in the central nervous system. Acts via ionotropic (NMDA, AMPA, kainate) and metabotropic (mGluR) receptors. Excessive glutamate signaling causes excitotoxicity, implicated in neurodegeneration and potentially in ME/CFS central sensitization and cognitive dysfunction.

Glutamine (Gln): The most abundant free amino acid in the body. A key fuel for immune cells (particularly lymphocytes and macrophages), a precursor for glutamate and GABA, and essential for nitrogen transport and acid-base balance. Glutamine supplementation may benefit ME/CFS by supporting immune function and gut barrier integrity.

glycolysis: The cytoplasmic breakdown of glucose to pyruvate, producing 2 ATP and NADH. In ME/CFS, impaired pyruvate dehydrogenase activity may shunt metabolism toward anaerobic glycolysis, producing lactate even at rest.

Glymphatic system: The brain’s perivascular waste clearance system: CSF flows along periarterial spaces into the brain interstitium, driven by arterial pulsatility and AQP4 channels on astrocyte end-feet, then exits via perivenous routes carrying metabolic waste (amyloid-β, tau, lactate). Glymphatic function peaks during slow-wave sleep and is suppressed by norepinephrine — directly linking ME/CFS sleep pathology, sympathetic overactivation, and impaired brain clearance.

GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor: a cytokine that stimulates bone-marrow production of granulocytes and macrophages. GM-CSF is a severity-correlated inflammatory marker in ME/CFS and is elevated (as is G-CSF) in Alzheimer’s disease, suggesting a shared myeloid-axis signal across inflammatory CNS conditions.

GPCR: G Protein-Coupled Receptor: the largest receptor superfamily, mediating signals from hormones, neurotransmitters, and sensory stimuli through heterotrimeric G proteins. GPCR signaling dysregulation (e.g., adrenergic, histaminergic, serotonergic) is widespread in ME/CFS.

GPCR autoantibody: Autoantibodies targeting G protein-coupled receptors (β-adrenergic, muscarinic acetylcholine, angiotensin II AT1R, endothelin ETA receptors), found in subsets of ME/CFS and POTS. These can be agonistic (activating) or antagonistic (blocking), directly dysregulating autonomic, cardiovascular, and immune function.

GPR52: GPR52: an orphan G-protein-coupled receptor that negatively regulates huntingtin levels. A GPR52 risk locus is shared between fibromyalgia and ME/CFS genetics; GPR52 is an investigational Huntington’s disease drug target.

GPX: Glutathione Peroxidase: a selenium-dependent enzyme reducing hydrogen peroxide and lipid hydroperoxides, using glutathione. GPX dysfunction impairs antioxidant defense in ME/CFS.

GR: Glucocorticoid receptor: a nuclear receptor activated by cortisol, regulating transcription of genes involved in metabolism, inflammation, and stress response. GR expression peaks in early morning (04:00-08:00) and is the target of corticosteroid drugs.

GRADE: Grading of Recommendations Assessment, Development and Evaluation: a framework for rating certainty of evidence and strength of recommendations. NICE ME/CFS guidelines used GRADE methodology.

Graded Exercise Therapy (GET): A progressive exercise program formerly recommended for ME/CFS. Contraindicated in ME/CFS — NICE (2021) and CDC (2021) explicitly recommend against GET due to risk of harm (PEM exacerbation). Distinct from pacing/energy management. See GET entry.

Granzyme: A family of serine proteases (granzyme A, B, K, M) released by cytotoxic T cells and NK cells. Granzymes enter target cells through perforin-formed pores and induce apoptosis by activating caspases or directly cleaving mitochondrial proteins. Reduced granzyme B expression contributes to impaired NK cytotoxicity in ME/CFS.

GSH: Glutathione (reduced): the body’s master intracellular antioxidant. Reduced GSH and low GSH/GSSG ratios are frequently reported in ME/CFS, indicating oxidative stress.

GSSG: Glutathione Disulfide (oxidized): the oxidized form of glutathione. Elevated GSSG/GSH ratios indicate oxidative stress, a consistent finding in ME/CFS.

GTPCH: GTP Cyclohydrolase I: the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis. GTPCH dysfunction depletes BH4, linking to reduced nitric oxide, dopamine, and serotonin synthesis — a key node in ME/CFS metabolic dysfunction.

Gut–brain axis: The bidirectional communication system between the gastrointestinal tract and the central nervous system, involving neural (vagal), immune, endocrine, and microbial signaling pathways.

GWAS: Genome-Wide Association Study: a method scanning the entire genome for genetic variants associated with a disease. GWAS in ME/CFS have identified suggestive loci but no definitive genetic marker.

GWI: Gulf War Illness — a multi-symptom chronic illness affecting veterans of the 1991 Gulf War, involving fatigue, pain, cognitive problems, and autonomic dysfunction.

Gαq: G Protein Alpha-q Subunit: the α subunit of the Gq heterotrimeric G protein, which activates phospholipase C-β (PLC-β) upon GPCR stimulation, producing IP3 (calcium release) and DAG (PKC activation). Gαq-coupled receptors include H1 (histamine), M1/M3 (muscarinic), AT1 (angiotensin), and α1-adrenergic receptors — all implicated in ME/CFS autonomic and immune dysfunction.

7 H–I

H. pylori: Helicobacter pylori: a gastric bacterium infecting ~50% of the global population, causing chronic gastritis, peptic ulcers, and gastric cancer. H. pylori has been linked to autoimmune conditions (ITP, autoimmune gastritis) via molecular mimicry and chronic immune activation — relevant to ME/CFS autoimmune hypotheses and GI comorbidity.

H1 receptor: The histamine receptor type 1, a G-protein-coupled receptor mediating allergic and inflammatory responses (vasodilation, bronchoconstriction, pruritus). H1 antihistamines are first-line therapy for mast cell activation symptoms in ME/CFS.

H2 receptor: The histamine receptor type 2, a G-protein-coupled receptor primarily mediating gastric acid secretion. H2 antihistamines also modulate T-cell responses via cAMP elevation and have been investigated for immunomodulation in ME/CFS.

HADS: Hospital Anxiety and Depression Scale. A 14-item self-report screen (7 anxiety, 7 depression items) designed for medically ill populations that excludes somatic symptoms (fatigue, sleep disturbance) to avoid confounding with physical illness.

half-life: The time required for the plasma concentration of a drug to decrease by 50%. Longer half-life drugs (e.g., fluoxetine, ~4–16 days for active metabolite) require cautious dosing in ME/CFS patients who may have altered drug metabolism.

Hb: Hemoglobin: the iron-containing oxygen-carrying protein in red blood cells. Normal in ME/CFS but occasionally low due to comorbid iron deficiency.

HbA1c: Glycated Hemoglobin A1c: reflects average blood glucose over the preceding 2–3 months. Used to screen for diabetes, which can cause fatigue resembling ME/CFS and must be excluded.

HBOT: Hyperbaric Oxygen Therapy: breathing 100% oxygen at elevated atmospheric pressure. Investigated in ME/CFS for mitochondrial support, tissue oxygenation, and anti-inflammatory effects. Evidence is limited.

HCA2: Hydroxycarboxylic Acid Receptor 2 (GPR109A): a Gαi-coupled receptor activated by niacin (vitamin B3) and β-hydroxybutyrate (ketone body). Expressed on mast cells, adipocytes, and immune cells; HCA2 activation on mast cells mediates the niacin flush (PGD2 release). Also mediates the anti-inflammatory effects of ketone bodies — relevant to ketogenic diet strategies in ME/CFS.

HCN: Hyperpolarization-activated Cyclic Nucleotide-gated channel: the channel carrying the If (‘funny’) current in cardiac pacemaker cells (SA node) and neurons. cAMP directly activates HCN channels, accelerating heart rate. HCN blockade by ivabradine is used therapeutically in ME/CFS/POTS to reduce sinus tachycardia without lowering blood pressure.

HDL: High-Density Lipoprotein: the ‘good’ cholesterol particle mediating reverse cholesterol transport. HDL particle function (not just concentration) may be impaired in ME/CFS due to oxidative modification.

Head-down tilt bed rest: A research model where healthy volunteers lie at a 6° head-down angle for extended periods (e.g. 60 days) to simulate the effects of microgravity and extreme physical deconditioning.

Heart Failure with Preserved Ejection Fraction (HFpEF): A form of heart failure where the heart pumps normally but is too stiff to fill properly. Shares with ME/CFS the feature of impaired peripheral oxygen extraction and exercise intolerance despite normal cardiac output.

Heart rate recovery: The rate at which heart rate decreases after exercise cessation, reflecting parasympathetic reactivation. Delayed heart rate recovery (HR remains elevated for longer) is documented in ME/CFS and indicates impaired vagal tone — the parasympathetic system fails to re-engage after exertion.

hEDS: Hypermobile Ehlers-Danlos Syndrome: the most common subtype of EDS, characterized by generalized joint hypermobility, musculoskeletal pain, skin fragility, and dysautonomia. hEDS is strongly comorbid with ME/CFS and POTS; distinguishing features include the Beighton score, atrophic scarring, and positive family history.

Herpes simplex encephalitis: HSV-1 infection of the brain causing necrotizing encephalitis, primarily in the temporal lobes. A landmark model for infection-triggered autoimmunity: ~25% of patients develop anti-NMDAR antibodies (via molecular mimicry between HSV and NMDA receptor), causing autoimmune encephalitis months after the infection clears — directly relevant to post-infectious ME/CFS autoimmune mechanisms.

HERV (Human Endogenous Retrovirus): Remnants of ancient retroviral integrations in the human genome, comprising ~8% of human DNA. Normally silenced by epigenetic mechanisms, HERVs can be reactivated by viral infections (EBV, SARS-CoV-2) and inflammatory stimuli. HERV-K and HERV-W envelope proteins have been implicated in ME/CFS and multiple sclerosis as triggers of immune activation.

heterogeneity: Variability between patients — a defining feature of ME/CFS. Clinical heterogeneity (symptom presentation, severity, triggers) reflects underlying biological heterogeneity (endotypes), explaining why no single treatment works for all patients.

Hexokinase (HK): The first enzyme of glycolysis, phosphorylating glucose to glucose-6-phosphate. Hexokinase is inhibited by its product glucose-6-phosphate (feedback regulation). Hexokinase II (HK2) binds to mitochondrial VDAC, coupling glycolysis to mitochondrial metabolism and inhibiting apoptosis.

HGS: Hand Grip Strength. Objective measure of muscle force produced by squeezing a handheld dynamometer, used as a functional measure of upper-body muscle strength and a general health indicator.

HHV-6: Human Herpesvirus 6: a herpesvirus commonly infecting children (roseola). HHV-6 reactivation has been linked to ME/CFS onset and severity.

hibernation: A prolonged state of deep torpor in which an animal drastically lowers body temperature and metabolic rate over weeks to months to survive winter; distinguished from brief interbout arousal episodes.

HIC: High-Income Country — World Bank classification. Nearly all published ME/CFS research, prevalence data, and clinical guidelines originate from HICs.

Hidradenitis suppurativa: A chronic inflammatory skin disease of hair follicles in intertriginous areas (axillae, groin), causing painful nodules, abscesses, and sinus tracts. Proposed as an ME/CFS comorbidity via shared inflammatory pathways (TNF-α, IL-1β, IL-17) and potential mast cell involvement.

HIF-1α: Hypoxia-Inducible Factor 1 Alpha: a transcription factor that coordinates cellular adaptation to low oxygen, upregulating glycolysis, angiogenesis (VEGF), and erythropoiesis. Stabilized by mitochondrial ROS and succinate accumulation; HIF-1α activation may drive the glycolytic shift in ME/CFS.

High-resolution respirometry: A laboratory technique (e.g. Oroboros O2k) that measures mitochondrial oxygen consumption in permeabilized muscle fibres to quantify respiratory chain function.

Hill function: A mathematical function describing cooperative binding or sigmoidal dose–response relationships: f(x) = x^n / (K^n + x^n), where n is the Hill coefficient and K is the half-saturation constant.

HIP-B: Hormetic Inversion-Point Battery — a proposed 6-drug within-patient crossover trial (LDN, sulforaphane, duloxetine, modafinil, rapamycin, allopregnanolone) testing whether hormetic inversion-points correlate across mechanistically distinct drugs, testing whether hormetic reserve is a systems-level trait. Estimated cost: $600,000–$800,000.

hippocampus: A seahorse-shaped structure in the medial temporal lobe critical for memory formation, spatial navigation, and HPA axis negative feedback. Reduced hippocampal volume has been reported in ME/CFS, possibly due to chronic cortisol/neuroinflammatory effects.

Hippurate: A urinary metabolite formed by conjugation of benzoic acid with glycine, largely reflecting dietary benzoate intake and gut microbial benzoate metabolism. BioMapAI links an increase in the benzoate-to-hippurate transformation to sleep, emotional, and fatigue symptoms in ME/CFS, but the axis rests on a single model plus small neighbouring-population pilots.

histamine: A biogenic amine stored in mast cell and basophil granules, released upon degranulation. Histamine mediates vasodilation, bronchoconstriction, gastric acid secretion, and wakefulness. Histamine intolerance and excess (from MCAS or reduced DAO enzyme activity) drives flushing, headache, tachycardia, and GI symptoms in ME/CFS.

histamine intolerance: Histamine Intolerance: a condition where ingested or released histamine exceeds the body’s degradation capacity (impaired DAO or HNMT enzyme activity), producing flushing, headache, tachycardia, gut symptoms and nasal congestion. Mechanistically distinct from — but overlapping with — MCAS; often managed with a time-limited low-histamine diet. See also HIT.

Histidine: An essential amino acid and precursor for histamine synthesis via histidine decarboxylase. Also a precursor for carnosine. Histidine availability can become rate-limiting for histamine production in mast cell activation states.

HIT: Histamine Intolerance: a condition where histamine ingestion or release exceeds degradation capacity (impaired DAO/HNMT enzymes), causing flushing, headache, tachycardia, GI symptoms, and nasal congestion. Frequently comorbid with ME/CFS and MCAS; managed with low-histamine diet and DAO supplementation.

HIV: Human Immunodeficiency Virus: the virus causing AIDS. HIV-associated fatigue and ME/CFS share overlapping features; HIV must be excluded before ME/CFS diagnosis.

HIV/AIDS: Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome — a viral infection and resulting immunodeficiency disease whose activist movement in the 1980s–90s provides a model of patient participation in research governance.

hives: Colloquial name for urticaria: itchy, raised skin wheals caused by histamine-driven local swelling (weals) in the skin. A hallmark histamine/mast-cell symptom.

HLA (Human Leukocyte Antigen): The human major histocompatibility complex (MHC), encoded by genes on chromosome 6. HLA class I (A, B, C) present endogenous antigens to CD8⁺ T cells; HLA class II (DR, DQ, DP) present exogenous antigens to CD4⁺ T cells. Specific HLA alleles are associated with autoimmune disease risk and may influence ME/CFS susceptibility.

HMGB1: High Mobility Group Box 1: a nuclear protein that, when released extracellularly, acts as a damage-associated molecular pattern (DAMP), activating TLR4 and RAGE. HMGB1 is elevated in ME/CFS and links cellular stress to neuroinflammation.

HNMT: Histamine N-methyltransferase: an intracellular enzyme that breaks down (methylates) histamine. A common genetic variant can reduce its activity in roughly 15-20% of people. Reduced HNMT function could, in principle, cause a ‘clearing’ problem where normal mast-cell histamine release builds up — but its effect in ME/CFS has not been measured in a cohort, and there is no routine clinical test for it.

HO-1: Heme Oxygenase-1: the inducible enzyme degrading heme to biliverdin, carbon monoxide, and free iron. HO-1 is a key NRF2-target antioxidant and anti-inflammatory gene; HO-1 induction may be impaired in ME/CFS despite oxidative stress.

Holmes Criteria (1988): The first formal CDC case definition of chronic fatigue syndrome (CFS), published in 1988. Required new-onset persistent fatigue plus 8 of 11 symptom criteria. Did not require post-exertional malaise (PEM) as a defining feature. Superseded by Fukuda criteria (1994).

HOMA-IR: Homeostatic Model Assessment of Insulin Resistance: calculated from fasting glucose and insulin. Assesses insulin resistance; metabolic studies suggest insulin resistance may be present in a subset of ME/CFS patients.

Homocysteine: Homocysteine: a sulfur-containing amino acid intermediate in methionine metabolism. Elevated homocysteine indicates impaired methylation (B12/folate deficiency, MTHFR variants) and is an independent cardiovascular risk factor; reported elevated in some ME/CFS cohorts.

Hormesis: A biphasic dose-response phenomenon in which low-dose exposure to a stressor (drug, toxin, radiation) triggers compensatory adaptive upregulation — producing benefit — while higher doses suppress the same pathway, eliminating benefit or causing harm. Also called the inverted-U dose-response. The Calabrese corpus (Nature 2003, et seq.) establishes hormesis as the default dose-response model in pharmacology, not the exception. In ME/CFS, 17 medications (LDN, LDA, lithium, melatonin, sulforaphane, corticosteroids, DORAs, duloxetine, beta-blockers, modafinil, H1 antihistamines, NAC, rapamycin, allopregnanolone, ketotifen, quercetin, taVNS) exhibit non-monotonic dose-response through four mechanistic clusters: Nrf2-mediated compensatory upregulation, catecholamine inverted-U at prefrontal D1/α2A receptors, mTORC1/mTORC2 dose selectivity, and biphasic GABA-A/neurosteroid concentration-response.

Hormetic Reserve: A hypothesized quantitative trait reflecting the width of an individual’s hormetic dose-response windows across multiple drugs. If the dose at which a drug’s benefit inverts (inversion-point) correlates across mechanically distinct drugs (r ≥ 0.4), hormetic reserve is a general systems property — narrow reserve indicates fragile adaptive stress-response networks. If inversion-points do not correlate (r < 0.2), dose-response curves are drug-specific, not a unified trait. Untested in any condition; the HIP-B (Hormetic Inversion-Point Battery) trial — 6 drugs, 20 patients, within-patient crossover — would be the first direct test.

HPA: Hypothalamic-Pituitary-Adrenal axis: the central stress-response system. Blunted HPA axis responsiveness (low cortisol output) is a replicated finding in ME/CFS.

HPG: Hypothalamic-pituitary-gonadal axis: the hormonal control loop linking the brain’s hypothalamus and pituitary to the ovaries or testes, regulating reproduction and sex-hormone levels.

HR: Hazard Ratio: the ratio of instantaneous event rates between groups in survival analysis. In ME/CFS, HR can describe recovery or deterioration rates over time.

HRI: Heme-Regulated Inhibitor: an eIF2α kinase activated by heme deficiency, oxidative stress, and mitochondrial dysfunction. HRI may link mitochondrial distress to ISR activation in ME/CFS.

HRQOL: Health-Related Quality of Life: the impact of a disease and its treatment on a person physical, mental, and social well-being, typically measured with instruments such as SF-36.

HRR: Heart rate recovery — the decrease in heart rate from peak exercise or stress to 1 or 2 minutes post-stimulus. Reflects parasympathetic (vagal) reactivation capacity. Attenuated HRR (≤34.5 bpm at 1 min) is documented in ME/CFS and predicts mortality in cardiovascular populations.

HRT: Hormone Replacement Therapy: estrogen (and usually progestogen where a uterus is present) given to replace ovarian hormones after menopause; benefit in ME/CFS is unproven, and venous-thromboembolism risk is lower with transdermal than oral estrogen.

HRV: Heart Rate Variability: the variation in time between successive heartbeats, reflecting autonomic nervous system balance. Reduced HRV (low parasympathetic tone) is consistently reported in ME/CFS.

HSC: Haematopoietic Stem Cell: multipotent stem cells in bone marrow that give rise to all blood cell lineages. HSC dysfunction or exhaustion has been hypothesized in ME/CFS as a mechanism for persistent immune abnormalities, though direct evidence is lacking.

HSD: Hypermobility Spectrum Disorder: a connective tissue disorder characterized by joint hypermobility with associated symptoms (pain, fatigue, GI dysfunction, dysautonomia). Closely related to and often co-occurring with ME/CFS.

HSP70: Heat Shock Protein 70: a molecular chaperone that refolds misfolded proteins and prevents aggregation under cellular stress. HSP70 is released extracellularly as a DAMP, activating TLR2/TLR4. Elevated extracellular HSP70 in ME/CFS may reflect chronic cellular stress and contribute to sterile inflammation.

HSP90α: Heat shock protein 90 alpha: a molecular chaperone, a fraction of which is secreted extracellularly, where it modulates integrin activation and ligand-receptor signalling. Extracellular HSP90α supports irisin signalling through the αvβ5 integrin; its deficiency contributes to irisin signalling resistance. HSP90 inhibitors degrade this co-receptor and are NOT indicated.

HSV: Herpes Simplex Virus: HSV-1 (oral) and HSV-2 (genital). Reactivation may contribute to ME/CFS symptom flares.

HTA: Health Technology Assessment — a systematic process used by government agencies to evaluate the clinical and cost-effectiveness of healthcare interventions, informing coverage and reimbursement decisions.

HTA Agency: A government body that conducts Health Technology Assessments — evaluating whether healthcare interventions (drugs, devices, care models) are clinically effective and cost-effective enough to warrant public funding.

HTN: Hypertension: chronically elevated blood pressure. Paradoxically present in some hyperadrenergic ME/CFS/POTS patients despite orthostatic intolerance; supine hypertension with orthostatic hypotension/tachycardia complicates pharmacological management.

HTT: HTT (huntingtin): the gene encoding huntingtin, whose expansion causes Huntington’s disease. A coding variant in HTT was the strongest risk signal in the largest fibromyalgia GWAS.

Hyaluronan (HA): A large glycosaminoglycan that forms part of the extracellular matrix. In ME/CFS, overproduction and TSG-6-mediated crosslinking of HA may contribute to capillary basement membrane thickening, impairing oxygen diffusion.

hyperacusis: Reduced tolerance to ordinary environmental sounds, perceived as uncomfortably loud or painful. Common in ME/CFS and linked to central auditory processing dysfunction.

hyperalgesia: Increased pain sensitivity — an exaggerated pain response to a normally painful stimulus. Hyperalgesia in ME/CFS is driven by central sensitization and neuroinflammation-mediated lowering of pain thresholds.

Hypometabolism: A state of reduced metabolic activity. In ME/CFS, refers to the systemic downregulation of metabolic pathways documented by metabolomics studies.

hypothalamus: A small but critical brain region below the thalamus controlling homeostasis: HPA axis, autonomic balance, sleep-wake cycles, temperature, hunger, and thirst. Hypothalamic dysfunction is a unifying node in ME/CFS pathology — linking sleep, endocrine, autonomic, and metabolic dysregulation.

hypovolemia: Reduced blood volume: absolute (decreased total blood volume) or relative (normal volume but increased vascular capacity). Hypovolemia is common in ME/CFS/POTS, contributing to orthostatic intolerance, tachycardia, and reduced cerebral perfusion.

H₁ Receptor: Histamine H₁ receptor: a Gₐq-coupled GPCR that mediates classical allergic and inflammatory responses — vasodilation, bronchoconstriction, pruritus, and pain. Blocked by first-generation (diphenhydramine, hydroxyzine) and second-generation (loratadine, fexofenadine, cetirizine) antihistamines. H₁ antagonism is used in ME/CFS for MCAS-related symptoms and sleep disturbance.

H₂ Receptor: Histamine H₂ receptor: a Gₐs-coupled GPCR that stimulates gastric acid secretion, increases vascular permeability, and modulates immune cell function. Blocked by H₂ antagonists (famotidine, cimetidine, ranitidine). Famotidine is used alongside H₁ blockade in ME/CFS for dual histamine receptor antagonism in MCAS management.

H₂O₂: Hydrogen Peroxide: a reactive oxygen species produced by superoxide dismutase (SOD) from superoxide, and by NADPH oxidases (NOX). H₂O₂ is a signaling molecule at low levels but causes oxidative damage at high levels; elevated H₂O₂ production in ME/CFS reflects mitochondrial electron leak and NOX activation.

H₂S: Hydrogen Sulfide: a gaseous signaling molecule (gasotransmitter) with dual roles — at physiological levels, H₂S is a vasodilator, mitochondrial electron donor (at Complex II), and antioxidant; at excess levels from gut dysbiosis (sulfate-reducing bacteria), H₂S is a mitochondrial toxin inhibiting Complex IV. H₂S dysregulation links gut dysbiosis to mitochondrial dysfunction in ME/CFS.

IA: Immunoadsorption: a therapeutic apheresis procedure that selectively removes pathogenic antibodies (IgG) from plasma while returning other plasma components. Used experimentally in ME/CFS to test whether removal of GPCR autoantibodies improves autonomic and fatigue symptoms; temporary benefit suggests autoantibody-mediated pathophysiology in responsive patients.

IACFS/ME: International Association for CFS/ME: the primary professional organization for ME/CFS clinicians and researchers. Hosts biennial conferences and publishes the ME/CFS Primer for clinicians.

IACI: Infection-Associated Chronic Illnesses — a term coined by the National Academies’ 2024 workshop encompassing ME/CFS, Long COVID, post-Lyme, and other post-infectious syndromes that share overlapping mechanisms. The framework calls for unified research approaches across these conditions.

IBD: Inflammatory Bowel Disease: a group of chronic inflammatory conditions of the GI tract (Crohn’s disease, ulcerative colitis). Overlaps with ME/CFS in symptom burden but is a distinct inflammatory pathology.

IBS: Irritable Bowel Syndrome: a functional gastrointestinal disorder characterized by abdominal pain, bloating, and altered bowel habits. Highly prevalent in ME/CFS (30–60%).

ICB: Integrated Care Board — UK NHS body responsible for planning and commissioning healthcare services for a geographic population.

ICC: International Consensus Criteria (2011): ME diagnostic criteria requiring post-exertional neuroimmune exhaustion (PENE) plus neurological, immune, and energy metabolism impairments. More specific than Fukuda/CDC but excludes patients with primary psychiatric disorders.

ICD: International Classification of Diseases — the WHO’s global standard for coding health conditions and causes of death.

ICD-10: International Classification of Diseases, 10th Revision. ME/CFS classified under G93.3 (postviral fatigue syndrome / benign myalgic encephalomyelitis).

ICD-11: International Classification of Diseases, 11th Revision. ME/CFS classified under 8E49 (postviral fatigue syndrome) in the diseases of the nervous system chapter, reinforcing its neurological classification.

ICF: International Classification of Functioning, Disability and Health — a WHO framework for describing health and health-related states in terms of body functions, activities, and participation.

ICP: Intracranial Pressure: the pressure inside the skull and on brain tissue. Abnormal ICP dynamics have been hypothesized in ME/CFS, particularly in the context of CCI.

ICP0: Infected Cell Protein 0 — HSV-1 immediate-early protein expressed at the first step of viral reactivation from latency. A transcriptional activator that initiates the lytic gene cascade.

Idiopathic chronic fatigue: Persistent fatigue not meeting ME/CFS diagnostic criteria and not attributable to another condition. ICF lacks PEM — the cardinal ME/CFS symptom. The 2-day CPET distinguishes ICF from ME/CFS: only ME/CFS patients show a significant drop in VO₂ peak and workload at anaerobic threshold on day 2.

IDO: Indoleamine 2,3-Dioxygenase: enzyme diverting tryptophan metabolism from serotonin to the kynurenine pathway. IDO is induced by IFN-γ and inflammation; IDO activation is linked to ME/CFS tryptophan depletion and neurotoxicity.

IENFD: Intraepidermal Nerve Fiber Density: the number of small unmyelinated nerve fibers per millimeter of epidermis, measured by skin punch biopsy with PGP9.5 immunostaining. Reduced IENFD is the gold-standard diagnostic marker for small-fiber neuropathy, found in a significant subset of ME/CFS patients, linking to neuropathic pain and autonomic dysfunction.

IFN-γ: Interferon Gamma: a key Th1 cytokine involved in antiviral and immune responses. Abnormal IFN-γ signaling is found in ME/CFS immune dysfunction.

IgE: Immunoglobulin E: the antibody isotype mediating allergic responses by binding to high-affinity FcεRI receptors on mast cells and basophils. Elevated IgE in ME/CFS may indicate an atopic/MCAS endotype; however, most MCAS presents with normal IgE.

IGF-1: Insulin-like Growth Factor 1: hormone mediating many GH effects. Reduced IGF-1 has been reported in subsets of ME/CFS patients.

IgG: Immunoglobulin G — the most abundant antibody class in blood, providing long-term immunity and able to cross the placenta.

IgM: Immunoglobulin M — the first antibody produced during an immune response, forming pentamers that efficiently activate complement.

IIH: Idiopathic Intracranial Hypertension: elevated intracranial pressure of unknown cause, producing headache, visual disturbances, and pulsatile tinnitus. May overlap with ME/CFS symptomatology.

IL: Interleukin: a broad family of cytokines primarily mediating communication between leukocytes. Key interleukins in ME/CFS include IL-1β (pro-inflammatory, sickness behavior), IL-6 (fatigue, neuroinflammation), IL-10 (anti-inflammatory, often reduced), and IL-17 (Th17, gut barrier).

IL-17A: Interleukin-17A: the defining cytokine of Th17 cells, recruiting neutrophils and promoting inflammation. Elevated in Alzheimer’s disease and in depression/persons with mental illness, and relevant to Th17-axis signalling in ME/CFS; crossing the blood-brain barrier, it may contribute to CNS inflammation.

IL-17F: Interleukin-17F: a Th17-family cytokine structurally related to IL-17A, produced by Th17 cells and promoting neutrophil recruitment. Part of early-disease ME/CFS cytokine signatures.

IL-1β: Interleukin-1 Beta: a master pro-inflammatory cytokine that mediates fever, fatigue, and sickness behavior. Elevated in subsets of ME/CFS patients and known to activate the HPA axis.

IL-6: Interleukin-6: a pleiotropic cytokine with both pro- and anti-inflammatory roles. Elevated in many ME/CFS patients, associated with fatigue severity and neuroinflammation.

ILMI: Ipsilateral Limb Metabolic Index: a measure comparing FDG-PET glucose uptake between left and right limb muscles, quantifying metabolic asymmetry. Abnormal ILMI suggests lateralized mitochondrial or vascular dysfunction — a novel biomarker approach in ME/CFS.

immune checkpoint: Inhibitory receptors (e.g. PD-1, CTLA-4) that restrain T-cell activation. Tumors exploit checkpoints to evade immunity; checkpoint-blockade antibodies are a cancer therapy. In ME/CFS, elevated checkpoint markers indicate T-cell exhaustion.

Immune Checkpoint: A regulatory receptor or ligand that dampens T cell activation to maintain self-tolerance and prevent autoimmunity. Key checkpoints include PD-1, CTLA-4, TIM-3, and LAG-3. Upregulation of checkpoint receptors contributes to T-cell exhaustion in chronic infection and ME/CFS.

Immune exhaustion: Progressive loss of effector function in T cells or NK cells due to chronic antigen stimulation. Characterized by upregulation of inhibitory receptors (PD-1, Tim-3, LAG-3).

Immunoadsorption (IA): A therapeutic apheresis technique that removes specific antibodies, immune complexes, or inflammatory mediators from blood by passing plasma through columns containing immobilized ligands (e.g., protein A, tryptophan, anti-IgG antibodies). Used experimentally in ME/CFS to deplete autoantibodies targeting GPCRs (β₂-adrenergic, M₃ muscarinic), with some patients reporting sustained symptom improvement.

Immunohistochemistry (IHC): A laboratory technique that uses antibodies to detect specific proteins in tissue sections. Used in ME/CFS muscle biopsy studies to quantify capillary density and identify immune cell infiltration.

Immunomodulation: The therapeutic adjustment of immune system activity — either suppression of excessive inflammation or enhancement of deficient immune responses. In ME/CFS, immunomodulatory approaches include low-dose naltrexone (LDN), IVIG, rituximab (B-cell depletion), immunoadsorption, and various cytokine-targeting biologics.

immunotherapy: Treatments that modulate the immune system to fight disease (e.g. checkpoint inhibitors, CAR-T). No evidence base supports oncology-style immunotherapy for ME/CFS; unselected immune therapy has failed in trials.

IMPase: Inositol Monophosphatase: the enzyme that regenerates free inositol from inositol monophosphate, a critical step in the phosphatidylinositol (PI) cycle. IMPase is inhibited by lithium; this inhibition depletes PIP2, reducing IP3/DAG second messenger production and attenuating Gαq-coupled receptor signaling — a mechanism by which lithium may modulate hyperactive GPCR signaling in ME/CFS.

inflammaging: Low-grade chronic inflammation that increases with age and is linked to immunosenescence (deteriorating immune function). Implicated across neuroinflammatory CNS conditions including Alzheimer’s disease and proposed as a contributor to chronic illness.

Inflammasome: A multi-protein cytosolic complex (NLRP3, NLRC4, AIM2, pyrin) that assembles in response to pathogens or cellular stress, activating caspase-1 which cleaves pro-IL-1β and pro-IL-18 to their active forms and cleaves gasdermin D to trigger pyroptosis. NLRP3 inflammasome activation from mitochondrial ROS, DAMPs, and microclots is a candidate driver of the chronic inflammatory state in ME/CFS.

influenza: An orthomyxovirus causing seasonal epidemics of respiratory illness. Influenza is a well-documented trigger of post-infectious ME/CFS; the 1918 influenza pandemic produced a wave of ‘encephalitis lethargica’ with striking ME/CFS-like features including profound fatigue and post-exertional collapse.

INR: International Normalized Ratio: a standardized PT ratio used to monitor warfarin therapy and assess liver synthetic function. Normal in ME/CFS.

insula: A cortical region folded deep within the lateral sulcus, integrating interoceptive signals (body state awareness) with emotional and cognitive processing. Insular dysfunction in ME/CFS may explain altered interoception — the ‘body feeling wrong’ — and autonomic dysregulation.

Insulin: A pancreatic β-cell hormone promoting glucose uptake, glycogenesis, and lipogenesis while inhibiting gluconeogenesis. Insulin resistance has been reported in subsets of ME/CFS, potentially contributing to metabolic inflexibility. Insulin also has CNS effects on cognition and appetite.

interbout arousal: The periodic, spontaneous return to normal body temperature and metabolism that hibernating animals make between torpor bouts; the molecular signals of this reversible ‘wake-up’ are the focus of hibernation-based drug-discovery for low-energy states.

Interleukin-1 (IL-1): A family of pro-inflammatory cytokines (IL-1α, IL-1β) produced primarily by macrophages and monocytes. IL-1β is processed by the NLRP3 inflammasome and caspase-1. Drives fever, sickness behavior, and systemic inflammation. Elevated IL-1 in ME/CFS contributes to fatigue, pain, and neuroinflammation.

Interleukin-10 (IL-10): A key anti-inflammatory cytokine produced by Tregs, macrophages, and B cells. Suppresses pro-inflammatory cytokine production (TNF-α, IL-1, IL-6) and inhibits antigen presentation. IL-10 dysregulation in ME/CFS may contribute to inadequate resolution of inflammation.

Interleukin-15 (IL-15): A cytokine that promotes NK cell and CD8⁺ memory T cell survival and proliferation. Shares the γ-chain receptor subunit with IL-2. Elevated IL-15 in ME/CFS may drive NK and CD8⁺ T cell dysfunction through chronic activation leading to exhaustion.

Interleukin-17 (IL-17): A pro-inflammatory cytokine produced primarily by Th17 cells. Recruits neutrophils, induces antimicrobial peptides and MMPs, and is central to autoimmune inflammation. IL-17 elevation may contribute to the autoimmune and neuroinflammatory features observed in ME/CFS subsets.

Interleukin-2 (IL-2): A T cell growth factor essential for lymphocyte proliferation, differentiation, and survival. Produced primarily by activated CD4⁺ T cells. Low-dose IL-2 therapy selectively expands Tregs and is investigated in autoimmune diseases. IL-2 signaling abnormalities contribute to T-cell dysfunction in ME/CFS.

Interstitial cells of Cajal: The ‘pacemaker’ cells of the stomach and bowel that generate the electrical rhythm driving muscle contraction. Loss of these cells is found in diabetic and idiopathic gastroparesis.

Inverted-U: Shorthand for the inverted-U dose-response curve — a non-monotonic relationship where benefit increases with dose to a maximum, then declines or inverts to harm at higher doses. The dose at which inversion occurs reveals the receptor reserve, endogenous tone, and fragility of the target system. See also: hormesis, hormetic reserve.

IOM: Institute of Medicine (US, now National Academy of Medicine): published the 2015 report ‘Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome’, proposing SEID criteria and affirming ME/CFS as a serious biomedical disease.

Ion Channel: A pore-forming transmembrane protein that allows the passive flow of specific ions (Na⁺, K⁺, Ca²⁺, Cl⁻) down their electrochemical gradient. Ion channels are classified by gating mechanism (voltage-gated, ligand-gated, mechanosensitive, temperature-sensitive) and ion selectivity. Channel dysfunction (channelopathy) underlies numerous neurological, cardiac, and metabolic disorders.

IP receptor: Prostacyclin I2 Receptor: a Gαs-coupled receptor activated by prostacyclin (PGI2), mediating vasodilation and inhibition of platelet aggregation. IP receptor dysfunction or impaired PGI2 synthesis by endothelial COX-2 may contribute to microvascular constriction in ME/CFS.

IP3: Inositol 1,4,5-Trisphosphate: a second messenger produced by PLC that opens IP3 receptors on the ER, releasing calcium into the cytoplasm. IP3-mediated calcium signaling is essential for immune cell activation and neurotransmitter release.

IP3R: IP3 Receptor: an ER calcium release channel gated by IP3. IP3R-mediated calcium release couples surface receptor activation to intracellular calcium signals driving immune function and metabolism.

iPSC: Induced Pluripotent Stem Cells: adult cells reprogrammed back to an embryonic-like state, then differentiated into cell types of interest (e.g., neurons) for disease modeling in the laboratory. Referenced here as a way to test whether patient-derived neurons reproduce the cellular defects seen in Angelman-syndrome models.

IRE1: Inositol-Requiring Enzyme 1: a UPR sensor with endoribonuclease activity that splices XBP1 mRNA. IRE1 activation links ER stress to inflammatory signaling via JNK and NF-κB.

IRF3: Interferon Regulatory Factor 3: a transcription factor driving type I interferon and chemokine gene expression downstream of cGAS-STING and RIG-I/MAVS pathways. Phosphorylated by TBK1.

IRF7: Interferon Regulatory Factor 7: the master transcription factor for type I interferons. IRF7 amplifies IFN responses in a positive feedback loop; dysregulated IRF7 may sustain the interferon signature in ME/CFS.

IRIS: Immune Reconstitution Inflammatory Syndrome: a paradoxical worsening of symptoms when the immune system recovers and mounts a strong response to persistent antigens; invoked as a model for postpartum ME/CFS onset.

Irisin: A 112-amino-acid myokine (hormone-like protein) released from muscle during exercise, produced by cleavage of FNDC5. It signals through αV integrins (including αvβ5) and promotes mitochondrial biogenesis, glucose uptake, and metabolic adaptation. Proposed (Souma 2026) to be functionally antagonised by elevated thrombospondin-1 in ME/CFS, contributing to blunted metabolic adaptation during PEM.

Iron Regulatory Proteins (IRP1/IRP2): Iron Regulatory Proteins 1 and 2 — master regulators of cellular iron homeostasis. They bind to iron-responsive elements (IREs) on mRNAs encoding ferritin, ferroportin, transferrin receptor, and other iron proteins, controlling their translation in response to cellular iron levels. IRP dysfunction can trap iron independently of hepcidin.

Isocitrate: A Krebs cycle intermediate produced from cis-aconitate by aconitase. Oxidized to α-ketoglutarate by isocitrate dehydrogenase (IDH), generating NADPH. IDH1/IDH2 mutations produce the oncometabolite 2-hydroxyglutarate and alter cellular redox and epigenetic states.

ISR: Integrated Stress Response: a conserved eukaryotic signaling network activated by diverse stresses (ER stress, amino acid deprivation, heme deficiency, viral infection). Converges on eIF2α phosphorylation, attenuating global translation while selectively translating stress-response genes. Chronic ISR activation is hypothesized in ME/CFS and may explain the impaired cellular energy metabolism.

ITT: Intention-To-Treat: a clinical trial analysis method that includes all randomized participants regardless of whether they completed the trial. ITT analysis preserves randomization and prevents selection bias.

IU: International Unit: a unit of measurement for biological substances (vitamins, hormones, enzymes) standardized by their biological activity rather than mass. Used for vitamin D, IgE, and other laboratory values relevant to ME/CFS assessment.

IU/mL: International Units per milliliter: a concentration unit for biological substances. Commonly used for IgE levels in MCAS/atopy evaluation and for antibody titers in autoimmune and infectious disease testing.

IV: Intravenous: medication administration directly into a vein. IV therapies in ME/CFS include IVIG, saline infusions (for POTS/hypovolemia), and vitamin infusions.

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JAK: Janus Kinase: a family of tyrosine kinases (JAK1, JAK2, JAK3, TYK2) that phosphorylate STAT proteins downstream of cytokine receptors. JAK-STAT signaling is central to immune activation in ME/CFS.

JNK: c-Jun N-terminal Kinase: a stress-activated MAPK responding to cytokines, oxidative stress, and ER stress. JNK activation may drive inflammation and apoptosis in ME/CFS.

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KAT: Kynurenine Aminotransferase: the enzyme that converts kynurenine to kynurenic acid (KYNA), the neuroprotective NMDA receptor antagonist branch of the kynurenine pathway. KAT activity determines the KYNA/QUIN balance; impaired KAT shifts toward QUIN-mediated excitotoxicity in ME/CFS neuroinflammation.

Keap1: Kelch-like ECH-associated protein 1 — a sensor protein that binds Nrf2 and targets it for degradation under basal conditions. Under oxidative stress, Keap1 releases Nrf2, allowing it to activate protective genes.

ketone: Ketone bodies (β-hydroxybutyrate, acetoacetate, acetone): water-soluble fuels produced by the liver from fatty acids during carbohydrate restriction or fasting. Ketones can bypass the PDH gate, directly feeding the TCA cycle. Ketogenic metabolism has been proposed as a therapeutic strategy in ME/CFS to circumvent impaired glucose oxidation.

Ki67: A nuclear protein expressed during active cell division, used as a marker of proliferating (dividing) cells in tissue studies.

Klebsiella: A genus of gram-negative enteric bacteria implicated in gut dysbiosis and molecular mimicry. Klebsiella pneumoniae carries carbohydrate antigens that cross-react with HLA-B27, driving ankylosing spondylitis — a classic example of infection-triggered autoimmunity relevant to ME/CFS autoimmune hypotheses.

KMO: Kynurenine 3-Monooxygenase: the enzyme that diverts kynurenine toward the neurotoxic QUIN branch (via 3-hydroxykynurenine). KMO is the key branch-point enzyme in the kynurenine pathway; KMO upregulation by IFN-γ shifts metabolism toward QUIN (excitotoxic NMDA agonist) and away from KYNA (neuroprotective NMDA antagonist), contributing to excitotoxicity and cognitive dysfunction in ME/CFS.

Krebs cycle: (Also: citric acid cycle, tricarboxylic acid cycle.) The metabolic pathway in the mitochondrial matrix that oxidizes acetyl-CoA to CO2, generating NADH, FADH2, and GTP.

KYN: Kynurenine: the first intermediate of the kynurenine pathway from tryptophan. The KYN/tryptophan ratio is a marker of IDO activation and immune dysfunction in ME/CFS.

KYNA: Kynurenic Acid: a neuroprotective metabolite of the kynurenine pathway acting as an NMDA receptor antagonist. The KYNA/QUIN ratio determines neuroprotection vs neurotoxicity balance in ME/CFS.

Kynurenic Acid (KYNA): A neuroprotective metabolite in the kynurenine pathway, produced from kynurenine by kynurenine aminotransferases (KATs). Acts as an NMDA receptor antagonist and α7 nAChR negative allosteric modulator. Imbalance between kynurenic acid (protective) and quinolinic acid (toxic) is relevant to ME/CFS neuroinflammation hypotheses.

Kynurenine: The primary metabolite of tryptophan via IDO/TDO-catalyzed indole ring cleavage. Kynurenine is further metabolized to kynurenic acid (neuroprotective) via KAT or to quinolinic acid (neurotoxic) via the kynurenine-3-monooxygenase pathway. Kynurenine pathway activation is implicated in ME/CFS immune-metabolic dysregulation.

Labile Iron Pool (LIP): The small, metabolically active fraction of cellular iron that is loosely bound and available for redox reactions. The LIP is both the substrate for essential iron-dependent enzymes and the catalytic iron that drives ferroptosis. Measured in research using fluorescent calcein-AM quenching.

lactate: The conjugate base of lactic acid, produced during anaerobic glycolysis when pyruvate cannot enter the TCA cycle. Elevated resting and post-exertional lactate in ME/CFS indicates impaired oxidative metabolism and premature glycolytic shift.

lactate-to-creatine ratio (Lac/tCr): A ratio derived from proton magnetic resonance spectroscopy that indexes brain lactate levels against creatine as an internal reference. An elevated resting Lac/tCr in the thalamus is reported in ME/CFS and is interpreted as evidence of a glycolytic shift or bioenergetic inefficiency.

LAG-3 (Lymphocyte Activation Gene 3): An immune checkpoint receptor on T cells that binds MHC class II with higher affinity than CD4. Inhibits T cell proliferation and effector function. Co-expressed with PD-1 on exhausted T cells in chronic infection and cancer. Upregulated in ME/CFS T cells.

LASSO: Least Absolute Shrinkage and Selection Operator: a regression method performing variable selection and regularization. Used in ME/CFS biomarker discovery to identify minimal sets of predictive analytes.

LC: Long COVID: shorthand for PASC. Approximately 43–58% of Long COVID patients meet ME/CFS criteria; the two conditions share PEM, orthostatic intolerance, cognitive dysfunction, and metabolic abnormalities.

LC-NE: Locus Coeruleus-Norepinephrine system: the brainstem nucleus (LC) that is the primary source of norepinephrine in the CNS, projecting widely to cortex, thalamus, and spinal cord. The LC-NE system regulates arousal, attention, stress responses, and sympathetic tone; LC hyperactivity at night drives the ‘tired but wired’ state in ME/CFS.

LDA: Low-dose aripiprazole: aripiprazole used at sub-antipsychotic doses (~0.25–2 mg/day), acting as a partial dopamine D2 agonist. Hypothesized to modulate microglial activation and dopamine tone in ME/CFS neuroinflammation.

LDH: Lactate Dehydrogenase: enzyme interconverting pyruvate and lactate. Elevated LDH may reflect metabolic shift toward anaerobic glycolysis in ME/CFS.

LDL: Low-Density Lipoprotein: the ‘bad’ cholesterol particle carrying cholesterol to tissues. Oxidized LDL (oxLDL) is a marker of oxidative stress that may be elevated in ME/CFS.

leaky gut: Increased intestinal permeability allowing bacterial products (LPS, flagellin) to translocate from the gut lumen into systemic circulation. Intestinal permeability may drive chronic low-grade immune activation (‘metabolic endotoxemia’) in ME/CFS.

LepR: Leptin receptor: the cell-surface receptor for the metabolic hormone leptin. Leptin-receptor neurons in the hypothalamus transmit satiety and energy-status signals and help couple metabolic state to circadian rhythms.

Leptin: An adipokine hormone produced by adipose tissue that signals energy sufficiency to the hypothalamus, suppressing appetite and increasing energy expenditure. Leptin also modulates immune function (promoting Th1 responses). Leptin dysregulation may contribute to ME/CFS metabolic and immune dysfunction.

leukotriene: Inflammatory lipid mediators derived from arachidonic acid via the LOX pathway. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent bronchoconstrictors and pro-inflammatory agents released by mast cells; leukotriene overproduction contributes to MCAS symptoms in ME/CFS.

LFDRR: Luteal-to-Follicular Drug Response Ratio. A single-number biomarker computed as mean drug efficacy during the luteal phase (days 21–28) divided by mean efficacy during the follicular phase (days 7–14). LFDRR < 0.7 suggests oestrogen-coupled mechanism; > 1.3 suggests progesterone/GABA-coupled; 0.7–1.3 suggests hormone-independent.

LH: Luteinizing hormone: a pituitary hormone whose surge triggers ovulation; measured to confirm menstrual-cycle phase.

Lipid Peroxidation: The oxidative degradation of lipids by reactive oxygen species, where free radicals steal electrons from cell membrane fatty acids, producing chain reactions that damage membranes. The hallmark of ferroptosis (iron-dependent cell death). Measured via 4-HNE and MDA.

Lipocalin-2 (LCN2 / NGAL): Lipocalin-2, also known as NGAL (neutrophil gelatinase-associated lipocalin), is a protein that binds siderophore-iron complexes and delivers them to cells, bypassing the normal transferrin-based iron delivery system. Elevated LCN2 can create a futile iron cycle that traps iron in macrophages.

Lipopolysaccharide (LPS): A component of gram-negative bacterial cell walls. A potent activator of innate immunity through TLR4 signaling. Elevated circulating LPS (endotoxemia) may result from intestinal barrier dysfunction in ME/CFS.

Lithium (Li): An alkali metal element and psychotropic medication. At low doses (<10 mg/day, as lithium orotate or aspartate), lithium has neuroprotective effects through GSK-3β inhibition, BDNF upregulation, and inositol depletion. Hypothesized in ME/CFS for neuroprotection, circadian rhythm stabilization, and antiviral effects against HHV-6.

LLLT: Low-Level Laser Therapy (photobiomodulation): non-thermal light application (red/NIR) to tissues, proposed to enhance mitochondrial function via cytochrome c oxidase photostimulation. Experimental in ME/CFS; limited evidence.

LMIC: Low- and Middle-Income Country — World Bank classification based on gross national income per capita. Includes most countries in Sub-Saharan Africa, South Asia, and parts of Latin America and Southeast Asia where ME/CFS diagnostic infrastructure is limited.

locus coeruleus: A small nucleus in the brainstem that is the primary source of norepinephrine in the brain. The LC regulates arousal, attention, stress responses, and autonomic tone; LC dysfunction is central to the ‘tired but wired’ state and hyperadrenergic symptoms in ME/CFS.

Long COVID: Post-COVID-19 condition (PASC): persistent symptoms ≥3 months after SARS-CoV-2 infection, including fatigue, PEM, brain fog, orthostatic intolerance, and sleep disturbance. ~43-58% of Long COVID patients meet ME/CFS diagnostic criteria; Long COVID has created the largest-ever cohort of post-viral ME/CFS and provides an unprecedented opportunity to study ME/CFS pathophysiology from a known infectious trigger.

Low T3 syndrome: Non-thyroidal illness syndrome (sick euthyroid syndrome): a pattern of low serum T3 with normal TSH and T4, reflecting impaired peripheral T4→T3 conversion during systemic illness. Well-documented in ME/CFS; may represent an adaptive energy-conservation response rather than true hypothyroidism. TSH is normal — this is NOT primary thyroid disease.

LOX: Lipoxygenase: enzyme producing leukotrienes and other inflammatory mediators from arachidonic acid. LOX pathway activation contributes to oxidative stress in ME/CFS.

Lp(a): Lipoprotein(a): an LDL-like particle with apolipoprotein(a) covalently bound to apoB. Genetically determined; elevated Lp(a) is an independent cardiovascular risk factor.

LTD4: Leukotriene D4: a potent cysteinyl leukotriene released by mast cells that causes sustained bronchoconstriction (1000× more potent than histamine), increased vascular permeability, and mucous secretion. LTD4 is a major mediator of MCAS respiratory symptoms; CysLT1 blockade by montelukast targets LTD4 signaling.

LTP: Long-Term Potentiation: a persistent strengthening of synaptic connections based on recent patterns of activity, considered the cellular basis of learning and memory. Impaired LTP in ME/CFS (via NMDA receptor dysfunction, neuroinflammation, or reduced BDNF) may underlie the cognitive dysfunction and ‘brain fog’ that patients report as difficulty learning new information.

Lyme: Lyme disease (Lyme borreliosis): a tick-borne infection caused by Borrelia burgdorferi spirochetes, producing erythema migrans rash, arthritis, neurological symptoms, and carditis. Chronic Lyme disease (PTLDS, post-treatment Lyme disease syndrome) shares substantial clinical overlap with ME/CFS including fatigue, cognitive dysfunction, and PEM. The two conditions may coexist — diagnosing ME/CFS in a Lyme patient requires excluding active Borrelia infection.

Lysozyme: An antimicrobial enzyme found in secretions (tears, saliva, mucus) that cleaves peptidoglycan in bacterial cell walls. Also present in neutrophil and macrophage granules. A key component of innate mucosal immunity.

Machine Learning: A field of computer science where algorithms learn patterns from data without explicit programming. In ME/CFS research, ML is used for biomarker discovery but is susceptible to overfitting when applied to small samples (n<100) without external validation.

Macrophage: A large phagocytic immune cell of the innate system that engulfs pathogens, clears cellular debris, and orchestrates inflammation and tissue repair. Macrophages polarize along an M1 (pro-inflammatory) to M2 (anti-inflammatory/repair) spectrum. Macrophage dysfunction contributes to chronic inflammation in ME/CFS.

MAGMA: Multi-marker Analysis of GenoMic Annotation: a computational method that tests whether groups of genes (gene sets) are collectively associated with a disease or trait, used for gene-set enrichment analysis of genome-wide association study (GWAS) results.

MAIT: Mucosal-Associated Invariant T cell: an innate-like T cell enriched at mucosal surfaces (gut, lung) that responds rapidly to microbial metabolites. In ME/CFS, AI-driven multi-omics models report heightened MAIT inflammatory activity (IFN-gamma, granzyme A), while single-cell studies in Long-COVID report MAIT depletion — a possibly-orthogonal activation-versus-depletion tension that remains unresolved.

Malate: A Krebs cycle intermediate produced from fumarate by fumarase. Oxidized to oxaloacetate by malate dehydrogenase (generating NADH). The malate-aspartate shuttle transfers reducing equivalents from the cytosol into the mitochondrial matrix.

Malondialdehyde (MDA): A product of lipid peroxidation and a biomarker of oxidative stress and ferroptosis. Elevated MDA indicates free-radical damage to polyunsaturated fatty acids in cell membranes. Often measured alongside 4-HNE in ferroptosis research.

MAO: Monoamine Oxidase: enzyme breaking down monoamine neurotransmitters (serotonin, dopamine, norepinephrine). MAO inhibitors (MAOIs) are a class of antidepressants rarely used in ME/CFS.

MAO-B: Monoamine Oxidase B: the MAO isoform that preferentially degrades dopamine (and phenylethylamine). MAO-B activity increases with age and in neuroinflammation; elevated MAO-B may contribute to dopamine depletion in ME/CFS. MAO-B inhibitors (selegiline, rasagiline) are used in Parkinson’s disease.

MAPK: Mitogen-Activated Protein Kinase: a signaling pathway regulating cell proliferation, differentiation, and stress responses. MAPK/ERK and p38 MAPK activation have been reported in ME/CFS immune cells.

MAPK/ERK: Mitogen-Activated Protein Kinase / Extracellular signal-Regulated Kinase signalling cascade. A major intracellular signalling pathway that controls gene expression, cell proliferation, and synaptic plasticity. Activated downstream of oestrogen receptor transactivation.

Markov model: A mathematical model used in health economics that simulates a patient’s progression through different health states over time, each with associated costs and quality-of-life weights, to estimate long-term cost-effectiveness.

Mass Hysteria (Mass Psychogenic Illness): A contested diagnostic concept attributing clusters of unexplained physical symptoms to psychological contagion. Applied to ME/CFS outbreaks by McEvedy and Beard (1970), who reinterpreted the 1955 Royal Free epidemic as mass hysteria. This interpretation was later contradicted by long-term follow-up (Ramsay 1986) and mathematical modeling (Underhill 2021). The episode remains a cautionary case in diagnostic overreach when standard laboratory tests are negative.

mast cell: Tissue-resident immune cells containing granules of histamine, tryptase, prostaglandins, leukotrienes, and cytokines. Inappropriate mast cell degranulation (MCAS) is a major ME/CFS comorbidity, driving flushing, itching, GI symptoms, tachycardia, and neuroinflammation.

mast cell activation syndrome: MCAS (spelled out): a condition of inappropriate mast cell degranulation producing multi-system symptoms — flushing, hives, gut cramping, tachycardia and more — with no established trigger or a threshold that appears lowered. Diagnostic criteria are contested. See MCAS.

Mast cell degranulation: The rapid release of preformed mediators (histamine, tryptase, heparin, TNF-α) and newly synthesized mediators (PGD2, LTC4, PAF) from mast cell granules upon activation. Can be triggered by IgE/FcεRI crosslinking, MRGPRX2 (substance P, drugs), or complement (C3a, C5a). Inappropriate degranulation defines MCAS, a major ME/CFS comorbidity.

maternal immune activation: An inflammatory response during pregnancy — often triggered by infection, autoimmunity, or stress — in which maternal cytokines, chemokines, and antibodies cross the placenta or act via the fetal-placental interface to alter fetal neurodevelopment. MIA is a documented risk factor for autism, and the mechanism (maternal antibodies affecting fetal brain development) parallels the broader theme of transplacental neuroimmune effects relevant to the PANS/PANDAS-autism-ME/CFS convergence.

MAVS: Mitochondrial Antiviral Signaling protein: the mitochondrial adaptor for RIG-I and MDA5. MAVS activation on the mitochondrial outer membrane links antiviral innate immunity to mitochondrial stress signaling.

MBSR: Mindfulness-Based Stress Reduction: an 8-week structured program teaching mindfulness meditation. Used supportively in ME/CFS for coping and symptom management, though effects on core pathophysiology are unclear.

MCAS: Mast Cell Activation Syndrome: a condition of inappropriate mast cell degranulation causing multi-system symptoms (flushing, itching, GI distress, tachycardia, wheezing). Frequently comorbid with ME/CFS and POTS.

MCID: Minimal Clinically Important Difference — the smallest change in an outcome measure that patients perceive as meaningful. Used to determine whether a statistically significant treatment effect is clinically relevant.

MCS: Multiple Chemical Sensitivity: a condition of heightened reactivity to low levels of chemicals (fragrances, solvents, cleaning products). Reported comorbidity in a subset of ME/CFS patients.

MCT1: Monocarboxylate Transporter 1: transports lactate, pyruvate, and ketone bodies across cell membranes. MCT1 at the blood-brain barrier imports ketones and lactate as alternative brain fuels; MCT1 dysfunction could worsen cerebral energy deficits in ME/CFS.

MCU: Mitochondrial Calcium Uniporter: the primary channel for calcium uptake into the mitochondrial matrix. MCU-mediated mitochondrial calcium regulates ATP production and apoptosis; MCU dysfunction may impair mitochondrial energetics in ME/CFS.

MDA5: Melanoma Differentiation-Associated protein 5: a cytosolic RNA sensor recognizing long dsRNA. Together with RIG-I, MDA5 detects viral RNA and signals through MAVS to drive interferon responses.

MDD: Major Depressive Disorder: mood disorder characterized by persistent low mood and anhedonia. Depression is a common comorbidity but ME/CFS is a distinct disease entity with distinct pathophysiology.

ME Association: A UK-based charity providing patient support, information, and funding biomedical research into ME/CFS. Publishes the ME Medical magazine and clinical guidance for GPs.

ME/CFS: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: a complex, chronic, multi-system neuroimmune disease characterized by severe fatigue, post-exertional malaise, unrefreshing sleep, cognitive dysfunction, and autonomic dysregulation.

median preoptic nucleus: A hypothalamic nucleus whose neurons, in rodents, regulate entry into and exit from a torpor-like hypometabolic state; relevant as a neural circuit that may mediate the low-energy metabolic state proposed in ME/CFS.

MEG: Magnetoencephalography: technique mapping brain activity by recording magnetic fields from neuronal currents. MEG has been used to study altered cortical excitability in ME/CFS.

Mendelian randomization: A method using genetic variants as instrumental variables to assess causal relationships between modifiable exposures and outcomes. MR studies in ME/CFS are emerging, using GWAS data to probe causal directions (e.g., does cytokine elevation cause fatigue, or vice versa?).

Meningeal Lymphatic Vessels: Functional lymphatic vessels lining the dural sinuses of the brain, discovered in 2015 by Louveau et al. and Aspelund et al. These vessels drain CSF, immune cells, and macromolecules from the CNS to the deep cervical lymph nodes, providing the exit route for glymphatic waste clearance and an interface between CNS immune privilege and peripheral immune surveillance.

meta-analysis: A statistical synthesis of results from multiple independent studies addressing the same question, providing a pooled effect estimate with greater precision than individual studies. Meta-analyses in ME/CFS are limited by heterogeneous diagnostic criteria and small sample sizes.

metabolic inflexibility: Impaired ability to switch between glucose and fatty acid oxidation in response to demand. A core metabolic phenotype in ME/CFS: cells remain locked in glycolysis even when fatty acid oxidation would be more efficient, contributing to early fatigue and lactate accumulation.

Metabolic trap: A hypothesis proposing that ME/CFS involves a stable biochemical state in which a metabolic pathway remains locked in a dysfunctional configuration due to bistability in enzyme kinetics.

Metabolomics: The comprehensive measurement of small-molecule metabolites (sugars, lipids, amino acids, organic acids) in a biofluid or tissue. Plasma metabolomics is one omics layer used to profile ME/CFS; integrated multi-omics analyses combine it with metagenomics and immune profiling to detect disease signatures invisible to any single layer.

Metagenomics: Sequencing of DNA directly from a microbial community (e.g., the gut microbiome) without culturing individual species, revealing taxonomic composition and functional gene potential. Gut metagenomics is a core omics layer in ME/CFS microbiome-immune-metabolome crosstalk models such as BioMapAI.

Methyl-donor: A nutrient that supplies methyl groups (−CH₃) for methylation reactions including DNA methylation, neurotransmitter synthesis, and creatine synthesis. Key methyl-donors include methylfolate, methylcobalamin (B12), and S-adenosylmethionine (SAMe). Methylation cycle dysfunction may contribute to ME/CFS epigenetic alterations.

MFI-20: Multidimensional Fatigue Inventory: a 20-item self-report questionnaire measuring five fatigue dimensions (general, physical, reduced activity, reduced motivation, mental fatigue). Measures general fatigue; does not by itself capture post-exertional malaise.

MFN1: Mitofusin 1: a GTPase on the mitochondrial outer membrane that mediates mitochondrial fusion. Together with MFN2, counterbalances DRP1-mediated fission to maintain mitochondrial network integrity.

MFN2: Mitofusin 2: a GTPase on the mitochondrial outer membrane that mediates mitochondrial fusion and ER-mitochondrial contact sites. Mutations cause Charcot-Marie-Tooth type 2A.

MHC (Major Histocompatibility Complex): A set of cell surface proteins essential for antigen presentation to T cells. MHC class I (expressed on all nucleated cells) presents intracellular peptides to CD8⁺ T cells. MHC class II (on antigen-presenting cells) presents extracellular peptides to CD4⁺ T cells.

Michaelis–Menten kinetics: A model of enzyme-catalyzed reaction rates: v = V_(max)[S]/(K_m + [S]), where V_(max) is the maximal rate and K_m is the substrate concentration at half-maximal rate.

microglia: The resident immune cells of the CNS, continuously surveying the brain environment. Activated microglia in ME/CFS shift from a surveillant to a pro-inflammatory state, producing cytokines, ROS, and quinolinic acid that drive neuroinflammation.

microglial priming: A state where microglia become hypersensitive to subsequent stimuli after an initial insult, producing exaggerated inflammatory responses. May explain why ME/CFS patients experience symptom flares from minor triggers that would not affect healthy individuals.

microvascular: Pertaining to the smallest blood vessels: arterioles, capillaries, and venules. Microvascular dysfunction in ME/CFS — impaired oxygen delivery and waste removal at the capillary level — likely contributes to muscle and brain symptoms independent of macrovascular function.

Mitochondria: Double-membrane organelles responsible for aerobic ATP production via the Krebs cycle and electron transport chain. Mitochondrial dysfunction is a central feature of ME/CFS pathophysiology.

mitochondrial dysfunction: Impaired mitochondrial ATP production due to electron transport chain defects, reduced mitochondrial biogenesis, oxidative damage, or substrate limitation. A leading hypothesis for the profound fatigability and PEM in ME/CFS.

mitochondrial membrane potential (ΔΨm): The electrochemical proton gradient across the inner mitochondrial membrane, the driving force for ATP synthesis. Measured by TMRE or TMRM flow cytometry. Reduced ΔΨm in CD8+ T cells is documented in ME/CFS (Mandarano et al. 2020).

mitophagy: The selective autophagic degradation of damaged or dysfunctional mitochondria. Mitophagy failure in ME/CFS leads to accumulation of defective mitochondria, impaired energy production, and increased ROS generation.

MMP: Matrix Metalloproteinase: a family of zinc-dependent endopeptidases that degrade extracellular matrix proteins (collagen, elastin, proteoglycans). MMP-2 and MMP-9 are elevated in ME/CFS and may contribute to blood-brain barrier disruption, tissue remodeling in hypermobility, and cleavage of cytokines/receptors.

MMP-9 (Matrix Metalloproteinase 9): A zinc-dependent endopeptidase that degrades extracellular matrix components including collagen IV, fibronectin, and elastin. MMP-9 is elevated in inflammatory conditions and can disrupt the blood-brain barrier. Elevated MMP-9 has been reported in ME/CFS, contributing to neuroinflammation.

molecular mimicry: A process by which pathogen-derived proteins share structural similarity with host proteins, causing immune responses directed against the pathogen to cross-react with self-tissues. In PANS/PANDAS, GAS M protein and other streptococcal antigens generate antibodies that bind basal ganglia neurons. Parallel mechanisms are hypothesized in post-infectious ME/CFS, where infectious triggers may generate antibodies cross-reactive with autonomic GPCRs or other host targets.

MPO (Myeloperoxidase): A heme enzyme released by neutrophils and monocytes that produces hypochlorous acid (HOCl) from hydrogen peroxide and chloride. A key component of the antimicrobial oxidative burst. Elevated MPO indicates neutrophil activation and oxidative stress in inflammatory conditions.

mPTP: Mitochondrial Permeability Transition Pore: a high-conductance channel in the mitochondrial inner membrane that opens under conditions of calcium overload, oxidative stress, and ATP depletion. mPTP opening dissipates the proton gradient, halts ATP synthesis, and releases pro-apoptotic factors. mPTP opening is a candidate terminal mechanism for the acute energy failure in PEM.

MRC: UK Medical Research Council: a major funder of ME/CFS biomedical research. The MRC PACE trial (2011) and its aftermath fundamentally shaped the debate about GET/CBT in ME/CFS.

MRGPRX2: Mas-related G Protein-Coupled Receptor X2: a mast-cell-specific receptor activated by basic secretagogues (compound 48/80, substance P, certain drugs including quinolones, vancomycin, and neuromuscular blockers). MRGPRX2 mediates IgE-independent mast cell degranulation — a mechanism by which certain medications, stress (substance P), and endogenous peptides could trigger MCAS flares in ME/CFS without requiring allergen sensitization.

MRI: Magnetic Resonance Imaging: neuroimaging showing structural and functional brain abnormalities in ME/CFS, including white matter changes, reduced gray matter volume, and altered connectivity.

MRS: Magnetic Resonance Spectroscopy: an MRI technique measuring brain metabolite concentrations (lactate, NAA, choline, creatine, glutamate, GABA). MRS in ME/CFS has revealed elevated brain lactate, reduced NAA (indicating neuronal dysfunction), and altered glutamate/GABA ratios.

MS: Multiple Sclerosis: a demyelinating autoimmune disease of the CNS. Fatigue is the most common symptom of MS; MS is a key differential diagnosis for ME/CFS.

MSLT: Multiple Sleep Latency Test. An objective daytime sleepiness test that measures how quickly a person falls asleep in a quiet environment during the day, repeated at 2-hour intervals. Mean sleep latency below 8 minutes indicates pathological sleepiness.

MSNA: Muscle Sympathetic Nerve Activity: a direct measure of the sympathetic nervous system’s outflow to muscles, used in autonomic research.

MTHFR: Methylenetetrahydrofolate Reductase: enzyme critical to folate metabolism and methylation. MTHFR polymorphisms (e.g., C677T) have been investigated in ME/CFS for methylation cycle dysfunction.

mTOR: Mechanistic Target of Rapamycin: a central nutrient/energy sensor regulating cell growth and metabolism. mTOR dysregulation is linked to ME/CFS metabolic inflexibility.

mTORC1: Mechanistic Target of Rapamycin Complex 1: an anabolic signaling complex that promotes protein synthesis, lipid synthesis, and mitochondrial biogenesis while inhibiting autophagy. mTORC1 is activated by nutrients, growth factors, and energy status. mTORC1 overactivation in ME/CFS could inhibit autophagy/mitophagy, leading to accumulation of damaged mitochondria.

Multi-omics: The integrated analysis of multiple molecular data layers (genomics, metagenomics, transcriptomics, proteomics, metabolomics, immune profiling) in the same samples. Multi-omics integration can reveal coordinated cross-compartment disease signatures — e.g., the BioMapAI finding that no single omics layer separates ME/CFS from controls, but their integration does.

Muscarinic Acetylcholine Receptor (mAChR): A G protein-coupled receptor responsive to acetylcholine and muscarine. Five subtypes (M₁-M₅): M₁, M₃, M₅ couple to Gαq (PLC activation, Ca²⁺ mobilization); M₂, M₄ couple to Gαi (cAMP inhibition, channel modulation). Autoantibodies against M₃ and M₄ mAChRs have been identified in ME/CFS, potentially impairing autonomic and cognitive cholinergic signaling.

10 N–O

N-acetylaspartate: See NAA. A metabolite synthesized in neurons, often used as a neuronal-health marker in MRS.

Na/K-ATPase: Sodium-potassium adenosine triphosphatase: the membrane pump that maintains the resting potential of excitable cells (muscle fibres, nerves) by exporting three Na⁺ and importing two K⁺ per ATP. Failure depolarizes cells, contributing to cramps and hyperexcitability.

NAA: N-acetylaspartate: a neuronal and mitochondrial metabolite measured by magnetic resonance spectroscopy (MRS). NAA declines in neurodegenerative disease, so an elevation in long COVID is read cautiously as possibly compensatory or osmotic rather than clearly pathological.

nAChR: Nicotinic Acetylcholine Receptor: a ligand-gated ion channel activated by acetylcholine and nicotine. Neuronal nAChRs (α7, α4β2) regulate cognition, attention, and autonomic tone; nAChR dysfunction may contribute to cognitive and autonomic symptoms in ME/CFS.

NAD+: Nicotinamide Adenine Dinucleotide (oxidized): a critical coenzyme in energy metabolism (glycolysis, TCA cycle, OXPHOS). NAD+ depletion is hypothesized as a key metabolic bottleneck in ME/CFS.

NADPH: Nicotinamide Adenine Dinucleotide Phosphate (reduced): essential for antioxidant defense (glutathione recycling) and biosynthetic reactions. NADPH depletion may impair redox balance in ME/CFS.

NAFLD: Non-Alcoholic Fatty Liver Disease: hepatic fat accumulation without significant alcohol consumption. Associated with metabolic syndrome and may co-occur in ME/CFS patients with metabolic comorbidities.

Narcolepsy Type 1 (NT1): An autoimmune condition caused by T-cell-mediated destruction of ≥90% of hypothalamic orexin neurons, producing CSF orexin-A <110 pg/mL, cataplexy, and excessive daytime sleepiness. Triggered by post-infectious molecular mimicry (H1N1, Streptococcus), strongly associated with HLA-DQB1*06:02.

NCLX: Mitochondrial Sodium/Calcium/Lithium Exchanger: the primary calcium efflux mechanism from the mitochondrial matrix, exchanging intramitochondrial Ca²⁺ or Li⁺ for cytosolic Na⁺. NCLX inhibition by lithium prolongs mitochondrial calcium retention, potentially enhancing ATP production but also increasing mPTP opening risk. NCLX is the molecular entry point for lithium’s effects on mitochondrial calcium handling in ME/CFS research.

NCOA4: Nuclear receptor coactivator 4 — a selective cargo receptor that targets ferritin to the autophagosome for degradation (ferritinophagy). NCOA4 suppression traps iron inside ferritin, contributing to functional iron deficiency.

NCX1: Sodium/Calcium Exchanger 1: the primary plasma membrane transporter extruding one Ca²⁺ ion in exchange for three Na⁺ ions. NCX1 is critical for calcium homeostasis in cardiomyocytes and neurons; NCX1 dysfunction may contribute to calcium overload and impaired contractility in ME/CFS muscle and vascular smooth muscle.

NE: Norepinephrine (Noradrenaline): a catecholamine neurotransmitter and hormone driving sympathetic nervous system activation. Sustained elevated NE at night is a hallmark of autonomic dysfunction in ME/CFS.

necroptosis: A regulated form of necrosis mediated by RIPK1/RIPK3/MLKL, releasing cellular contents that trigger inflammation. Necroptosis is distinct from apoptosis and pyroptosis; may be activated in ME/CFS under conditions where apoptosis is inhibited.

nestin: An intermediate-filament protein expressed by neural stem and progenitor cells, used as a marker of stem-cell activity in the brain.

NET: Norepinephrine Transporter: protein reuptaking norepinephrine from synapses. NET dysfunction may contribute to sympathetic overactivity in ME/CFS.

NETosis: NETosis: a form of programmed neutrophil death releasing neutrophil extracellular traps (NETs) — webs of DNA, histones, and antimicrobial proteins. NETosis is a key innate immune defense; excessive NETosis has been implicated in autoimmune and inflammatory conditions that overlap with ME/CFS.

neuroimmune encephalopathy spectrum (NES): A proposed framework conceptualizing conditions such as PANS, PANDAS, Sydenham chorea, anti-NMDA receptor encephalitis, and ME/CFS as points along a common neuroimmune encephalopathy continuum, differing in age of onset, trigger, and predominant symptom domain but sharing underlying immune-mediated CNS dysfunction. The NES framework emphasizes shared mechanisms — autoantibodies, microglial activation, BBB disruption — rather than arbitrary diagnostic silos.

neuroinflammation: Inflammatory activation of microglia and astrocytes within the CNS, producing cytokines, chemokines, and reactive species. PET imaging and CSF studies confirm neuroinflammation in ME/CFS, particularly in the brainstem, thalamus, and cortex.

neuropathic pain: Pain caused by damage or dysfunction of the somatosensory nervous system, characterized by burning, shooting, tingling, or electric shock sensations. SFN and central sensitization contribute to neuropathic pain in ME/CFS.

NF-κB: Nuclear Factor Kappa B: a master transcription factor driving pro-inflammatory gene expression. Chronic NF-κB activation is a candidate mechanism for sustained neuroinflammation in ME/CFS.

NFAT: Nuclear Factor of Activated T-cells: a calcium/calcineurin-activated transcription factor driving T-cell activation genes (IL-2, IFN-γ, TNF-α). NFAT also regulates cardiac hypertrophy and neuronal function; NFAT dysregulation is reported in ME/CFS immune studies.

NfL: Neurofilament light: a structural protein released into blood and cerebrospinal fluid when nerve fibres are damaged. Elevated NfL is used as a general marker of ongoing axonal/neuronal injury and neurodegeneration, and is being explored as a cross-disease marker of CNS pathology.

NGF: Nerve Growth Factor: a neurotrophin important for sensory and sympathetic neuron survival. Elevated NGF may contribute to pain and hyperalgesia in ME/CFS.

NHE1: Sodium/Hydrogen Exchanger 1: the ubiquitous plasma membrane transporter exchanging intracellular H⁺ for extracellular Na⁺, regulating intracellular pH and cell volume. NHE1 is activated by oxidative stress and inflammation; sustained NHE1 activation in ME/CFS may contribute to intracellular sodium overload and altered cellular energetics.

NICE: National Institute for Health and Care Excellence (UK): published landmark ME/CFS guidelines (NG206, 2021) recommending against GET, emphasizing pacing/energy management, and recognizing ME/CFS as a complex multi-system disease.

NIH: National Institutes of Health (US): the primary US biomedical research agency. The NIH intramural ME/CFS study (2016–2024) provided key immunological, metabolic, and neurological findings.

NIHR: UK National Institute for Health and Care Research: funds and delivers health research. The NIHR has invested in ME/CFS research including the DecodeME DNA study (largest ME/CFS GWAS) and trials of medications.

NIRS: Near-Infrared Spectroscopy: non-invasive optical technique measuring tissue oxygenation. Used in ME/CFS to assess cerebral and muscle oxygenation during orthostatic challenge and exercise.

NK: Natural Killer cells: cytotoxic lymphocytes of the innate immune system. Reduced NK cell function (but not number) is one of the most consistently replicated immune abnormalities in ME/CFS.

NK cell: Natural Killer Cell: a cytotoxic lymphocyte of the innate immune system that kills virus-infected and tumor cells without prior sensitization. Reduced NK cell cytotoxic function (but not number) is one of the most consistently replicated immune abnormalities in ME/CFS, suggesting impaired innate antiviral surveillance.

NLRP3: NACHT, LRR and PYD domains-containing protein 3: the sensor component of the NLRP3 inflammasome, a multi-protein complex that activates caspase-1 and cleaves pro-IL-1β and pro-IL-18 to their active forms, and cleaves gasdermin D to trigger pyroptosis. NLRP3 inflammasome activation is implicated in ME/CFS neuroinflammation.

NMDA: N-Methyl-D-Aspartate receptor: a glutamate receptor subtype involved in synaptic plasticity, learning, and excitotoxicity. NMDA receptor overactivation is implicated in ME/CFS central sensitization and neurotoxicity.

NMDA Receptor (NMDAR): An ionotropic glutamate receptor gated by NMDA (N-methyl-D-aspartate). Passes Ca²⁺ and Na⁺ upon binding glutamate and the co-agonist glycine/D-serine, with channel opening blocked by Mg²⁺ at resting potential. NMDAR overactivation contributes to excitotoxicity and central sensitization in ME/CFS.

NMH: Neurally Mediated Hypotension: a form of orthostatic intolerance where blood pressure drops after prolonged standing due to a neurally mediated reflex. Also called vasovagal syncope or neurocardiogenic syncope.

NNT: Number Needed to Treat: the number of patients who must be treated for one to benefit. High NNTs in ME/CFS treatment trials reflect the heterogeneous response to any single intervention.

NO: Nitric Oxide: a gaseous signaling molecule involved in vasodilation, neurotransmission, and immune defense. Dysregulated NO metabolism (excess peroxynitrite formation) is central to the NO/ONOO cycle hypothesis of ME/CFS.

nociplastic: Nociplastic pain: pain arising from altered nociceptive processing (central sensitization) in the nervous system, without clear peripheral tissue damage or inflammation. Fibromyalgia is the prototypical nociplastic pain syndrome.

Non-Transferrin-Bound Iron (NTBI): A labile, redox-active form of iron circulating in plasma that is not bound to transferrin. NTBI can enter cells through unregulated pathways and catalyse lipid peroxidation (ferroptosis). Elevated NTBI is a risk factor for tissue iron loading and oxidative damage.

Norepinephrine: The primary sympathetic nervous system neurotransmitter and adrenal hormone. Norepinephrine (noradrenaline) drives arousal, vasoconstriction, and cardiac stimulation. Sustained elevated norepinephrine — especially at night — is a hallmark of autonomic dysfunction in ME/CFS, producing the ‘tired but wired’ state.

NOS: Nitric Oxide Synthase: the enzyme family producing nitric oxide. Dysregulation of NOS isoforms (iNOS, eNOS, nNOS) is implicated in ME/CFS vascular and inflammatory pathology.

NPV: Negative Predictive Value: the probability that a person with a negative test result truly does not have the disease. Important for ruling out ME/CFS mimics via diagnostic testing.

NQO1: NAD(P)H Quinone Dehydrogenase 1: an NRF2-target enzyme reducing quinones to hydroquinones, preventing redox cycling and oxidative damage. Reduced NQO1 activity is reported in ME/CFS.

NREM: Non-Rapid Eye Movement sleep: sleep stages N1–N3 (light to deep/slow-wave sleep). Reduced N3 (slow-wave sleep) and alpha intrusion into NREM are characteristic EEG findings in ME/CFS.

NRF1: Nuclear Respiratory Factor 1: a transcription factor coordinating nuclear-encoded mitochondrial gene expression with mitochondrial biogenesis. NRF1 works with PGC-1α and TFAM; NRF1 impairment may contribute to the mitochondrial phenotype in ME/CFS.

Nrf2: Nuclear Factor Erythroid 2-Related Factor 2: the master transcriptional regulator of the antioxidant response, controlling expression of glutathione synthesis enzymes, thioredoxin, HO-1, NQO1, and phase II detoxification enzymes. Impaired Nrf2 activation in ME/CFS leads to reduced antioxidant capacity, exacerbating oxidative stress — a pathway therapeutically targeted by DMF, sulforaphane, and curcumin.

NSCa: A quiescent neural stem-cell state in the adult hippocampal dentate gyrus; accumulation of NSCa cells is used as evidence that neurogenesis is stalled rather than depleted.

NT2: Narcolepsy Type 2 — excessive daytime sleepiness without cataplexy, distinguished from Type 1 by normal orexin/hypocretin levels.

NTD: Neglected Tropical Disease — a diverse group of 21 conditions identified by WHO, concentrated in poor populations, under-researched relative to burden, and amenable to community-based interventions. ME/CFS shares structural features with NTDs but has not been formally classified as one.

NTS: Nucleus Tractus Solitarius: the primary visceral sensory nucleus in the brainstem, receiving afferent input from the vagus nerve (baroreceptors, chemoreceptors, gut stretch, immune signals). The NTS integrates visceral information and projects to the DMV (parasympathetic output) and RVLM (sympathetic output). NTS dysfunction may impair baroreflex sensitivity and autonomic integration in ME/CFS.

nucleus accumbens: A key structure in the ventral striatum mediating reward, motivation, and effort-based decision making. Reduced nucleus accumbens activation in ME/CFS may explain the perceived effort cost of cognitive and physical tasks.

OCD: Obsessive-Compulsive Disorder: a condition of intrusive thoughts and compulsive behaviors. Reported at elevated rates in ME/CFS cohorts.

off-label: Use of a medication for an indication, dose, route, or population not approved by regulatory agencies. Essentially all pharmacological treatments for ME/CFS are off-label, as no drug has FDA/EMA approval specifically for ME/CFS.

OGTT: Oral Glucose Tolerance Test: measures the body’s ability to handle a glucose load over 2 hours. Used to detect impaired glucose tolerance and diabetes; both can cause fatigue and must be excluded in ME/CFS assessment.

OH: Orthostatic Hypotension: a sustained drop in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg within 3 minutes of standing. OH is a form of orthostatic intolerance distinct from POTS; some ME/CFS patients have OH, others have POTS, and some have both or neither.

OI: Orthostatic Intolerance: the inability to maintain blood pressure and cerebral perfusion when upright. Common in ME/CFS, manifesting as dizziness, lightheadedness, palpitations, and presyncope upon standing.

OMF: Open Medicine Foundation: a non-profit funding and coordinating ME/CFS biomedical research, including the Severely Ill Patient Study and the Harvard ME/CFS Collaboration.

ONOO: Peroxynitrite: a potent oxidant formed by the reaction of nitric oxide with superoxide. Central to the NO/ONOO cycle hypothesis of ME/CFS pathophysiology.

OPA1: Optic Atrophy 1: a dynamin-related GTPase on the inner mitochondrial membrane that mediates inner membrane fusion and cristae maintenance. OPA1 long form promotes fusion; short form promotes fission. Disrupted cristae architecture from OPA1 dysfunction impairs OXPHOS efficiency.

OPRM1: Gene encoding the mu-opioid receptor (MOR), the primary target of endogenous endorphins and opioid drugs. The A118G polymorphism reduces receptor signalling and alters response to opioid antagonists including low-dose naltrexone (LDN).

Opsonization: The coating of a pathogen or particle with opsonins (antibodies, complement C3b, lectins) to enhance recognition and phagocytosis by immune cells expressing Fc receptors or complement receptors. Opsonization bridges innate and adaptive immunity.

OR: Odds Ratio: a measure of association between exposure and outcome in case-control studies. Used in ME/CFS epidemiology to quantify risk factors.

orexin: Orexin (hypocretin): a hypothalamic neuropeptide promoting wakefulness, appetite, and reward-seeking. Dysregulated orexin signaling (reduced overall tone but abnormal temporal patterns) produces daytime sleepiness with nighttime wakefulness — the core of ME/CFS sleep-wake pathology.

orthostatic intolerance: Difficulty keeping blood pressure and heart rate stable when standing, producing dizziness, light-headedness, palpitations and sometimes fainting on standing. Closely linked to POTS and common in ME/CFS; mast-cell mediators that dilate blood vessels can worsen it.

OSA: Obstructive Sleep Apnea: recurrent upper airway collapse during sleep causing intermittent hypoxia and sleep fragmentation. OSA is a common comorbidity and must be excluded in ME/CFS patients with unrefreshing sleep.

OTC: Over-The-Counter: medications and supplements available without a prescription. Many ME/CFS supplements (CoQ10, NAC, BCAAs, vitamins) are OTC.

Overtraining syndrome: A condition in athletes caused by excessive training with inadequate recovery, characterized by performance decline, persistent fatigue, mood disturbance, and autonomic dysfunction. OTS shares features with early ME/CFS (pre-hysteresis stage) — the transition from functional overreaching → OTS → ME/CFS may represent a single disease trajectory once the hysteresis threshold is crossed.

OX2R agonist: A selective agonist of the orexin-2 receptor (OX2R). Danavorexton (TAK-925, IV) and oveporexton (TAK-861, oral) are in clinical development for narcolepsy. Hypothesized as potential ME/CFS treatments if functional orexin deficiency is confirmed.

Oxaloacetate (OAA): A Krebs cycle intermediate formed from malate by malate dehydrogenase, and the substrate for citrate synthase (condensation with acetyl-CoA). Oxaloacetate is also a key substrate for gluconeogenesis. Low oxaloacetate may limit TCA cycle flux in ME/CFS, contributing to energy deficit.

Oxford Criteria (1991): The broadest ME/CFS case definition ever proposed, requiring only fatigue as the principal symptom with definite onset plus functional impairment. Explicitly allowed inclusion of patients with concurrent psychiatric diagnoses and did not require PEM, pain, or neurological symptoms. Used in the PACE trial; widely criticized for over-inclusion of depression and deconditioning. Superseded by NICE 2021 criteria.

oxidative stress: An imbalance between reactive oxygen species (ROS) production and antioxidant defenses, leading to oxidative damage of lipids, proteins, and DNA. One of the most consistently replicated biological abnormalities in ME/CFS, driving the NO/ONOO cycle hypothesis.

OXPHOS: Oxidative Phosphorylation: the mitochondrial process coupling electron transport chain activity to ATP synthesis via Complex V (ATP synthase). Impaired OXPHOS is one of the most consistently replicated metabolic abnormalities in ME/CFS.

oxytocin: A hypothalamic neuropeptide mediating social bonding, trust, and parasympathetic tone. Oxytocin has anti-inflammatory and analgesic properties; low oxytocin has been hypothesized in ME/CFS.

O₂: Molecular Oxygen: the terminal electron acceptor in the mitochondrial electron transport chain. Oxygen delivery to tissues depends on cardiac output, hemoglobin, and microvascular perfusion — all potentially impaired in ME/CFS. VO₂ (oxygen uptake) measured by CPET is the gold-standard assessment of integrated cardiorespiratory-metabolic function.

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P3b: P3b: the late (300-600 ms) centroparietal component of the event-related potential (ERP) that indexes attentional resource allocation and target evaluation. In the L-theanine-caffeine ADHD trial, increased P3b amplitude and decreased latency indicated enhanced neural allocation to selective attention.

PACE Trial: The largest (n=641) and most influential ME/CFS treatment trial (2011). Originally reported CBT and GET as moderately effective, but independent reanalysis found effects consistent with expectation bias from unblinded design with subjective outcomes. Mid-trial changes to recovery thresholds inflated efficacy 3-4×. NICE 2021 reversed GET/CBT recommendations partly in response to the reanalysis.

PACE Trial: The largest ME/CFS treatment trial ever conducted (n=641, published in The Lancet, 2011). Compared CBT, GET, adaptive pacing, and specialist medical care. Reported CBT and GET as ‘moderately effective’ but was later shown to have weakened recovery thresholds mid-trial (SF-36 ≥85→≥60). Under original protocol thresholds, recovery rates were ~6% across all groups with no CBT/GET advantage. Led to institutional reversals by Cochrane (2019), NICE (2021), and CDC (2021).

pacing: An energy management strategy where the patient stays within their energy envelope, balancing activity and rest to avoid triggering PEM. Pacing is the cornerstone of ME/CFS self-management, endorsed by NICE (2021), and is fundamentally different from graded exercise therapy (GET).

PAF (Platelet-Activating Factor): A potent phospholipid mediator of inflammation, produced by various cell types including platelets, mast cells, and endothelial cells. Induces platelet aggregation, neutrophil activation, increased vascular permeability, and anaphylaxis. PAF degradation by PAF acetylhydrolase (PAF-AH) is impaired in some inflammatory conditions.

PAMP: Pathogen-Associated Molecular Pattern: conserved microbial molecules (LPS, flagellin, viral dsRNA) detected by pattern recognition receptors (TLRs, RIG-I, NLRs). Persistent PAMP exposure from chronic infections or leaky gut may drive immune activation in ME/CFS.

PANDAS: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections: a subset of PANS in which onset or exacerbations are specifically linked to Group A Streptococcal (GAS) infection. Anti-neuronal antibodies generated against GAS cross-react with basal ganglia targets, including tubulin and lysosomal proteins, altering dopamine and glutamate signaling. Models the molecular mimicry mechanism increasingly investigated in post-infectious ME/CFS.

PANS: Pediatric Acute-onset Neuropsychiatric Syndrome: a condition in which children develop abrupt, dramatic neuropsychiatric symptoms (severe OCD, restricted eating, tics, anxiety, emotional lability) triggered by infections (streptococcal, viral, or other pathogens). Shares immune-mediated basal ganglia pathology with Sydenham chorea and PANDAS; provides a pediatric parallel to infection-triggered neuroimmune dysfunction in ME/CFS.

Parathyroid: Four small glands on the thyroid that secrete parathyroid hormone (PTH), regulating calcium and phosphate homeostasis. Hyperparathyroidism can cause fatigue mimicking ME/CFS and must be excluded; hypoparathyroidism can cause neuromuscular irritability resembling ME/CFS muscle symptoms.

PARP: Poly(ADP-Ribose) Polymerase: a DNA damage-sensing enzyme that consumes NAD+. Excessive PARP activation depletes cellular NAD+, impairing glycolysis and mitochondrial function — a candidate mechanism for ME/CFS energy failure.

PASC: Post-Acute Sequelae of SARS-CoV-2 infection (Long COVID): persistent symptoms following COVID-19, with substantial clinical and biological overlap with ME/CFS.

PCA: Principal Component Analysis: a dimensionality reduction technique identifying orthogonal components explaining maximal variance in multivariate data. Used in ME/CFS metabolomics and cytokine studies to identify latent biological dimensions.

PCOS: Polycystic Ovary Syndrome: a hormonal condition causing irregular periods, elevated androgens, and metabolic changes; there is currently no direct evidence linking it to ME/CFS.

PCr: Phosphocreatine. A high-energy phosphate compound stored in muscle and brain tissue that rapidly regenerates ATP (adenosine triphosphate) from ADP during short bursts of high energy demand. Phosphocreatine recovery rate measured by 31P-MRS reflects mitochondrial oxidative capacity.

PD: Parkinson’s Disease: a neurodegenerative disorder of the dopaminergic system. Fatigue and autonomic dysfunction overlap with ME/CFS symptoms.

PD-1 (Programmed Cell Death Protein 1): An immune checkpoint receptor expressed on activated T cells. Upon binding its ligands PD-L1/PD-L2, PD-1 inhibits T cell proliferation, cytokine production, and cytotoxicity. Upregulated PD-1 on CD8⁺ T cells in ME/CFS is a marker of T-cell exhaustion.

PD-L1 (Programmed Death-Ligand 1): The ligand for the PD-1 immune checkpoint receptor, expressed on antigen-presenting cells and many tumors. PD-L1 binding PD-1 suppresses T-cell activation; in ME/CFS, PD-L1 upregulation on monocytes is proposed as a suppressor of CD8+ T-cell function.

PDE4: Phosphodiesterase 4: the predominant cAMP-degrading enzyme in immune and inflammatory cells. PDE4 inhibitors (roflumilast, apremilast) increase cAMP, suppressing TNF-α and other pro-inflammatory cytokines. PDE4 is of interest in ME/CFS for its role in regulating cAMP/PKA signaling and inflammatory tone.

PDH: Pyruvate Dehydrogenase: the enzyme complex converting pyruvate to acetyl-CoA, linking glycolysis to the TCA cycle. PDH is inhibited by PDK phosphorylation; PDK/PDH ratio dysregulation is a candidate mechanism for metabolic inflexibility in ME/CFS.

PDK: Pyruvate Dehydrogenase Kinase: kinases (PDK1–4) that phosphorylate and inactivate PDH, reducing glucose oxidation. PDK upregulation may lock ME/CFS cells into a glycolytic metabolic state even when oxygen is available.

PE: Pulmonary Embolism: a blood clot lodged in the pulmonary arteries, often from a DVT. A differential diagnosis for acute dyspnea and chest pain in ME/CFS patients.

PEM: Post-Exertional Malaise: the cardinal symptom of ME/CFS — a disproportionate and delayed worsening of all symptoms following physical, cognitive, or emotional exertion, often appearing 24–72 hours after the trigger and lasting days to weeks.

PEM Ratchet: A speculative model proposing that post-exertional malaise in ME/CFS has a glymphatic component: exertion generates metabolic waste that a compromised clearance system cannot fully eliminate, producing progressive accumulation of neuroactive metabolites. Each overexertion episode increases the baseline waste load — a ‘ratchet’ effect explaining why repeated crash-boom cycles produce progressive worsening. Entirely inferential; not directly tested with glymphatic imaging.

PEMF: Pulsed Electromagnetic Field therapy: application of electromagnetic fields to tissues, proposed to reduce inflammation and enhance tissue repair. Anecdotal use in ME/CFS but lacks rigorous evidence.

PER2: Period circadian regulator 2: a core clock gene whose protein product forms a negative feedback loop with CLOCK-BMAL1, generating ~24h oscillations in gene expression. PER2 also regulates cell cycle and metabolism.

Perceived exertion: The subjective sensation of how hard the body is working during physical activity, integrating cardiorespiratory, metabolic, and central motor command signals. Perceived exertion is consistently elevated in ME/CFS relative to objective workload, indicating altered interoception and amplified central motor command.

Perforin: A pore-forming protein released by cytotoxic T cells and NK cells. Perforin polymerizes on the target cell membrane, creating pores that allow granzyme entry, triggering apoptosis. Reduced perforin expression and NK cell cytotoxicity are among the most replicated findings in ME/CFS.

Periodontitis: Chronic inflammatory destruction of tooth-supporting tissues driven by bacterial biofilm and host immune responses. Proposed as a model for IgE-mediated connective tissue degradation relevant to the MCAS-hEDS hypothesis in ME/CFS: mast cell degranulation in gingival tissue releases tryptase and MMPs that degrade collagen.

PERK: Protein kinase R-like ER Kinase: a UPR sensor that phosphorylates eIF2α to suppress global translation. Prolonged PERK activation drives the ISR; may be chronically activated in ME/CFS, reducing cellular protein synthesis capacity.

PET: Positron Emission Tomography: nuclear imaging of metabolic activity. PET studies in ME/CFS show neuroinflammation (microglial activation) and metabolic abnormalities.

PFC: Prefrontal Cortex: the anterior frontal lobes mediating executive function, working memory, decision-making, and attention. PFC hypoperfusion and altered functional connectivity are consistently reported in ME/CFS neuroimaging, correlating with cognitive symptom severity.

PGAM5 (Phosphoglycerate Mutase Family Member 5): A mitochondrial serine/threonine phosphatase that regulates mitochondrial dynamics, mitophagy, and the PINK1/Parkin pathway. PGAM5 also activates the KEAP1/NRF2 antioxidant pathway and the NLRP3 inflammasome. Acts as a convergence point between mitochondrial stress and immune activation.

PGC-1α: Peroxisome proliferator-activated receptor Gamma Coactivator 1-Alpha: the master regulator of mitochondrial biogenesis. Reduced PGC-1α expression may underlie mitochondrial impairment in ME/CFS.

PGD2: Prostaglandin D2: the primary prostaglandin produced by mast cells upon activation, via hematopoietic PGD2 synthase. PGD2 mediates vasodilation, bronchoconstriction, and sleep regulation; elevated urinary PGD2 metabolites are a biomarker of MCAS and may be useful in identifying ME/CFS patients with a mast-cell-driven endotype.

PGDS: Prostaglandin D2 Synthase: the enzyme converting PGH2 to PGD2. The hematopoietic isoform (H-PGDS) is expressed in mast cells; the lipocalin-type (L-PGDS) is in the CNS. Mast-cell PGDS activity determines PGD2 production — elevated in MCAS and potentially in ME/CFS endotypes with mast cell involvement.

PGE2: Prostaglandin E2: the most abundant prostaglandin, produced by COX-2 and PGE2 synthases. PGE2 mediates inflammation, pain (sensitizes TRPV1), fever (hypothalamus), and vasodilation. Elevated PGE2 in ME/CFS may drive pain sensitization and neuroinflammatory symptoms.

PGH2: Prostaglandin H2: the unstable intermediate produced by COX-1/COX-2 from arachidonic acid. PGH2 is the common precursor for all prostaglandins (PGD2, PGE2, PGF2α, PGI2) and thromboxane (TXA2) — the branch point where COX activity diverges into different lipid mediator profiles that determine the inflammatory phenotype.

Phagocytosis: The process by which immune cells (macrophages, neutrophils, dendritic cells) engulf and digest large particles including pathogens, apoptotic cells, and cellular debris. Impaired phagocytosis can contribute to chronic inflammation through failure of debris clearance.

phonophobia: Abnormal sensitivity or intolerance to sound. Sound sensitivity in ME/CFS is part of the broader sensory overload pattern and may involve impaired auditory gating (reduced P50 suppression).

Phosphatase: An enzyme that removes phosphate groups from substrates by hydrolysis. Counterbalances kinase activity in cellular signaling. Key examples: calcineurin (protein phosphatase 3), PP2A, PTEN (lipid phosphatase). Phosphatase dysregulation can alter immune signaling and metabolic pathways.

Phosphate (PO₄³⁻): An essential mineral and component of ATP, DNA, RNA, phospholipids, and bone mineral (hydroxyapatite). Phosphate is central to cellular energy metabolism as the high-energy bond in ATP and phosphocreatine. Mitochondrial phosphate transport is mediated by the phosphate carrier (PiC).

Phosphocreatine (PCr): A high-energy phosphate reservoir in muscle and brain, synthesized from creatine by creatine kinase. PCr rapidly regenerates ATP from ADP during increased energy demand via the creatine kinase reaction. Reduced PCr recovery after exercise in ME/CFS indicates impaired mitochondrial ATP synthesis.

Phospholipase: An enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic molecules. Phospholipase A₂ (PLA₂) releases arachidonic acid for eicosanoid synthesis. Phospholipase C (PLC) cleaves PIP₂ into IP₃ and DAG, mobilizing intracellular calcium and activating PKC.

Phospholipid: A lipid consisting of a glycerol backbone, two fatty acid chains, and a phosphate-containing head group. The fundamental building block of all cell membranes. Phospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine) are precursors for signaling molecules including PIP₂ and arachidonic acid.

photophobia: Abnormal sensitivity or intolerance to light, a common sensory hypersensitivity symptom in ME/CFS. May reflect thalamocortical sensory gating dysfunction.

PI3K: Phosphatidylinositol 3-Kinase: a lipid kinase producing PIP3 from PIP2, activating AKT/mTOR signaling. PI3K/AKT integrates growth factor, insulin, and energy signals; PI3K pathway dysfunction may impair metabolic switching in ME/CFS.

Picolinic Acid: A minor branch metabolite of the kynurenine pathway, produced from 2-amino-3-carboxymuconate-6-semialdehyde via ACMSD. Chelates zinc and iron, possesses antiviral and immunomodulatory properties. May play a role in regulating neuroinflammation and immune function.

PIEZO: Mechanosensitive cation channels (PIEZO1, PIEZO2) that convert mechanical force into electrical signals. PIEZO1 mediates vascular shear sensing; PIEZO2 in proprioception and touch. PIEZO dysfunction may contribute to orthostatic intolerance and altered body perception in ME/CFS.

PIP: Personal Independence Payment — a UK benefit for people aged 16 to State Pension age with long-term health conditions or disabilities, replacing Disability Living Allowance (DLA) for working-age adults since 2013.

PIP₂ (Phosphatidylinositol 4,5-Bisphosphate): A membrane phospholipid that serves as both a signaling precursor and a direct regulator of ion channels and transporters. Hydrolyzed by phospholipase C (PLC) to IP₃ and DAG, which mobilize intracellular calcium and activate PKC. PIP₂ is the essential gating cofactor for TRPM3, TRPM7, and other TRP channels — depletion of PIP₂ (via PLC overactivity) disinhibits or silences these channels, with implications for ME/CFS channelopathy hypotheses.

PK: Pharmacokinetics: the study of how a drug is absorbed, distributed, metabolized, and eliminated by the body. PK parameters determine whether a drug reaches its target at therapeutic concentrations.

PKA: cAMP-dependent Protein Kinase A: a serine/threonine kinase activated by cAMP. PKA phosphorylates numerous targets including metabolic enzymes, ion channels, and transcription factors (CREB). PKA signaling may be blunted in ME/CFS.

PKC: Protein Kinase C: a family of serine/threonine kinases activated by diacylglycerol (DAG) and calcium. PKC regulates immune cell activation, vascular tone, and neuronal excitability; PKC dysregulation may contribute to immune dysfunction in ME/CFS.

PKR: Double-stranded RNA-dependent Protein Kinase: an eIF2α kinase activated by viral dsRNA. PKR links antiviral responses to the ISR; chronic low-level PKR activation from persistent viral material could drive ME/CFS metabolic shutdown.

PLA2: Phospholipase A2: the enzyme that liberates arachidonic acid from membrane phospholipids, the rate-limiting step in prostaglandin and leukotriene synthesis. PLA2 is activated by calcium, oxidative stress, and inflammatory signals; PLA2 overactivation in ME/CFS may drive excessive pro-inflammatory eicosanoid production.

PLC: Phospholipase C: an enzyme cleaving PIP2 into DAG and IP3 upon GPCR or RTK activation. IP3 triggers calcium release from ER stores; DAG activates PKC. PLC-γ is critical for T cell and mast cell activation in ME/CFS.

PLC-β: Phospholipase C Beta: the enzyme activated by Gαq-coupled GPCRs, cleaving PIP2 into IP3 (triggers ER Ca²⁺ release) and DAG (activates PKC). PLC-β is the signaling hub for histamine (H1), angiotensin (AT1), and norepinephrine (α1) receptors — all hyperactive in subsets of ME/CFS.

PLRC: Patient-Led Research Collaborative — a group of patient-researchers formed during the COVID-19 pandemic who authored landmark reviews on Long COVID in Nature Reviews Microbiology.

PMC: Post-Masking Crash: a now-withdrawn concept proposed by Chang et al. (2025) suggesting that unmasked PEM — the natural crash after overexertion — somehow differs from ‘true’ PEM, based on a methodologically flawed survey using non-validated recall items and no objective PEM provocation. No clinical or physiological basis exists for this distinction; PEM is the same phenomenon regardless of the triggering context. The terminology risked implying that patients who must push through activities (work, caregiving, medical appointments) are not experiencing authentic PEM — an implication at odds with the biomedical consensus that PEM is a single, objectively demonstrable pathophysiological response to exertion exceeding individual capacity.

PNS: Parasympathetic Nervous System: the ‘rest and digest’ branch of the autonomic nervous system. Parasympathetic tone is reduced in ME/CFS, contributing to the ‘tired but wired’ state.

polysome: A string of ribosomes translating a single messenger RNA at once; a reduced polysome-to-monosome ratio indicates translational stalling, a marker of the cellular energy-conservation (adaptive pausing) response.

Potassium (K⁺): The primary intracellular cation. The K⁺ gradient across cell membranes, maintained by Na⁺/K⁺-ATPase, sets the resting membrane potential. Potassium channel dysfunction contributes to neuronal excitability abnormalities, cardiac arrhythmia risk, and fatigue in metabolic disorders.

POTS: Postural Orthostatic Tachycardia Syndrome: a form of orthostatic intolerance defined by a heart rate increase of ≥30 BPM (≥40 in adolescents) within 10 minutes of standing, without orthostatic hypotension. Frequent comorbidity of ME/CFS.

PPAR: Peroxisome Proliferator-Activated Receptor: a nuclear receptor family (PPARα, β/δ, γ) regulating lipid metabolism, inflammation, and mitochondrial biogenesis. PPAR agonists have been proposed as experimental ME/CFS therapies targeting metabolic dysfunction.

PPAR-alpha: Peroxisome Proliferator-Activated Receptor Alpha: a nuclear receptor regulating fatty acid oxidation, ketogenesis, and anti-inflammatory responses. PPAR-α is activated by PEA (palmitoylethanolamide) and fibrates. PPAR-α activation reduces NF-κB-driven inflammation — of interest in ME/CFS metabolic and neuroinflammatory dysfunction.

PPV: Positive Predictive Value: the probability that a person with a positive test result actually has the disease. PPV depends on disease prevalence; low PPV in rare diseases means many positive results are false positives, a key limitation in ME/CFS biomarker studies.

prefrontal cortex: The anterior part of the frontal lobes mediating executive function, working memory, decision making, and attention. PFC hypoperfusion and altered connectivity are consistently reported in ME/CFS neuroimaging.

Pressure ulcer: A localised injury to skin and underlying tissue caused by prolonged pressure, typically over bony areas in immobile or bedbound patients; can become infected and progress to sepsis.

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses: a guideline and checklist for systematic reviews. Used extensively in ME/CFS evidence synthesis.

prodrug: An inactive compound that requires metabolic conversion in the body to become pharmacologically active. Valacyclovir (prodrug of acyclovir), codeine (prodrug of morphine), and lisdexamfetamine (prodrug of dextroamphetamine) require functional hepatic metabolism, which may be altered in ME/CFS.

Progesterone: A steroid hormone produced by the corpus luteum, placenta, and adrenal cortex. Progesterone and its metabolite allopregnanolone are positive allosteric modulators of GABA-A receptors with neurosteroid, anti-inflammatory, and neuroprotective effects. Pregnenolone is the direct precursor of progesterone.

Project ECHO: A provider-education model in which specialist clinicians train community practitioners on a complex specialty (here ME/CFS) through videoconference case-based mentoring, spreading specialist knowledge beyond the specialist clinic.

Prokinetic: A class of drug that stimulates the movement of food through the gastrointestinal tract, used to treat gastroparesis. Examples include metoclopramide, domperidone, and prucalopride.

PROM: Patient-Reported Outcome Measure — a questionnaire completed by patients to assess their health status, symptoms, or functional capacity without clinician interpretation.

PROMS: Patient-Reported Outcome Measures — questionnaires that capture patients’ own assessments of their symptoms, function, and quality of life.

prospective: A study design that follows participants forward in time from exposure to outcome. Dubbo and other post-infectious fatigue cohort studies are prospective ME/CFS designs capturing disease evolution from onset — uniquely valuable.

Prostacyclin (PGI₂): A potent vasodilator and inhibitor of platelet aggregation, produced by vascular endothelial cells from arachidonic acid via cyclooxygenase and prostacyclin synthase. Prostacyclin analogs (iloprost, treprostinil) are used for pulmonary hypertension. Impaired prostacyclin production may contribute to ME/CFS vascular and microcirculatory dysfunction.

prostaglandin: Lipid signaling molecules derived from arachidonic acid via COX enzymes. PGE2 promotes inflammation, pain, fever, and vasodilation; prostaglandin dysregulation is implicated in ME/CFS pain and vascular symptoms.

Proton-motive force: The electrochemical gradient across the inner mitochondrial membrane, composed of the membrane potential (Delta Psi) and the pH gradient (DeltapH). Drives ATP synthesis by Complex V.

PRS: Polygenic Risk Score: a single quantitative measure aggregating the effects of thousands of genetic variants to estimate an individual’s inherited disease liability.

PSD: Postsynaptic density: the protein-rich specialization on the receiving side of a synapse that anchors neurotransmitter receptors and scaffolding proteins; it is the site of the molecular machinery that builds and tunes synaptic connections.

PSG: Polysomnography: comprehensive overnight sleep study recording EEG, EOG, EMG, ECG, respiratory effort, airflow, and oxygen saturation. PSG in ME/CFS reveals reduced sleep efficiency, alpha intrusion, frequent arousals, and reduced slow-wave sleep.

PSQI: Pittsburgh Sleep Quality Index. A widely-used 19-item self-report questionnaire assessing sleep quality and disturbances over a 1-month period, producing a global score (0–21) where scores above 5 indicate poor sleep quality.

PSS: Perceived Stress Scale — a 10-item self-report questionnaire measuring perceived psychological stress over the past month. Widely used in psychoneuroimmunology research including HSV reactivation studies.

PT: Prothrombin Time: a coagulation test measuring the extrinsic and common pathways. INR is derived from PT. Generally normal in ME/CFS unless anticoagulated or liver disease present.

PTH: Parathyroid Hormone: regulates calcium and phosphate homeostasis. Elevated PTH may reflect vitamin D deficiency, common in housebound ME/CFS patients with limited sun exposure.

PTLDS: Post-Treatment Lyme Disease Syndrome — persistent fatigue, pain, and cognitive symptoms after standard antibiotic treatment for Lyme disease.

PTSD: Post-Traumatic Stress Disorder: a psychiatric condition following trauma with hyperarousal and avoidance. Higher prevalence in ME/CFS; trauma history may influence disease expression.

Purkinje cell: The sole output neuron of the cerebellar cortex, with the highest metabolic demand of any neuron — each Purkinje cell receives ~200,000 synaptic inputs and fires continuously. Purkinje cells are exquisitely vulnerable to energy failure, mitochondrial dysfunction, and hypoxia; Purkinje cell loss or dysfunction could explain the balance, coordination, and cognitive processing deficits in ME/CFS.

putamen: A dorsal-striatum structure involved in motor control and habit learning, innervated by dopamine from the substantia nigra. Loss of dopaminergic input to the putamen produces movement slowing (bradykinesia); reduced putamen dopaminergic terminals in long COVID correlate with slower movement and longer task completion.

pyroptosis: A highly inflammatory programmed cell death mediated by gasdermin D pores, releasing IL-1β, IL-18, and DAMPs. Driven by inflammasome activation (NLRP3, AIM2); pyroptosis may contribute to sustained inflammation in ME/CFS.

pyruvate: The end product of glycolysis. At the mitochondrial gateway, pyruvate dehydrogenase (PDH) converts pyruvate to acetyl-CoA for the TCA cycle. When PDH is inhibited (by PDK or dysfunction), pyruvate is instead reduced to lactate.

QALY: Quality-Adjusted Life Year — a health economics metric combining length of life with health-related quality of life; one QALY equals one year in perfect health; used to compare the value of different healthcare interventions.

QASAT: Quantitative Autonomic Systems Assessment Test. A battery of objective autonomic function tests including tilt table, sudomotor testing (sweat response), Valsalva maneuver, and heart rate variability analysis used to quantify autonomic dysfunction severity.

QEEG: Quantitative Electroencephalography. Computer-based analysis of EEG recordings that decomposes brain electrical activity into frequency bands (delta, theta, alpha, beta) and calculates spectral power for each, used to detect subtle abnormalities invisible to visual inspection.

QSM: Quantitative susceptibility mapping: an MRI technique that measures local magnetic susceptibility, used to quantify brain iron content. It helps distinguish iron deposition from myelin changes.

QUIN: Quinolinic Acid: a neurotoxic kynurenine metabolite and NMDA receptor agonist. Elevated QUIN promotes excitotoxicity and neuroinflammation; QUIN/KYNA imbalance is hypothesized in ME/CFS.

Quinolinic Acid (QUIN): A neurotoxic metabolite in the kynurenine pathway, produced from 3-hydroxyanthranilic acid. Acts as an NMDA receptor agonist and induces oxidative stress. Elevated quinolinic acid is associated with neuroinflammation and may contribute to cognitive dysfunction in ME/CFS and depression.

RA: Rheumatoid Arthritis: an autoimmune inflammatory arthritis. Joint pain and fatigue symptoms may overlap with ME/CFS; RA is a differential diagnosis.

RAAS: Renin-Angiotensin-Aldosterone System: the hormonal system regulating blood pressure, fluid balance, and vascular tone. RAAS dysfunction contributes to orthostatic intolerance and low blood volume in ME/CFS.

RAGE: Receptor for Advanced Glycation End-products: a multi-ligand receptor binding AGEs, HMGB1, S100 proteins, and amyloid-β. RAGE activation drives sustained NF-κB signaling and oxidative stress; implicated in ME/CFS neuroinflammation.

Raphe nucleus: A cluster of serotonin-producing neurons along the brainstem midline that project widely to the cortex, thalamus, hypothalamus, and spinal cord. The raphe nuclei regulate sleep-wake cycles, pain perception, mood, and autonomic function. Raphe dysfunction is implicated in ME/CFS sleep disturbance, pain, and altered serotonergic tone.

RBC: Red Blood Cells (Erythrocytes): oxygen-carrying blood cells. RBC deformability and morphology abnormalities have been reported in ME/CFS.

RCT: Randomized Controlled Trial: the gold standard study design for evaluating treatment efficacy. Few large RCTs exist in ME/CFS; sample sizes are typically small.

REAP: Rapid Extracellular Antigen Profiling — a high-throughput autoantibody screening method that detects functional antibodies binding to cell-surface receptors. Used in the largest ME/CFS autoantibody screen (Germain 2025, n=172) which found no significant GPCR autoantibody differences versus controls, contrasting with CellTrend ELISA-based studies.

RECOVER: Researching COVID to Enhance Recovery: the NIH’s $1.15 billion Long COVID research initiative. RECOVER findings have strong implications for ME/CFS given the substantial overlap between Long COVID and ME/CFS.

REE: Resting Energy Expenditure: the calories the body burns at complete rest, measured by indirect calorimetry. Some studies report paradoxically elevated REE in ME/CFS despite profound fatigue and reduced activity, suggesting a hypermetabolic state driven by immune activation or mitochondrial inefficiency.

Refeeding syndrome: A potentially fatal metabolic disturbance when a malnourished or starved person is re-fed too aggressively, marked by a drop in phosphorus, potassium, magnesium, and thiamine, with risk of respiratory or circulatory failure and seizures.

REM: Rapid Eye Movement sleep: the sleep stage associated with vivid dreaming, muscle atonia, and memory consolidation. REM sleep abnormalities (timing, density, fragmentation) are reported in ME/CFS.

REMBRANDT: Research Evaluation and Management of Brain-Related and Neurological Disorders and Treatments — a patient-initiated ME/CFS biobank created by Open Medicine Foundation.

renin: A kidney-derived enzyme initiating the RAAS cascade, cleaving angiotensinogen to angiotensin I. Inappropriately low renin in the setting of hypovolemia (the ‘renin-aldosterone paradox’) is reported in a subset of POTS/ME/CFS patients.

Resensitization: The process by which desensitized receptors are recycled back to the cell surface in a drug-responsive state after a drug-free interval. Requires receptor dephosphorylation in endosomes.

Respiratory supercomplex: Assemblies of multiple mitochondrial electron transport chain complexes (I, III, IV) that form functional units for efficient electron transfer. Disrupted by WASF3 overexpression in ME/CFS.

Retinal (Retinaldehyde): An aldehyde form of vitamin A (retinol). Retinal is the chromophore that binds opsin proteins to form visual pigments (rhodopsin) in the retina. Also converted to retinoic acid, which regulates gene expression through retinoic acid receptors. Retinoic acid modulates immune function and neuronal differentiation.

Rheb: Ras homolog enriched in brain — a small GTPase that activates mTORC1. TSC2 inactivates Rheb, forming the AMPK→TSC2→Rheb→mTORC1 signalling chain.

RIG-I: Retinoic acid-Inducible Gene I: a cytosolic pattern recognition receptor detecting viral RNA. RIG-I/MDA5/MAVS signaling drives type I interferon production; may be chronically activated by persistent viral material in ME/CFS.

RLS: Restless Legs Syndrome (Willis-Ekbom disease): an irresistible urge to move the legs, often with uncomfortable sensations, worsening at rest and at night. Highly prevalent in ME/CFS and contributes to sleep-onset difficulties.

RNS: Reactive Nitrogen Species: nitrogen-containing free radicals (peroxynitrite, nitric oxide). Combined ROS/RNS stress contributes to nitric oxide–peroxynitrite cycle dysfunction in ME/CFS.

ROC: Receiver Operating Characteristic curve: plots sensitivity vs 1-specificity across test thresholds. Used to evaluate ME/CFS diagnostic biomarkers and classifiers.

ROI: Return on Investment — in health economics, the ratio of benefits (e.g., reduced disease costs) to the cost of an intervention (e.g., research funding), used to evaluate whether spending is economically justified.

ROS: Reactive Oxygen Species: chemically reactive oxygen-containing molecules (superoxide, hydrogen peroxide, hydroxyl radical). Excessive ROS production (oxidative stress) is a consistent finding in ME/CFS.

RPE: Retinal pigment epithelium: the layer of pigmented cells behind the retina. In the context of the Fleury study, engineered RPE cells are used as an encapsulation platform to produce and deliver a therapeutic protein (leptin) in situ.

RR: Relative Risk (Risk Ratio): the ratio of outcome probability in exposed vs unexposed groups. Used in ME/CFS cohort studies.

RSV: Respiratory Syncytial Virus: a common respiratory virus causing bronchiolitis in infants and cold-like illness in adults. RSV is a documented trigger of post-infectious fatigue and ME/CFS, via the same pathways as other respiratory viruses (immune activation, neuroinvasion, mitochondrial damage).

RVLM: Rostral Ventrolateral Medulla: the primary sympathetic output nucleus in the brainstem, containing presympathetic neurons that drive tonic and reflex sympathetic vasomotor tone. RVLM overactivity may drive sustained sympathetic activation in ME/CFS, contributing to tachycardia and vasoconstriction at rest.

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S100B: S100 Calcium-Binding Protein B: an astrocyte-derived protein released during brain injury or neuroinflammation. Elevated serum S100B in ME/CFS suggests astrocyte damage or blood-brain barrier disruption, and may correlate with cognitive dysfunction severity.

S1R: Sigma-1 receptor: an endoplasmic reticulum chaperone protein that modulates ion channel function, Ca²⁺ signaling, and the unfolded protein response. S1R agonists like fluvoxamine may reduce ER stress by stabilizing the S1R–BiP complex.

SA node: Sinoatrial Node: the heart’s natural pacemaker in the right atrium, generating spontaneous action potentials via HCN channels (If current). SA node automaticity is modulated by sympathetic (NE → β1 → faster rate) and parasympathetic (ACh → M2 → slower rate) input; SA node dysfunction or excessive sympathetic drive produces inappropriate sinus tachycardia in ME/CFS/POTS.

Safranal: A volatile monoterpene aldehyde of saffron responsible for its aroma. It inhibits monoamine oxidase A/B and downregulates neurotoxic kynurenine-pathway components in rodent models.

sarcolemmal: Relating to the sarcolemma, the cell membrane of a muscle fibre; its resting potential and ion balance are maintained by the Na⁺/K⁺-ATPase pump.

SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2: the virus causing COVID-19. A major trigger for post-infectious ME/CFS-like illness (Long COVID / PASC), with ~50% of Long COVID patients meeting ME/CFS diagnostic criteria.

SAS: Survey of Autonomic Symptoms. A validated 12-item (women) or 11-item (men) questionnaire screening for autonomic dysfunction symptoms, including orthostatic, gastrointestinal, and secretomotor domains.

SASP: Senescence-Associated Secretory Phenotype: the cocktail of pro-inflammatory cytokines, chemokines, growth factors, and proteases secreted by senescent cells. SASP may contribute to systemic inflammation and tissue dysfunction in ME/CFS.

SC: Supercomplex (respirasome): a stable assembly of mitochondrial electron transport chain complexes (I+III₂+IV) that enhances electron transfer efficiency and reduces ROS production. WASF3 overexpression disrupts supercomplex assembly; SC instability may be a direct mechanism for impaired OXPHOS in ME/CFS.

SCFA: Short-Chain Fatty Acids: primarily acetate, propionate, and butyrate, produced by gut bacteria fermenting dietary fiber. Butyrate is the primary energy source for colonocytes and an HDAC inhibitor with anti-inflammatory properties. Reduced SCFA-producing bacteria in ME/CFS gut dysbiosis may impair gut barrier integrity and systemic immune regulation.

SCI: Spinal Cord Injury: damage to the spinal cord from trauma or disease. SCI-associated fatigue and autonomic dysfunction overlap with ME/CFS symptoms.

SCN: Suprachiasmatic nucleus: the small paired cluster of neurons in the hypothalamus that functions as the master circadian clock, driving daily rhythms in sleep, hormone release, temperature, and metabolism and re-setting to the environmental light-dark cycle.

scRNA-seq (single-cell RNA sequencing): A technique measuring gene expression in individual cells, used to characterize immune cell states such as T-cell exhaustion in ME/CFS and long COVID.

SDH: Succinate dehydrogenase — Complex II of the mitochondrial electron transport chain, also a TCA cycle enzyme. Used as a marker of mitochondrial content in muscle biopsies.

SEID: Systemic Exertion Intolerance Disease: the IOM (2015) proposed name for ME/CFS, emphasizing PEM and systemic dysfunction. Adopted by some researchers but not widely accepted by patients or clinicians.

senescence: A state of irreversible cell cycle arrest with a pro-inflammatory secretory phenotype (SASP). Accelerated cellular senescence has been proposed in ME/CFS based on epigenetic clock studies and may explain premature biological aging.

Sensitivity analysis: A mathematical technique for determining which model parameters most strongly influence model outputs. Global sensitivity analysis (Sobol indices) partitions output variance across parameters and interactions.

sensory overload: A state where multiple simultaneous sensory inputs (light, sound, touch, movement) overwhelm processing capacity, causing distress, cognitive shutdown, and PEM. Sensory gating dysfunction in ME/CFS prevents normal filtering of irrelevant stimuli.

Separatrix: In dynamical systems theory, the boundary that separates two or more basins of attraction. Crossing the separatrix moves the system from one stable state to another. In the ME/CFS disease-state model, the separatrix represents the threshold of perturbation required to transition between healthy and disease equilibria.

SERCA: Sarco/Endoplasmic Reticulum Calcium ATPase: the pump that transports calcium from the cytoplasm back into the ER/SR. SERCA dysfunction leads to ER calcium depletion, ER stress, and impaired calcium signaling — all documented in ME/CFS.

Serotonin (5-HT): A monoamine neurotransmitter derived from tryptophan via tryptophan hydroxylase. Regulates mood, sleep, appetite, pain perception, and GI motility. The kynurenine pathway shunt (IDO activation) diverts tryptophan away from serotonin synthesis in ME/CFS, contributing to low serotonin states. Most of the body’s serotonin is produced in the gut.

Serotonin syndrome: A potentially life-threatening condition caused by excessive serotonergic activity, typically from combining serotonergic drugs (SSRIs, SNRIs, MAOIs) or serotonergic supplements such as saffron or 5-HTP. Features include agitation, tachycardia, hyperthermia, and muscle rigidity; it requires urgent medical care.

SERT: Serotonin Transporter: protein reuptaking serotonin from synapses. Targeted by SSRIs; SERT polymorphisms (5-HTTLPR) have been studied in ME/CFS.

Severity-Weighted Re-Analysis: A proposed statistical correction for PEM-induced selection bias in ME/CFS research, adapting the Heckman selection correction (Nobel Prize 2000). Models the probability that a patient of a given severity participates in research and re-weights published effect sizes to estimate the full-population effect.

SF-36 Health Survey: A 36-item patient-reported health survey measuring eight health domains including physical functioning, bodily pain, and vitality. ME/CFS patients score worse than MS, rheumatoid arthritis, and cancer patients on physical function and vitality domains.

SFN: Small Fiber Neuropathy: damage to small unmyelinated nerve fibers (Aδ and C fibers), causing neuropathic pain, burning, tingling, and autonomic symptoms. Identified in a significant subset of ME/CFS patients via skin biopsy.

SHAP: SHapley Additive exPlanations: a game-theoretic method that attributes a machine-learning model’s prediction to its input features. In BioMapAI, SHAP values generate an explainable connectivity map linking omics features to symptom attributions — but these attributions are model output and were not held-out validated.

Short-chain fatty acids (SCFAs): Fatty acids with fewer than 6 carbon atoms (acetate, propionate, butyrate) produced by bacterial fermentation of dietary fiber in the colon.

SIBO: Small Intestinal Bacterial Overgrowth: excessive bacterial colonization of the small intestine causing bloating, malabsorption, and systemic symptoms. Highly prevalent in ME/CFS (reported in 40–70% of patients).

Sickle cell disease: A hemoglobinopathy where mutated hemoglobin S polymerizes under low oxygen, causing erythrocyte sickling, vaso-occlusive crises, and chronic hemolytic anemia. TRPV1-mediated vasoconstriction and lysophosphatidic acid (LPA) signaling contribute to vaso-occlusion — a parallel to the TRPV1-driven microvascular constriction model in ME/CFS PEM.

sickness behavior: A coordinated behavioral and physiological response to infection/inflammation: fatigue, anhedonia, social withdrawal, hyperalgesia, and cognitive slowing. Mediated by pro-inflammatory cytokines (IL-1β, TNF-α) acting on the brain; ME/CFS resembles a chronic sickness behavior state.

Sigma-1 Receptor (σ1R): An endoplasmic reticulum-resident chaperone protein that translocates upon ligand binding to modulate ion channels (NMDA, IP₃R, Cav), G protein-coupled receptors, and cellular stress responses. A pluripotent modulator of neuroprotection, neuroplasticity, and pain. Agonists (fluvoxamine, donepezil) are relevant to ME/CFS pharmacological hypotheses.

sigma1R: Sigma-1 Receptor: an endoplasmic reticulum chaperone protein activated by cellular stress, regulating calcium signaling, autophagy, ER stress responses, and mitochondrial-ER contact sites. sigma1R activation is neuroprotective; sigma1R dysfunction may impair the integrated stress response in ME/CFS. Fluvoxamine is a potent sigma1R agonist.

siRNA: Small Interfering RNA: double-stranded RNA molecules that silence gene expression via RNA interference. Used to study gene function in ME/CFS cellular models.

SIRT: Sirtuins: a family of NAD+-dependent deacetylase enzymes regulating metabolism, stress resistance, and aging. SIRT1 and SIRT3 dysfunction may contribute to ME/CFS metabolic dysregulation.

Sjögren syndrome: An autoimmune disease targeting exocrine glands (salivary, lacrimal), causing dry mouth (xerostomia) and dry eyes (xerophthalmia), with severe fatigue, joint pain, and systemic manifestations. Sjögren’s is an important differential diagnosis for ME/CFS — fatigue is the most disabling symptom, and both conditions can coexist. Anti-SSA/Ro and anti-SSB/La antibodies are diagnostic.

SLE: Systemic Lupus Erythematosus: a systemic autoimmune disease affecting multiple organs. Fatigue is a dominant symptom; SLE must be ruled out before diagnosing ME/CFS.

SLF: Superior longitudinal fasciculus: a major white-matter fibre tract connecting frontal, parietal, and temporal lobes, implicated in attention and language. Altered diffusion measures in the SLF are reported in long COVID and ME/CFS.

small-fiber neuropathy: Damage to the small-diameter nerve fibres that transmit pain and temperature and control autonomic function; documented in a proportion of ME/CFS patients and associated with cramps and dysautonomia.

SNP: Single Nucleotide Polymorphism: a single base-pair variation in DNA. Certain SNPs (e.g., MTHFR, COMT) have been investigated for association with ME/CFS.

SNS: Sympathetic Nervous System: the ‘fight or flight’ branch of the autonomic nervous system. Sympathetic overactivation at rest and during sleep is a hallmark of ME/CFS.

SOD: Superoxide Dismutase: the primary antioxidant enzyme converting superoxide to hydrogen peroxide. Reduced SOD activity is reported in ME/CFS.

Sodium (Na⁺): The primary extracellular cation and main determinant of plasma osmolarity. Sodium influx through voltage-gated sodium channels (Nav) drives action potential generation in neurons and muscle. Sodium handling is relevant to ME/CFS through blood volume regulation, POTS management (salt supplementation), and TRPV4 channel function.

Solve ME: Solve ME/CFS Initiative: a US-based non-profit funding research, maintaining the You + ME Patient Registry and Biobank. Originally founded as the CFIDS Association of America.

spare respiratory capacity (SRC): The difference between maximal and basal mitochondrial oxygen consumption, measured by Seahorse extracellular flux analysis. SRC represents the cell’s ability to respond to acute energy demands; low SRC predicts T-cell exhaustion and impaired recall responses.

SPECT: Single Photon Emission Computed Tomography: nuclear imaging of cerebral blood flow. SPECT studies consistently show reduced cerebral perfusion in ME/CFS, particularly in the brainstem and frontal lobes.

SPM: Specialized pro-resolving mediators: lipid mediators (resolvins, protectins, maresins, lipoxins) derived from omega-3 fatty acids that actively terminate inflammation and promote tissue repair without immunosuppression. SPM deficiency may contribute to non-resolving inflammation in ME/CFS.

SSDI: Social Security Disability Insurance — US federal program providing income to people unable to work due to disability.

SSI: Supplemental Security Income — US federal program providing financial assistance to elderly, blind, or disabled people with limited income.

SSR: Social Security Ruling — official policy interpretation issued by the U.S. Social Security Administration specifying how disability determinations should be made for specific impairments or across programs. SSR 14-1p governs immune system disorders including ME/CFS.

STAT1: Signal Transducer and Activator of Transcription 1: a transcription factor activated by IFN-γ and type I interferons via JAK phosphorylation. STAT1 drives antiviral and pro-inflammatory gene programs; STAT1 activation may be elevated in ME/CFS.

STAT3: Signal Transducer and Activator of Transcription 3: a transcription factor activated by IL-6 family cytokines and growth factors. STAT3 regulates inflammation, metabolism, and Th17 differentiation; STAT3/Th17 skewing is reported in ME/CFS.

STING: Stimulator of Interferon Genes: an ER-resident adaptor protein activated by cyclic dinucleotides from cGAS-detected cytosolic DNA. STING drives type I IFN responses; aberrant STING activation from mitochondrial DNA leakage may contribute to ME/CFS interferon signatures.

Streptococcal: Group A Streptococcus (GAS, Streptococcus pyogenes): a Gram-positive bacterium responsible for pharyngitis (‘strep throat’), scarlet fever, and skin infections. GAS is the primary infectious trigger of PANDAS and Sydenham chorea. Its M protein and other surface antigens are structurally similar to host proteins in the basal ganglia, enabling molecular mimicry — a model mechanism for infection-triggered autoimmune neuropsychiatric disease that applies to post-infectious ME/CFS triggers.

striatum: The largest structure of the basal ganglia, comprising the caudate nucleus, putamen, and nucleus accumbens. It integrates cortical, limbic, and dopaminergic input to mediate motor control, reward, and effort-based decision making; striatal dysfunction is implicated in the motivational and psychomotor symptoms of post-infectious ME/CFS and long COVID.

Subsarcolemmal: Located beneath the cell membrane (sarcolemma) of muscle fibres. Subsarcolemmal mitochondria are the population most vulnerable to structural damage in ME/CFS.

substance P: A neuropeptide neurotransmitter in pain (C-fiber) afferents that transmits nociceptive signals in the dorsal horn. Substance P also directly triggers mast cell degranulation via MRGPRX2, linking neurogenic inflammation to MCAS in ME/CFS — sensory nerve activation releases substance P, which degranulates mast cells, which release more inflammatory mediators, which further sensitize nerves.

substantia nigra: A midbrain structure whose dopaminergic neurons project to the dorsal striatum (caudate/putamen) and control movement initiation. Degeneration of these neurons underlies Parkinson’s disease; animal models show SARS-CoV-2 can invade the substantia nigra, raising the question of whether direct viral invasion contributes to dopaminergic-terminal loss in long COVID.

Succinate: A Krebs cycle intermediate produced from succinyl-CoA by succinyl-CoA synthetase. Oxidized to fumarate by succinate dehydrogenase (Complex II of the electron transport chain). Succinate accumulates during ischemia and inflammation, acting as a signaling molecule through SUCNR1 (GPR91). Elevated succinate indicates mitochondrial dysfunction.

SV2A: Synaptic Vesicle Glycoprotein 2A: a transmembrane protein on synaptic vesicles regulating neurotransmitter release. SV2A is the binding site of levetiracetam (Keppra), which modulates SV2A to reduce excessive glutamate release. Levetiracetam’s off-label use for ME/CFS brain fog targets SV2A-mediated neurotransmitter modulation.

SWS: Slow-Wave Sleep (N3): the deepest non-REM sleep stage, characterized by high-amplitude delta waves. SWS is critical for glymphatic clearance, growth hormone secretion, and tissue repair. Reduced SWS and alpha-delta intrusion are hallmarks of ME/CFS sleep pathology.

Sydenham chorea: A neuropsychiatric manifestation of acute rheumatic fever caused by Group A Streptococcal infection, characterized by involuntary, irregular, jerky movements (chorea), emotional lability, and obsessive-compulsive behaviors. Sydenham chorea is the prototypical post-streptococcal autoimmune basal ganglia disorder and the historical model from which PANDAS was derived, establishing that anti-neuronal antibodies generated via molecular mimicry can produce neuropsychiatric disease.

Syncope: Fainting or a temporary loss of consciousness due to reduced blood flow to the brain. In ME/CFS most faints are orthostatic or neurally-mediated (benign), but syncope with cardiac features, injury, or an abnormal pulse warrants urgent assessment.

SynGO: Synapse Gene Ontology: an expert-curated knowledge base that systematically annotates synaptic genes and processes using Gene Ontology terms (87 synaptic locations and 179 synaptic processes, built from published evidence). Used for gene-set enrichment analysis of synapse-related biology.

SynVesT-1: A positron-emission tomography (PET) radiotracer (18F-SynVesT-1) that binds the synaptic vesicle glycoprotein 2A (SV2A), used to measure synaptic density in the living brain.

systematic review: A comprehensive review using explicit, reproducible methods to identify, appraise, and synthesize all relevant studies on a specific question. The gold standard for evidence synthesis in ME/CFS; NICE 2021 guidelines were informed by systematic reviews.

systemic mastocytosis: A clonal mast cell disease in which too many abnormal mast cells accumulate in the bone marrow and organs. More severe than MCAS but with overlapping symptoms (flushing, gut pain, bone pain, anaphylaxis). Because it is rare but serious and partly treated differently, it is among the conditions a clinician rules out (with a baseline tryptase test) before labelling symptoms ‘just MCAS’.

T Cell (T Lymphocyte): A lymphocyte that matures in the thymus and mediates adaptive cellular immunity. T cells express T-cell receptors (TCRs) that recognize antigen-bound MHC molecules. Subtypes include CD8⁺ cytotoxic T cells (kill infected cells), CD4⁺ helper T cells (orchestrate immune responses), and regulatory T cells (suppress autoimmunity). ME/CFS is associated with T-cell exhaustion, reduced cytotoxic function, and altered subset distributions.

t-SNE: t-distributed Stochastic Neighbor Embedding: a non-linear dimensionality reduction method preserving local structure in high-dimensional data. Used in ME/CFS for visualizing immune cell populations and metabolic profiles.

T1w/T2w: The ratio of T1-weighted to T2-weighted MRI signal, used as a proxy for myelin content. It is also sensitive to iron, water, and gliosis, so an elevated ratio cannot by itself distinguish remyelination from inflammation or iron deposition.

T3: Triiodothyronine: the active thyroid hormone. T3 levels may be low-normal in ME/CFS; some clinicians trial low-dose T3 for persistent hypothyroid-like symptoms despite normal TSH.

T4: Thyroxine: the primary thyroid hormone (prohormone), converted to active T3 in tissues. Standard thyroid replacement for hypothyroidism; typically normal in ME/CFS.

T90: Time to 90% baseline recovery — the duration required for heart rate to return to within 10% of its pre-stressor baseline after a physiological challenge such as thermal exposure or exercise. Used as an autonomic recovery endpoint.

TAD: Topologically associating domain: a self-interacting region of 3D chromosome architecture that constrains which enhancers contact which genes; measured by chromatin-conformation assays.

tanycyte: Specialized ependymal cells lining the base of the brain’s third ventricle that sense circulating metabolites and may participate in energy-state signaling including torpor arousal.

taVNS: Transcutaneous Auricular Vagus Nerve Stimulation: a non-invasive method of vagus nerve stimulation via electrodes placed on the auricular branch of the vagus nerve in the ear. taVNS increases parasympathetic tone, activates the cholinergic anti-inflammatory pathway, and may reduce sympathetic overactivation; investigational for ME/CFS/POTS autonomic dysfunction.

TB: Tuberculosis — a bacterial infection caused by Mycobacterium tuberculosis, primarily affecting the lungs. Endemic in many LMICs. Post-TB chronic fatigue is documented but has not been evaluated for ME/CFS diagnostic criteria.

TBI: Traumatic Brain Injury: brain damage from external force. TBI can trigger ME/CFS-like symptoms; post-concussion syndrome shares features with ME/CFS.

TBK1: TANK-Binding Kinase 1: a kinase that phosphorylates IRF3/IRF7 downstream of cGAS-STING and RIG-I/MAVS. TBK1 also regulates autophagy and mitophagy; TBK1 dysfunction may impair mitochondrial quality control in ME/CFS.

TCF7 (TCF-1): T-Cell Factor 7: a transcription factor identifying stem-like progenitor exhausted CD8+ T cells. In cancer immunotherapy, TCF7-high cells respond to PD-1 blockade while TCF7-low cells are terminally exhausted. Chromatin closure at TCF7 locus is documented in ME/CFS CD8+ TEM cells (Iu et al. 2024).

TCM: Traditional Chinese Medicine — a system of herbal medicine, acupuncture, massage, exercise (qigong, tai chi), and dietary therapy developed over two millennia. Widely used across East Asia and increasingly globally. Three systematic reviews have examined TCM modalities for chronic fatigue syndrome.

TCR (T-Cell Receptor): The antigen-specific receptor expressed on T cells. Composed of α and β chains (95% of T cells) or γ and δ chains (5%). Recognizes peptide antigens presented by MHC molecules. The TCR signaling complex includes CD3 co-receptor subunits. TCR repertoire alterations have been documented in ME/CFS.

TDO: Tryptophan 2,3-Dioxygenase: liver enzyme initiating the kynurenine pathway. Together with IDO, TDO activation shifts tryptophan away from serotonin/melatonin toward neurotoxic metabolites in ME/CFS.

Testosterone: The primary male sex hormone androgen, also present in women at lower levels. Testosterone has immunomodulatory, anabolic, and erythropoietic effects. Low testosterone is associated with fatigue and reduced muscle function; supplementation has been explored in ME/CFS primarily in male patients.

TFAM: Mitochondrial Transcription Factor A: the key regulator of mitochondrial DNA transcription, replication, and packaging. TFAM is downstream of PGC-1α/NRF1; reduced TFAM may impair mitochondrial gene expression and biogenesis in ME/CFS.

TGF-β: Transforming Growth Factor Beta: a cytokine with immunosuppressive and pro-fibrotic functions. Elevated in some ME/CFS studies, associated with Th2/Th17 skewing.

TH: Tyrosine Hydroxylase: the rate-limiting enzyme in catecholamine synthesis (converts tyrosine to L-DOPA). TH dysregulation may contribute to norepinephrine excess in ME/CFS.

Th1: Type 1 T helper cells: CD4+ T cells producing IFN-γ and IL-2, driving cellular immunity against intracellular pathogens. Th1/Th2 imbalance is a long-standing hypothesis in ME/CFS; some studies find Th2 skewing with reduced Th1 function.

Th17: Type 17 T helper cells: CD4+ T cells producing IL-17, driving neutrophil recruitment and mucosal defense. Th17 expansion is reported in ME/CFS and may drive autoimmune pathology and gut barrier dysfunction.

Th2: Type 2 T helper cells: CD4+ T cells producing IL-4, IL-5, IL-13, driving humoral immunity and allergic responses. Th2 skewing has been reported in some ME/CFS cohorts, potentially linking to MCAS and atopic comorbidity.

therapeutic index: The ratio between toxic and therapeutic doses of a drug. Drugs with a narrow therapeutic index (lithium, digoxin, warfarin) require careful monitoring in ME/CFS patients who may have altered drug sensitivity.

therapeutic plasma exchange (TPE): A procedure in which a patient’s plasma (containing antibodies, cytokines, and other inflammatory mediators) is removed and replaced with donor plasma or albumin. TPE is an established treatment for antibody-mediated autoimmune conditions and has shown efficacy in PANDAS, where it removes pathogenic anti-neuronal antibodies. Parallels immunoadsorption approaches investigated in ME/CFS for removal of functional GPCR autoantibodies.

Thrombospondin-1: TSP-1: a matricellular glycoprotein elevated in platelet/endothelial activation that suppresses nitric-oxide signalling via CD47 and inhibits angiogenesis. Proposed to act as a dominant antagonist of irisin signalling at the HSP90α/αvβ5 axis, contributing to irisin signalling resistance and impaired metabolic adaptation in ME/CFS. Also an endothelial-activation marker in some ME/CFS biomarker panels.

Thromboxane (TXA₂): A potent vasoconstrictor and platelet aggregator produced by platelets from arachidonic acid via thromboxane synthase. The balance between prostacyclin (vasodilatory) and thromboxane (vasoconstrictive) regulates vascular tone and hemostasis. Thromboxane predominance may contribute to microvascular dysfunction in ME/CFS.

Thyroid: An endocrine gland in the neck producing thyroxine (T4) and triiodothyronine (T3), regulating basal metabolic rate. Hypothyroidism produces fatigue that mimics ME/CFS and must be excluded; however, many ME/CFS patients with normal TSH exhibit ‘Low T3 Syndrome’ — a non-thyroidal illness pattern where peripheral T4→T3 conversion is impaired.

TIA: Transient Ischaemic Attack: a brief episode of neurological dysfunction caused by a temporary blockage of blood flow to the brain, without permanent damage. A TIA is a medical emergency because it signals high risk of a subsequent stroke and warrants urgent assessment.

TIBC: Total Iron-Binding Capacity: a measure of the blood’s capacity to bind iron with transferrin. Elevated TIBC indicates iron deficiency; relevant to ME/CFS fatigue differential diagnosis.

Tight junction: Intercellular protein complexes (claudins, occludins, ZO proteins) that seal the space between adjacent endothelial or epithelial cells, controlling paracellular permeability. Tight junction disruption in the gut epithelium (‘leaky gut’) allows bacterial product translocation; tight junction disruption at the blood-brain barrier contributes to neuroinflammation in ME/CFS.

Tilt table testing: A diagnostic procedure for orthostatic intolerance in which the patient is passively tilted from supine to upright while heart rate and blood pressure are monitored.

TIM-3 (T-cell Immunoglobulin and Mucin Domain 3): An immune checkpoint receptor expressed on IFN-γ-producing T cells, Tregs, and innate immune cells. Binding to its ligand galectin-9 induces T cell death and exhaustion. Upregulated in ME/CFS CD8⁺ T cells as part of the exhaustion program.

TLR: Toll-Like Receptor — a family of innate immune receptors that detect pathogen-associated molecular patterns and initiate inflammatory responses.

TLR2: Toll-Like Receptor 2: a pattern recognition receptor recognizing bacterial lipopeptides. TLR2 activation on immune cells contributes to inflammatory cytokine production in ME/CFS.

TLR4: Toll-Like Receptor 4: a pattern recognition receptor recognizing bacterial lipopolysaccharide (LPS) and endogenous danger signals (HMGB1, HSPs). TLR4 on microglia drives neuroinflammation; LDN acts in part as a TLR4 antagonist, a key mechanism for its off-label use in ME/CFS.

TMJ: Temporomandibular Joint dysfunction: pain and dysfunction of the jaw joint and muscles. Reported comorbidity in ME/CFS/fibromyalgia, possibly linked to hypermobility and central sensitization.

TMS: Transcranial Magnetic Stimulation: non-invasive brain stimulation using magnetic fields. Repetitive TMS (rTMS) has been explored for ME/CFS cognitive dysfunction and depression, with preliminary positive signals.

TNF: Tumour Necrosis Factor: a pro-inflammatory cytokine involved in systemic inflammation and immune signalling.

TNF-α: Tumor Necrosis Factor Alpha: a pro-inflammatory cytokine elevated in many ME/CFS patients. Promotes inflammation, sickness behavior, and sleep fragmentation via hypothalamic action.

torpor: An evolutionarily conserved hypometabolic state, analogous to hibernation in miniature, in which the body sharply reduces ATP-generating metabolism to conserve energy; mediated by dedicated preoptic neural circuits and invoked as a model for the low-energy metabolic state in some people with ME/CFS and long COVID.

TOX: Thymocyte Selection-Associated High-Mobility Group Box: the lineage-defining transcription factor for CD8+ T-cell exhaustion. TOX drives chromatin remodeling at exhaustion-effector loci and is elevated on CD8+ effector memory T cells in ME/CFS (Iu et al. 2024).

TPH: Tryptophan Hydroxylase: the rate-limiting enzyme in serotonin synthesis (converts tryptophan to 5-HTP). TPH dysregulation may alter serotonin levels in ME/CFS.

TPH1: Tryptophan Hydroxylase 1: the peripheral isoform of TPH, expressed in gut enterochromaffin cells, producing ~95% of the body’s serotonin. TPH1-derived serotonin regulates gut motility and is taken up by platelets. TPH1 dysfunction may link gut dysbiosis to altered peripheral serotonin in ME/CFS.

Treg: Regulatory T cell — a subset of CD4+ T cells that suppress immune responses and maintain self-tolerance, preventing autoimmunity.

Triglyceride (TG): An ester of glycerol with three fatty acid chains, the main form of energy storage in adipose tissue. Elevated triglycerides are a feature of metabolic syndrome; in ME/CFS, altered lipid profiles may reflect impaired fatty acid oxidation and metabolic inflexibility.

TRIM28: Tripartite motif-containing protein 28 (also KAP1): a chromatin-organising protein that maintains gene silencing and loops and regulates IL-2 in T cells; a proposed unifying node across 3D-genomic, HERV, and IL-2 findings in ME/CFS.

TRP: Transient Receptor Potential: a large superfamily of cation channels that respond to diverse stimuli (temperature, chemical ligands, mechanical stretch, osmolarity). TRP channels on sensory nerves and immune cells are implicated in ME/CFS pain, cramp threshold, and immune dysfunction.

TRPA1: Transient Receptor Potential Ankyrin 1: a chemosensor activated by irritants (mustard oil, acrolein), oxidative stress products (4-HNE, H₂O₂), and cold. TRPA1-mediated detection of endogenous reactive species links oxidative stress to pain in ME/CFS.

TRPM3: Transient Receptor Potential Melastatin 3: a calcium-permeable cation channel gated by PIP₂ (essential cofactor), pregnenolone sulfate (agonist), and heat (>40°C). Expressed on NK cells (cytotoxicity), sensory neurons (pain/heat detection), pancreatic β-cells (insulin secretion), and vascular smooth muscle (tone). TRPM3 calcium influx is significantly reduced in ME/CFS NK cells — the most replicated ion channel finding in the disease (six independent cohorts). LDN restores TRPM3-dependent calcium flux in vitro; the PIP₂ requirement links TRPM3 dysfunction to GPCR autoantibody-driven PIP₂ depletion.

TRPM7: Transient Receptor Potential Melastatin 7: a bifunctional ion channel/protein kinase (chanzyme) permeable to Ca²⁺, Mg²⁺, and trace metals. TRPM7 is gated by PIP₂ depletion and plays essential roles in cellular magnesium homeostasis, cell migration, and immune function. Dysregulation is implicated in neuronal injury, immune dysfunction, and fibrotic conditions.

TRPM8: Transient Receptor Potential Melastatin 8: the primary cold-sensing ion channel, activated by temperatures below ~25°C and by menthol. Dysregulation may contribute to cold intolerance and temperature perception abnormalities in ME/CFS.

TRPV1: Transient Receptor Potential Vanilloid 1: the capsaicin receptor and heat sensor (>43°C). Mediates inflammatory pain and thermal hyperalgesia; TRPV1 sensitization may contribute to widespread pain in ME/CFS/fibromyalgia.

TRPV4: Transient Receptor Potential Vanilloid 4: a mechano- and osmo-sensitive cation channel. Involved in vascular regulation, cell volume sensing, and nociception. Implicated in ME/CFS vascular and pain dysfunction.

Tryptase: A serine protease released primarily by mast cells during degranulation. Elevated serum tryptase indicates systemic mast cell activation. Mature tryptase is stored in secretory granules; the commercially measured total tryptase includes both mature and inactive protryptase. Tryptase is the most specific clinical marker for MCAS.

TSAT: Transferrin Saturation: the ratio of serum iron to TIBC, expressed as a percentage. Low TSAT (<20%) indicates iron deficiency, a common and treatable cause of fatigue that must be excluded in ME/CFS.

TSC2: Tuberous sclerosis complex 2 — a protein that regulates mTORC1 activity. AMPK phosphorylates TSC2 to suppress mTORC1, providing an indirect route of mTORC1 inhibition distinct from direct inhibitors like rapamycin.

TSG-6: TNF-stimulated gene 6 protein (also TNFAIP6) — an enzyme that cross-links hyaluronan with inter-α-inhibitor heavy chains, forming stable complexes in the extracellular matrix that contribute to capillary basement membrane thickening during inflammation.

TSH: Thyroid-Stimulating Hormone: pituitary hormone controlling thyroid hormone production. TSH is commonly tested but often normal in ME/CFS despite symptoms resembling hypothyroidism.

TSPO (Translocator Protein): An 18 kDa protein located on the outer mitochondrial membrane, highly expressed in activated microglia and astrocytes. TSPO PET imaging (using [¹¹C]PK11195 or newer ligands) is used to quantify neuroinflammation in vivo. Elevated TSPO binding in ME/CFS indicates ongoing neuroinflammation in multiple brain regions.

TST: Total Sleep Time: the actual time spent asleep during a sleep period. TST may be normal in quantity but severely deficient in quality in ME/CFS.

TTV: Torque teno virus: a member of the Anelloviridae family present in most healthy individuals. TTV burden rises when immune competence falls (e.g., in transplant immunosuppression) and is being studied as a marker of immune state in post-infectious fatigue conditions.

tVNS: Transcutaneous vagus nerve stimulation: a non-invasive technique delivering electrical stimulation to the auricular branch of the vagus nerve. Proposed to enhance parasympathetic tone and activate the cholinergic anti-inflammatory pathway in ME/CFS.

TXA2: Thromboxane A2: a platelet-derived eicosanoid produced by COX-1 from arachidonic acid (via thromboxane synthase). TXA2 is a potent vasoconstrictor and platelet aggregator. Altered TXA2/prostacyclin (PGI2) balance may contribute to microvascular dysfunction and platelet hyperactivity in ME/CFS.

TXNRD: Thioredoxin Reductase: a selenoprotein enzyme reducing oxidized thioredoxin using NADPH. Essential for ribonucleotide reductase activity (DNA synthesis) and antioxidant defense; TXNRD dysfunction may impair redox balance in ME/CFS.

Type I fibre: Slow-twitch oxidative muscle fibres — rich in mitochondria and capillaries, used for sustained low-intensity activity. Preferentially atrophied in ME/CFS.

Type II fibre: Fast-twitch glycolytic muscle fibres — rely primarily on anaerobic metabolism for quick bursts of power. Increased proportion in ME/CFS muscle biopsies.

13 U–Z

UBE3A: Ubiquitin Protein Ligase E3A (also called E6AP): the enzyme encoded by the UBE3A gene that tags target proteins for degradation by the proteasome. Loss of functional UBE3A causes Angelman syndrome; here it is used as a cross-disease model because its loss impairs mitochondrial energy production and inhibitory (GABAergic) signaling, two domains also implicated in ME/CFS.

Ubiquitin: A small (8.5 kDa) regulatory protein that is covalently attached to target proteins, marking them for proteasomal degradation, altering their activity, or directing their localization. The ubiquitin-proteasome system regulates protein turnover and is central to cellular stress responses, including mitophagy and NF-κB signaling.

UCB-J: A positron-emission tomography (PET) radiotracer (11C-UCB-J) that binds the synaptic vesicle glycoprotein 2A (SV2A), used to measure synaptic density in the living brain.

UCP: Uncoupling Protein: mitochondrial inner membrane proteins (UCP1–5) that dissipate the proton gradient as heat, reducing ATP synthesis. UCP2/3 upregulation in ME/CFS may reduce mitochondrial efficiency as an adaptive antioxidant response.

UMAP: Uniform Manifold Approximation and Projection: a dimensionality reduction technique preserving both local and global data structure, often preferred over t-SNE. Used in ME/CFS single-cell and metabolomics analyses.

UPR: Unfolded Protein Response: the ER stress response triggered by accumulation of misfolded proteins. Three branches (PERK, IRE1, ATF6) coordinate translational attenuation, chaperone induction, and ERAD. UPR activation is documented in ME/CFS and may link to metabolic dysfunction.

urticaria: Hives: raised, itchy, red or skin-coloured wheals on the skin, most often an allergic or mast-cell-mediated reaction. When it recurs for weeks to months with no obvious trigger it is called chronic spontaneous urticaria, and it is one of the settings where standard-dose antihistamines often, and appropriately, get up-dosed.

vagus nerve: Cranial nerve X: the primary parasympathetic nerve, innervating the heart, lungs, and GI tract. Vagal tone is reduced in ME/CFS, contributing to tachycardia, GI dysmotility, and impaired anti-inflammatory cholinergic reflex.

VAS: Visual Analogue Scale. A continuous measurement instrument where patients mark their symptom intensity on a line (typically 0–100 mm), providing finer granularity than categorical Likert-type scales.

vasodilation: The widening of blood vessels via relaxation of smooth muscle. Impaired NO-mediated vasodilation in ME/CFS contributes to microvascular dysfunction and orthostatic intolerance.

Vasomotion: Rhythmic oscillations in arteriolar diameter that drive cerebrospinal fluid influx along periarterial spaces. Noradrenaline-regulated vasomotion is the pump for glymphatic CSF flow; noradrenergic tone drops during sleep, enabling the vasomotion necessary for brain waste clearance (Hauglund et al., 2025). Autonomic dysfunction in ME/CFS — elevated sympathetic tone and blunted parasympathetic activation — would predictably impair this vasomotion.

vasopressin: Antidiuretic hormone (ADH): a hypothalamic hormone promoting water reabsorption in the kidneys and vasoconstriction. Vasopressin dysregulation may contribute to fluid balance abnormalities in ME/CFS/POTS.

VCA (Viral Capsid Antigen): An EBV structural protein, part of the viral capsid. IgM anti-VCA indicates acute/primary EBV infection; IgG anti-VCA indicates past infection or reactivation. Elevated IgG anti-VCA titers are one of the most replicated serological findings in ME/CFS, suggesting chronic EBV reactivation.

VDAC: Voltage-Dependent Anion Channel: the primary channel in the mitochondrial outer membrane, controlling metabolite flux (ATP, ADP, NADH) between mitochondria and cytoplasm. VDAC dysfunction impairs mitochondrial-cytosolic energy exchange in ME/CFS.

VDR: Vitamin D Receptor: a nuclear receptor activated by 1,25-dihydroxyvitamin D3. VDR regulates calcium homeostasis, immune function, and antimicrobial peptide production; vitamin D deficiency and VDR polymorphisms have been studied in ME/CFS.

VEGF: Vascular Endothelial Growth Factor: a signaling protein that stimulates blood vessel formation. Elevated VEGF has been reported in ME/CFS, potentially reflecting endothelial dysfunction.

Ventilatory threshold: The exercise intensity at which ventilation increases disproportionately to oxygen consumption, reflecting the onset of metabolic acidosis from lactate buffering. Ventilatory threshold is reduced in ME/CFS (occurs at lower workloads), and on 2-day CPET the day-2 threshold is even lower — a physiological signature of PEM.

ventral striatum: The reward-associated portion of the striatum, centred on the nucleus accumbens, mediating motivation and effort-based decision making. Reduced dopaminergic terminals in the ventral striatum correlate with apathy in long COVID.

Ventral Tegmental Area: The VTA is a midbrain nucleus containing dopamine neurons projecting to the nucleus accumbens, prefrontal cortex, and amygdala via the mesolimbic and mesocortical pathways. VTA dopamine dysfunction links to fatigue, anhedonia, and motivational deficits in ME/CFS.

ventromedial preoptic area: A hypothalamic region that receives inflammatory signals to produce appetite suppression, warmth-seeking, and fever — a component of the sickness behavior circuitry.

virtual hypoxia: A tissue state in which cells behave as if starved of oxygen despite normal blood oxygen levels, caused by impaired energy production (mitochondrial dysfunction) combined with increased energy demand rather than by a true oxygen shortage. Proposed as a mechanism in chronic demyelination (multiple sclerosis) and investigated in ME/CFS, where elevated resting brain lactate suggests the brain may be operating under chronic metabolic limitation.

VLM: Ventrolateral Medulla: the brainstem region containing both the rostral VLM (RVLM, sympathetic output) and caudal VLM (CVLM, sympathoinhibitory). VLM dysfunction impairs the baroreflex and autonomic regulation of blood pressure, directly contributing to orthostatic intolerance in ME/CFS.

VMAT2: Vesicular Monoamine Transporter 2: the transporter that packages dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles for release. DTBZ-PET measures VMAT2 density as a proxy for monoaminergic neuron integrity. VMAT2 dysfunction could impair neurotransmitter storage and release in ME/CFS.

VNS: Vagus Nerve Stimulation: electrical stimulation of the vagus nerve to increase parasympathetic tone. Non-invasive transcutaneous VNS (tVNS) devices are being investigated for ME/CFS autonomic dysfunction.

VO2max: Maximal Oxygen Uptake: the maximum rate of oxygen consumption during exercise, reflecting cardiorespiratory fitness. Reduced in ME/CFS, particularly on repeat testing (2-day CPET).

VT: Ventilatory threshold — the exercise intensity at which ventilation increases disproportionately to oxygen consumption, reflecting the onset of anaerobic metabolism. Also called the gas exchange threshold (GET). In ME/CFS, exercise above VT is associated with increased PEM risk and prolonged autonomic recovery as measured by HRV.

VTE: Venous Thromboembolism: a blood clot forming in a vein, including deep-vein thrombosis and pulmonary embolism; an important safety consideration with oral hormone therapy.

VZV: Varicella Zoster Virus: causes chickenpox and shingles. VZV reactivation is a possible trigger or contributor to ME/CFS.

V̇E/V̇CO₂ slope: Ventilatory efficiency — the relationship between minute ventilation and carbon dioxide output during exercise. An elevated slope indicates inefficient breathing and is used in heart failure and pulmonary hypertension assessment.

V̇Eₘₐₓ: Maximal minute ventilation — the highest volume of air a person can breathe per minute during maximal exercise.

Warburg effect: The metabolic shift from oxidative phosphorylation to aerobic glycolysis, originally described in cancer cells but also characteristic of activated immune cells.

WASF3: Wiskott-Aldrich Syndrome Protein Family Member 3: a protein that, when overexpressed, disrupts mitochondrial respiratory supercomplex assembly, impairing OXPHOS efficiency. WASF3 is a candidate driver of mitochondrial dysfunction in ME/CFS — elevated WASF3 → supercomplex destabilization → reduced ATP synthesis → exercise intolerance and PEM.

WASO: Wake After Sleep Onset: total time spent awake after initially falling asleep. Elevated WASO is typical in ME/CFS, reflecting sleep maintenance insomnia and frequent nocturnal arousals.

WBC: White Blood Cells (Leukocytes): immune cells including neutrophils, lymphocytes, monocytes, eosinophils, basophils. WBC counts are generally normal in ME/CFS.

WHO: World Health Organization: the UN agency classifying ME/CFS in ICD-10 (G93.3) and ICD-11 (8E49) under neurological disorders.

WT: Wild-Type: the normal, unmodified genetic background in experimental models. Used as the control in ME/CFS-related molecular studies.

XBP1: X-Box Binding Protein 1: a transcription factor activated by IRE1-mediated splicing that induces ER chaperones and ERAD components. The spliced form (XBP1s) is a master regulator of ER homeostasis.

14 Α

α-Ketoglutarate (α-KG): A key Krebs cycle intermediate produced by isocitrate dehydrogenase. α-KG is a substrate for α-ketoglutarate dehydrogenase complex and a cofactor for α-ketoglutarate-dependent dioxygenases including TET enzymes (DNA demethylation) and HIF prolyl hydroxylases. Links mitochondrial metabolism to epigenetic regulation.

15 Β

β-oxidation: The mitochondrial breakdown of fatty acids to acetyl-CoA, producing NADH and FADH₂ for the electron transport chain. Impaired β-oxidation in ME/CFS forces reliance on glycolysis, reducing total ATP yield and accelerating fatigue.

β2-adrenergic autoantibodies: Autoantibodies targeting the β2-adrenergic receptor, identified in subsets of ME/CFS patients. May contribute to vascular dysregulation and autonomic dysfunction by agonistically or antagonistically modulating receptor signaling.

16 Δ

ΔΨm: Mitochondrial Membrane Potential: the electrical potential difference across the inner mitochondrial membrane (~−180 mV), generated by the electron transport chain pumping protons. ΔΨm is the driving force for ATP synthesis; mitochondrial depolarization (reduced ΔΨm) has been reported in ME/CFS and may be a direct consequence of oxidative damage, mPTP opening, or respiratory chain dysfunction.

17 Μ

μOR: Mu-opioid receptor — the primary target of opioid painkillers (morphine, oxycodone, tramadol) and also of low-dose naltrexone. μOR blockade by LDN triggers compensatory endorphin upregulation.