ME/CFS E/I Imbalance + Calcium Overload — extends CA-I3 and CA-I4 via B4 bridge

One-paragraph summary

Review of ME/CFS and Long COVID neurotransmitter dysregulation across noradrenergic, serotonergic, GABAergic, and glutamatergic systems. Notable mechanistic claim — quoted from abstract: "Reduced GABAergic tone combined with increased glutamatergic and noradrenergic activity may elevate skeletal muscle tone, contributing to calcium overload, mitochondrial dysfunction, exertional intolerance." This is the cleanest published-literature link between excitatory/inhibitory imbalance and skeletal-muscle calcium overload in ME/CFS, and via the B4 bridge (ME/CFS post-viral neuroimmune) it extends to FM's CA-I3 intersection (RyR1 / SERCA / dantrolene in skeletal muscle). Combined with Wirth-Scheibenbogen 2026 already in the project, this is the second independent mechanism-paper anchoring calcium-overload as a recognized ME/CFS framework.

Claims as triples

• glutamatergic_activity — elevated_in → me_cfs [evidence: review consolidation; confidence: emerging]
• gabaergic_tone — reduced_in → me_cfs [evidence: review; confidence: emerging]
• noradrenergic_activity — elevated_in → me_cfs [evidence: review; confidence: established (replicates known sympathetic-hyperactivity finding)]
• skeletal_muscle_calcium_overload — caused_by → excitatory_inhibitory_imbalance [evidence: review's mechanism integration; confidence: emerging]
• skeletal_muscle_calcium_overload — causes → mitochondrial_dysfunction [evidence: review; confidence: emerging — anchored at Wirth-Scheibenbogen 2020/2026]
• skeletal_muscle_calcium_overload — causes → exertional_intolerance [evidence: review; confidence: emerging — phenomenological link]
• gut_brain_axis_disruption — contributing_factor_for → me_cfs_neurotransmitter_imbalance [evidence: review; confidence: bridging]
• post_covid_syndrome — shares_mechanism_with → me_cfs [evidence: review; confidence: established (well-documented overlap)]

Methods note

Narrative review integrating neurotransmitter findings across ME/CFS and Long COVID studies. Not systematic. The calcium-overload-via-E/I-imbalance claim is mechanism-integration; primary support is in cited animal studies and the Wirth-Scheibenbogen vasoconstriction/sympathetic-driven framework.

Limitations

• Narrative not systematic
• Integration across diverse primary studies with heterogeneous methodologies
• ME/CFS subtype heterogeneity not explicitly addressed
• Doesn't address dose-response or threshold effects in the E/I → Ca²⁺ overload pathway

Open questions raised

• Q-Ca-20 (new): Is FM skeletal muscle calcium overload mechanism-equivalent to ME/CFS? FM has skeletal-muscle symptoms (myalgia, tender points) but distinct from ME/CFS exertional intolerance — does the same RyR1/SERCA pathology operate, or does FM have a distinct calcium-handling defect?
• Q-Ca-21 (new): Are anti-VGCC autoantibodies elevated in FM at a level that would functionally drive skeletal-muscle calcium overload? (CA-clinical query candidate)
• Q-Ca-22 (new): Would dantrolene (RyR1 stabilizer, established in malignant hyperthermia) be a viable therapeutic-trial candidate in calcium-overload-stratified FM? FM-direct dantrolene trial evidence is absent.

Triangulation notes

• Reinforces CA-I3 (RyR1 / SERCA / dantrolene in skeletal muscle, calcium-dysregulation v0.2): this paper supplies the upstream-driver framework for CA-I3 — E/I imbalance is the driver that produces calcium overload at the RyR1/SERCA endpoint. CA-I3 was previously presented as the skeletal-muscle Ca²⁺ handling defect; this paper supplies the central neurotransmitter chain producing the demand for that handling.
• Reinforces CA-I4 (NMDA/CaMK central neuron intersection): the glutamatergic elevation in ME/CFS that this paper documents is the central-nervous-system driver of the I-4 intersection's NMDA-receptor-mediated calcium influx. CA-I3 and CA-I4 are not independent — this paper shows they connect via shared E/I-imbalance pathology.
• B4 bridge extension: ME/CFS is connected to FM via the post-viral neuroimmune chain (B4). This paper extends B4 with a mechanism layer at the neurotransmitter level, predicting that calcium-overload should appear in FM via the same upstream chain.
• Strengthens Wirth-Scheibenbogen 2026 as anchor: Wirth-Scheibenbogen 2026 (already in project) framed ME/CFS as vasoconstriction-driven skeletal-muscle calcium overload; this paper independently arrives at the same framework via the neurotransmitter route, increasing confidence in the framework.

Bridges

• B4 update: bridge gains a mechanism layer at the neurotransmitter level. Update synthesis/bridges.md to note this anchor.
• No new bridges, but reinforces the calcium-hypothesis cross-cutting tie to the B4 ME/CFS chain.

Cure-path-arm implications

• Dantrolene as candidate cure-path-arm at CA-I3 endpoint: needs FM-direct trial evidence. Currently absent from cure-path-arm-decisions document; should be added at watchlist tier.
• Magnesium supplementation as candidate: low-evidence current-OTC tier; magnesium is a physiological calcium antagonist at multiple intersections (NMDA receptor block, calcium channel modulation, RyR1 modulation). Already cited in FM symptomatic literature but absent from cure-path-arm document.

Confidence-tier framing

• The E/I imbalance finding in ME/CFS: emerging (review-tier, multiple primary studies)
• The calcium-overload mechanistic claim: emerging (anchored at Wirth-Scheibenbogen + this paper, both consolidating mechanism rather than primary measurement)
• The FM-direct extension: inferred (via B4 bridge; not yet measured in FM-specific cohorts)