Autonomic Medications
1 Pyridostigmine (Mestinon)
Pyridostigmine, an acetylcholinesterase inhibitor, has shown benefit for autonomic dysfunction in ME/CFS, particularly for orthostatic intolerance and POTS.
1.1 Mechanism of Action
Pyridostigmine inhibits acetylcholinesterase, prolonging acetylcholine activity at:
- Autonomic ganglia: Enhances sympathetic and parasympathetic neurotransmission
- Neuromuscular junction: Increases muscle strength (though this is not the primary target in ME/CFS)
- Heart: Vagal effects may improve heart rate variability
In POTS and autonomic dysfunction, pyridostigmine improves ganglionic transmission, enhancing the autonomic nervous system’s ability to regulate cardiovascular function.
1.2 Evidence in POTS and ME/CFS
Randomized Controlled Trials.
Raj et al. (2005) (Raj et al. 2005): Randomized crossover trial in POTS patients demonstrated reduced standing tachycardia without supine bradycardia.
Joseph et al. (2022) (Joseph, Arevalo, et al. 2022): The first ME/CFS-specific RCT of pyridostigmine (n=45, double-blind, placebo-controlled). Using invasive cardiopulmonary exercise testing (iCPET), a single 60 mg dose improved peak VO2 (+13.3 vs. \(-\) 40.2 mL/min; \(P\\<0.05\)) and right atrial filling pressure (+1.0 vs. \(-\) 0.6 mmHg; \(P\\<0.05\)), demonstrating that pyridostigmine acutely ameliorates the preload failure underlying exercise intolerance in ME/CFS (see also Section Primary Site of Autonomic Dysfunction Unresolved). The worsening of neurovascular parameters after placebo—i.e., from exercise alone—provides objective evidence for the hemodynamic mechanism of post-exertional malaise.
Squires et al. (2023) (Squires, Al-Zayer, and Systrom 2023): Long-term follow-up (mean $ 690 $ days, n=37 treated vs. n=16 controls) demonstrated sustained improvement in oxygen uptake efficiency slope (OUES: 1.82 to 1.98, \(P=0.044\)) and pulmonary vascular capacitance (486 to 540 mL\(dot\)mmHg, \(P=0.040\)). Dose range in this cohort was 24–360 mg/day, indicating that some ME/CFS patients tolerate and benefit from doses well above the conservative starting range.
The Squires et al. long-term cohort used doses up to 360 mg/day—substantially higher than the 15–60 mg/day range recommended for initial ME/CFS titration (Section pyridostigmine). The conservative starting protocol remains appropriate, but clinicians should be aware that upward titration beyond 60 mg/day may be warranted in patients who tolerate the medication well but have not achieved adequate symptom control.
Systematic Reviews and Comparative Effectiveness.
Pavic et al. (2025) (Pavic et al. 2025): Meta-analysis of 6 RCTs (\(\sim\) 216 patients) found pyridostigmine monotherapy produced a non-significant reduction in orthostatic systolic drop (\(-\) 2.07 mmHg, 95% CI \(-\) 4.20 to 0.06). However, pyridostigmine combined with midodrine showed a significant improvement (\(-\) 6.74 mmHg, 95% CI \(-\) 13.15 to \(-\) 0.33, \(P\\<0.05\)). No significant effect on supine blood pressure was observed—an important safety advantage.
Pierson et al. (2025) (Pierson et al. 2025): Systematic review of 32 studies found pyridostigmine achieved 51% symptomatic improvement—the lowest among studied medications. Comparators: ivabradine (75%), midodrine (78%), beta-blockers (64%). Adding pyridostigmine to beta-blockers did not significantly improve symptom scores beyond beta-blockers alone. Evidence quality for pyridostigmine was rated as Low.
2 Pyridostigmine (Mestinon)
The Squires et al. long-term cohort used doses up to 360 mg/day—substantially higher than the 15–60 mg/day range recommended for initial ME/CFS titration (Section pyridostigmine). The conservative starting protocol remains appropriate, but clinicians should be aware that upward titration beyond 60 mg/day may be warranted in patients who tolerate the medication well but have not achieved adequate symptom control.
Systematic reviews consistently rank pyridostigmine below ivabradine, midodrine, and beta-blockers for POTS symptom control (Pierson et al. 2025). Its primary value may lie in combination therapy (particularly with midodrine (Pavic et al. 2025)) and in the specific ME/CFS context where preload failure—rather than tachycardia alone—is the dominant mechanism (Joseph, Arevalo, et al. 2022). Pyridostigmine’s unique advantage of not causing supine hypertension remains clinically relevant for patients who cannot tolerate midodrine or fludrocortisone.
ME/CFS patients typically require 1/4 to 1/3 of standard pyridostigmine doses.
Standard POTS dosing: 30–60 mg three times daily (90–180 mg/day total)
ME/CFS-specific considerations:
- Starting dose: 15–20 mg once daily (not 60 mg)
- Titration: Increase by 15–20 mg increments every 1–2 weeks
- Maximum tolerated: Many ME/CFS patients stabilize at 20–30 mg 1–3\(\\times\) daily
- Standard dose intolerance: 60 mg may cause severe symptoms requiring bed rest
Rationale: ME/CFS patients often exhibit heightened sensitivity to neuroactive medications. The autonomic nervous system may be hyperreactive, such that standard doses produce excessive cholinergic effects. Start low and titrate slowly.
Side effects at excessive doses:
- Severe fatigue and weakness (paradoxical)
- Gastrointestinal distress (cramping, diarrhea)
- Excessive salivation
- Muscle fasciculations
- Bradycardia
If gastrointestinal symptoms occur, reduce dose rather than discontinuing.
If pyridostigmine’s anti-inflammatory effects in severe COVID-19 are mediated by the cholinergic anti-inflammatory pathway (vagal acetylcholine acting on \(\alpha\) 7 nicotinic receptors on macrophages and T cells), similar immunomodulatory benefit might occur in ME/CFS, where vagal tone is reduced and low-grade neuroinflammation is documented. This would represent a dual mechanism of action—autonomic and immune—beyond the conventional framing as a purely autonomic agent. The absence of measurable cytokine changes in the PISCO trial (Fragoso-Saavedra et al. 2022) suggests that standard inflammatory panels may be insensitive to vagally-mediated immune modulation, which operates at the tissue rather than systemic level.
Certainty: 0.25 (single trial in a different disease context; no direct ME/CFS immune data for pyridostigmine).
Testable prediction: ME/CFS patients on chronic pyridostigmine should show improved heart rate variability (reflecting enhanced vagal tone) that correlates with reductions in tissue-level inflammatory markers (e.g., neuroimaging-detected neuroinflammation) even without changes in serum cytokines.
The PEM kindling hypothesis (Section Kindling Analogy: Neurological Extrapolation Without ME/CFS Data, Chapter Neurological and Neurocognitive Dysfunction) proposes that each autonomic crisis—orthostatic tachycardia, preload failure during exertion, vasovagal episodes—acts as a metabolic stress event that primes microglia and lowers the PEM threshold. In this framework, the number of autonomic crises per day directly determines the rate of progressive sensitization: more crises → more microglial priming → faster threshold decline.
Pyridostigmine, by stabilizing autonomic function and reducing the frequency and severity of orthostatic decompensation, would reduce the daily “kindling trigger load” even without directly targeting neuroinflammation. This makes pyridostigmine anti-kindling by proxy: it prevents the peripheral events that drive central sensitization progression.
If correct, this reframes pyridostigmine from a purely symptomatic autonomic agent into a potentially disease-modifying intervention whose benefit extends beyond hemodynamic improvement. A specific prediction follows: ME/CFS patients on chronic pyridostigmine should show slower progression of PEM threshold decline over 6–12 months compared to matched untreated patients, independent of any improvement in autonomic symptoms per se.
This anti-kindling framing also suggests a synergistic rationale for combining pyridostigmine (reducing kindling triggers) with a direct anti-kindling agent such as levetiracetam (reducing the kindling response to each trigger)—addressing both the frequency and the impact of sensitizing events. The LIFT trial’s factorial design (pyridostigmine \(\\times\) LDN) (Meadows et al. 2025) will not test this specific combination, but its cognitive outcome data (DANA Brain Vital) may provide indirect evidence for disease modification.
Certainty: 0.20 (inferred from combining the kindling hypothesis with pyridostigmine’s autonomic mechanism; no direct evidence that autonomic stabilization slows PEM progression).
2.1 Mechanism of Action
2.2 Evidence in POTS and ME/CFS
2.3 Dosing Protocol for ME/CFS
2.4 Predictors of Response
2.5 Cholinergic Anti-Inflammatory Pathway
2.6 Ongoing Trials
2.7 What Pyridostigmine Reveals About Capillary BM Thickening
Pyridostigmine’s mechanism — acetylcholinesterase inhibition at autonomic ganglia → enhanced cholinergic tone → improved cardiac preload, vasodilation, and HRV — addresses functional perfusion deficits: blood reaches the capillary bed in greater volume and with better distribution. It does NOT address structural capillary BM thickening — no amount of improved preload or cholinergic vasodilation can accelerate O₂ diffusion through a pathologically thickened basement membrane.
The Joseph et al. (2022) invasive CPET trial (Joseph, Pari, et al. 2022) provides the key data point: pyridostigmine 60 mg improved peak VO₂ by +0.9 mL/kg/min (\(p = 0.002\)) in 45 ME/CFS patients. This is a statistically significant but modest improvement — approximately 10% of the O₂ extraction deficit (estimated from VO₂ data: 0.69 vs 0.77 at baseline, yielding a total deficit of 0.08; the +0.9 mL/kg/min VO₂ improvement corresponds to roughly 10–15% of that deficit after converting to extraction ratio units; the exact partition between perfusion-mediated and structural deficit has not been directly measured — this is an inference, not a measured value).
This has direct diagnostic implications at the individual patient level and is formalized in ch34 (Pyridostigmine reduces lactate by 30% and thiamine reduces it by another 40% F0):
Substantial pyridostigmine response (VO₂ improvement > 10%): The patient’s O₂ extraction deficit is predominantly functional — preload failure, autonomic dysregulation, or impaired cholinergic vasodilation is rate-limiting. This patient may benefit from continued pyridostigmine, midodrine, or compression. The capillary BM may or may not be thickened — but even if it is, it is NOT the rate-limiting step for THIS patient’s exercise capacity. The response itself is the diagnostic result: a large pyridostigmine response localizes the bottleneck to the autonomic/perfusion level.
Minimal pyridostigmine response (≤ 10% improvement): The patient’s O₂ extraction deficit is predominantly structural — capillary BM thickening is the rate-limiting barrier. Further perfusion-enhancing interventions (higher-dose pyridostigmine, midodrine, compression) are unlikely to produce meaningful additional benefit because they cannot overcome a physical diffusion barrier. This patient should be directed away from perfusion-targeted therapies toward: (a) direct BM-directed interventions (ARB-mediated TGF-β suppression, theoretical; hyaluronidase, cert 0.25) at the research level, (b) downstream mitochondrial protection rather than upstream O₂ delivery, or (c) EM muscle biopsy to confirm the structural lesion and rule out competing mechanisms. The modest improvement from pyridostigmine should not create false hope that “more flow = more oxygen” — the structural ceiling is real and the perfusion pathway is near its limit at standard therapeutic doses.
Combined pyridostigmine + pentoxifylline + midodrine + compression: Maximizing perfusion through all functional pathways simultaneously is the cleanest discriminator. If the combination normalizes VO₂peak → the deficit was entirely functional (Step F1, ch34 Pyridostigmine reduces lactate by 30% and thiamine reduces it by another 40%). If the combination produces minimal or no improvement → the deficit is structural BM thickening (Step F0a). No clinical trial has tested this multi-probe combination in ME/CFS.
Certainty: 0.55. The cascade from capillary BM thickening → O₂ diffusion impairment is structurally plausible and the BM finding is replicated in 3 countries (Charlton et al. 2025) (Aschman et al. 2023) (Agergaard et al. 2023). The ~10%/90% partition is an estimate from a single pyridostigmine trial (n=45) — not a validated partition ratio. The multi-probe combination discriminators are entirely untested. (Evidence source: single RCT — Inference target: individual patient perfusion-vs-structural partition. Link is indirect — the Joseph 2022 trial reports group means, not individual patient BM-to-O₂-extraction correlations.)
(Origin: brainstorm — Phase 5c + 5d cross-referenced differential.)
Falsifiable predictions: + In a cohort where both EM-measured %BM coverage and pyridostigmine VO₂ response are measured in the same patients: patients with BM coverage > 65% show VO₂ improvement < 5%; patients with BM coverage < 63% (control-range) show VO₂ improvement > 10% + The pyridostigmine VO₂ response predicts EM-measured BM thickness with r > 0.7 — validating the perfusion-vs-structural partition at the individual level + Combined pyridostigmine + pentoxifylline + midodrine + compression in patients with BM coverage > 65% produces < 20% improvement in VO₂peak — confirming the structural ceiling is drug-independent + Falsified if: pyridostigmine VO₂ response does NOT correlate with EM-measured BM thickness — then the ~10% ceiling is NOT due to BM thickening but to ceiling effects in the cholinergic system itself or to trial power limitations. Falsified if: the combined multi-probe approach normalizes VO₂peak in patients with documented BM thickening — then BM thickening is not functionally rate-limiting despite its structural presence.
Consequence: A single dose of pyridostigmine during a CPET could tell a patient whether their exercise limitation is “fixable by more blood flow” (responder — pursue autonomic treatments) or “structural — the capillary wall itself is the barrier” (non-responder — don’t waste months on perfusion drugs that can’t touch the real problem). This turns pyridostigmine from a treatment trial into a diagnostic test — and changes the clinical conversation from “let’s try this drug and see” to “let’s use this drug to understand your specific pathology.”
2.8 Compounding Pharmacy Approach for MCAS-Overlap Patients
3 Pentoxifylline (Trental)
Pentoxifylline (Trental, oxpentifylline) is a methylxanthine-derivative hemorrheologic agent that improves red blood cell deformability and reduces blood viscosity. It is approved for peripheral vascular disease (intermittent claudication) and investigated off-label in microvascular disorders. In ME/CFS, its primary interest is as a diagnostic probe: it improves RBC flexibility, allowing stiff erythrocytes to transit narrowed capillaries, and therefore discriminates between capillary-level obstructions that flexible RBCs can bypass vs those they cannot.
3.1 Mechanism of Action
Pentoxifylline inhibits phosphodiesterase (PDE3/4), increasing intracellular cAMP in erythrocytes. This improves RBC membrane deformability — stiff RBCs regain their ability to elongate and squeeze through capillaries narrower than their diameter. Secondary effects include: (a) reduced blood viscosity via improved fibrinogen levels and erythrocyte flexibility; (b) TNF-α suppression via PDE inhibition in monocytes/macrophages, providing mild anti-inflammatory activity; (c) improved leukocyte deformability, reducing leukocyte plugging in microvasculature. The hemorrheologic effect onset is hours (single dose reduces blood viscosity); TNF-α suppression requires days to weeks (standard pharmacology; zero ME/CFS-specific pharmacokinetic data exist).
In ME/CFS specifically, the diagnostic signal comes from what pentoxifylline does NOT address: it does not thin capillary basement membranes, it does not restore lost capillary tortuosity, and it does not repair endothelial hypertrophy. If pentoxifylline improves NIRS-measured tissue O₂ extraction → the rate-limiting lesion is luminal narrowing that flexible RBCs can navigate (endothelial hypertrophy, Step F0c Pyridostigmine reduces lactate by 30% and thiamine reduces it by another 40%). If pentoxifylline does NOT improve O₂ extraction → the bottleneck is BM diffusion distance — a structural barrier that no degree of RBC flexibility can bypass (Step F0a Pyridostigmine reduces lactate by 30% and thiamine reduces it by another 40%).
3.2 Evidence in ME/CFS
No clinical trials of pentoxifylline in ME/CFS exist. All inferences below are mechanistic — derived from pentoxifylline’s established pharmacology applied to documented ME/CFS microvascular pathology (Charlton et al. 2025).
Pentoxifylline has zero published ME/CFS clinical data. All diagnostic inferences and proposed differentials are mechanistic extrapolation from its known pharmacology applied to documented ME/CFS microvascular pathology. It is not a validated ME/CFS treatment, and the diagnostic probe framework has not been tested in any ME/CFS cohort. Clinicians should not use pentoxifylline as a diagnostic algorithm — it is a research hypothesis requiring formal validation.
Pentoxifylline’s diagnostic value in ME/CFS lies in its specificity as a pure hemorrheologic probe: it improves RBC deformability without affecting vascular tone, coagulation, inflammation significantly (at standard doses), or capillary BM structure. Combined with pyridostigmine (preload/autonomic probe) and midodrine (perfusion pressure probe), pentoxifylline completes a three-probe dissection of the microvascular delivery deficit:
If pentoxifylline improves O₂ extraction (NIRS) while pyridostigmine and midodrine do not: the primary bottleneck is RBC-level — stiff erythrocytes cannot pass narrowed capillaries. This is the easiest target: pentoxifylline is low-risk (no bleeding, no immunosuppression) and targets a reversible rheological deficit.
If pentoxifylline improves but only partially: RBC deformability is contributory but not rate-limiting — endothelial hypertrophy is creating luminal narrowing so severe that even flexible RBCs struggle to pass. The ceiling is set by the residual luminal diameter after hypertrophy, not by RBC properties.
If pentoxifylline does NOT improve while pyridostigmine does: the bottleneck is at the functional perfusion level (preload, autonomic vasodilation), not at the capillary level. Cholinergic tone is rate-limiting; RBC deformability is adequate.
If neither pentoxifylline NOR pyridostigmine NOR midodrine improve: the bottleneck is structural — capillary BM thickening (Step F0a Pyridostigmine reduces lactate by 30% and thiamine reduces it by another 40%). No amount of improved flow, perfusion pressure, or RBC flexibility can accelerate O₂ diffusion through a pathologically thickened capillary wall. This is the most important null inference, and the most challenging therapeutically — no currently approved drug specifically thins capillary BM.
Certainty: 0.40. The multi-probe dissection framework is pharmacologically sound (each drug targets a distinct mechanism with known specificity). The framework is entirely untested — no study has combined pentoxifylline, pyridostigmine, and midodrine in ME/CFS. All differential predictions are inferential.
(Origin: brainstorm 3.2 — Phase 5d cascade trace.)
Falsifiable predictions: + In a 4-arm crossover trial (pentoxifylline, pyridostigmine, midodrine, combined), patients with EM-documented endothelial hypertrophy show greater pentoxifylline response than patients with normal endothelial morphology + Patients with BM coverage > 65% show < 10% improvement in O₂ extraction on any single drug, and < 20% on all three combined — confirming the structural ceiling + Pentoxifylline responders show larger pre-treatment RBC elongation index deficit than non-responders
Consequence: Pentoxifylline is a cheap, safe ($20/month generic), oral probe that can distinguish three distinct microvascular bottlenecks — RBC stiffness, endothelial hypertrophy, or BM thickening — and help patients and clinicians figure out which drug (if any) might help, avoiding months of trial-and-error with the wrong medications.
3.3 Dosing
Standard dose: 400 mg TID (total 1,200 mg/day). Start 400 mg once daily with food to assess GI tolerance (nausea is common), escalate to 400 mg BID after 3–5 days, then to 400 mg TID after 7–10 days. Modified-release 400 mg formulation preferred for compliance (fewer daily doses). Onset of hemorrheologic effect: hours; peak TNF-α suppression: 2–4 weeks. No dose adjustment for renal impairment at standard doses (contraindicated in severe renal failure GFR < 15 mL/min).
3.4 Safety and Interactions
Contraindications: recent cerebral or retinal hemorrhage (within 6 months), active peptic ulcer disease, severe hepatic impairment. Caution: concurrent use with anticoagulants (warfarin, DOACs) or antiplatelet agents (aspirin, clopidogrel) — pentoxifylline does NOT independently impair coagulation but may prolong bleeding time when combined.
ME/CFS-relevant interactions: no significant interactions with fludrocortisone, midodrine, LDN, or pyridostigmine. Theoretical additive vasodilation with beta-blockers (atenolol, propranolol) — monitor for hypotension. No interaction with antihistamines (cetirizine, diphenhydramine). Safe with gabapentin/pregabalin.
Pregnancy/lactation: Category C — no adequate human studies. Not recommended.
Severity applicability: safe for mild–moderate patients (ambulatory). Not tested in severe/bedbound — use with caution; the theoretical risk is minimal (no hemodynamic instability, no immunosuppression) but zero severe-ME/CFS data exist.
Consequence: Pentoxifylline is one of the lowest-risk repurposing candidates for ME/CFS — generic, affordable, well-tolerated at standard doses, no bleeding risk, no immunosuppression. Its clinical value may be primarily diagnostic (identifying which microvascular bottleneck is dominant) rather than therapeutic.
Pentoxifylline’s secondary TNF-α suppression complicates the clean “RBC probe” interpretation. If pentoxifylline improves symptoms or O₂ extraction, the improvement could be: (a) purely rheological — more flexible RBCs transiting narrowed capillaries (the intended probe function); (b) anti-inflammatory — reduced TNF-α attenuating endothelial activation and indirectly improving vasodilation (a pleiotropic, non-rheological effect); or (c) both simultaneously, with the relative contribution indeterminable without a cleaner probe.
The TNF-α effect is dose-dependent and delayed (onset 2–4 weeks), while the RBC effect is immediate (hours). A within-patient time-course design — measuring NIRS O₂ extraction at 2 hours (RBC effect only) and at 4 weeks (RBC + TNF-α effect) — could disambiguate. If improvement at 2 hours matches improvement at 4 weeks → TNF-α suppression contributes negligibly. If improvement at 4 weeks significantly exceeds improvement at 2 hours → TNF-α suppression is the dominant mechanism and pentoxifylline is not a clean rheological probe. This time-course has not been measured.
Consequence: Pentoxifylline may be doing two things at once — improving blood flow by making RBCs more flexible AND reducing inflammation. The timing of improvement tells us which mechanism dominates, and a careful study design can separate them. Until then, we cannot be sure what a patient’s response (or non-response) actually means about their capillary pathology.
The Squires et al. long-term cohort used doses up to 360 mg/day—substantially higher than the 15–60 mg/day range recommended for initial ME/CFS titration (Section pyridostigmine). The conservative starting protocol remains appropriate, but clinicians should be aware that upward titration beyond 60 mg/day may be warranted in patients who tolerate the medication well but have not achieved adequate symptom control.
Systematic reviews consistently rank pyridostigmine below ivabradine, midodrine, and beta-blockers for POTS symptom control (Pierson et al. 2025). Its primary value may lie in combination therapy (particularly with midodrine (Pavic et al. 2025)) and in the specific ME/CFS context where preload failure—rather than tachycardia alone—is the dominant mechanism (Joseph, Arevalo, et al. 2022). Pyridostigmine’s unique advantage of not causing supine hypertension remains clinically relevant for patients who cannot tolerate midodrine or fludrocortisone.
ME/CFS patients typically require 1/4 to 1/3 of standard pyridostigmine doses.
Standard POTS dosing: 30–60 mg three times daily (90–180 mg/day total)
ME/CFS-specific considerations:
- Starting dose: 15–20 mg once daily (not 60 mg)
- Titration: Increase by 15–20 mg increments every 1–2 weeks
- Maximum tolerated: Many ME/CFS patients stabilize at 20–30 mg 1–3\(\\times\) daily
- Standard dose intolerance: 60 mg may cause severe symptoms requiring bed rest
Rationale: ME/CFS patients often exhibit heightened sensitivity to neuroactive medications. The autonomic nervous system may be hyperreactive, such that standard doses produce excessive cholinergic effects. Start low and titrate slowly.
Side effects at excessive doses:
- Severe fatigue and weakness (paradoxical)
- Gastrointestinal distress (cramping, diarrhea)
- Excessive salivation
- Muscle fasciculations
- Bradycardia
If gastrointestinal symptoms occur, reduce dose rather than discontinuing.
If pyridostigmine’s anti-inflammatory effects in severe COVID-19 are mediated by the cholinergic anti-inflammatory pathway (vagal acetylcholine acting on \(\alpha\) 7 nicotinic receptors on macrophages and T cells), similar immunomodulatory benefit might occur in ME/CFS, where vagal tone is reduced and low-grade neuroinflammation is documented. This would represent a dual mechanism of action—autonomic and immune—beyond the conventional framing as a purely autonomic agent. The absence of measurable cytokine changes in the PISCO trial (Fragoso-Saavedra et al. 2022) suggests that standard inflammatory panels may be insensitive to vagally-mediated immune modulation, which operates at the tissue rather than systemic level.
Certainty: 0.25 (single trial in a different disease context; no direct ME/CFS immune data for pyridostigmine).
Testable prediction: ME/CFS patients on chronic pyridostigmine should show improved heart rate variability (reflecting enhanced vagal tone) that correlates with reductions in tissue-level inflammatory markers (e.g., neuroimaging-detected neuroinflammation) even without changes in serum cytokines.