Exploration of Neuroprotective Therapy

Table 2. Qualitative synthesis of multimodal biomarkers in ME/CFS

Domain	Key findings	Indicators	References
Neuroimaging & structural alterations	Cortical volume reduction in frontal and temporal lobes, prefrontal gray-matter hypodensity, and hypothalamic atrophy linked to HPA-axis dysregulation and fatigue severity.	MRI volumetry; VBM; DTI FA; DMN connectivity	[9, 35–38, 55]
Functional connectivity	Disrupted orexinergic network connectivity in hypothalamus and brainstem, with impaired attention, executive control, and autonomic regulation.	MRI and PET functional-connectivity analyses	[13, 34]
Neuroendocrine axis	HPA-axis hypoactivity characterized by reduced CRH secretion and blunted cortisol responses; low-T₃ syndrome; inconsistent GH/IGF-1 changes; catecholamine reduction with POTS features.	Serum cortisol and CRH assays; free T₃; IGF-1; plasma catecholamines	[19, 41–44]
Orexin-A biomarker	CSF orexin-A levels are reduced in subsets of patients, though findings remain variable and non-specific.	CSF orexin-A concentration	[19, 20, 41, 46, 47]
Proinflammatory profile	Elevated IL-1β, IL-6, TNF-α, IFN-γ, IL-10, and IL-5 correlate with poor sleep quality and immune dysfunction; cytokine signatures lack consistency.	Multiplex plasma cytokine panels	[11, 39, 40, 50, 51]
Digital phenotyping	Wearable devices and mobile applications enable real-time tracking of sleep, activity, and physiological parameters, facilitating dynamic biomarker discovery and patient stratification.	Wearable sensor data; mobile-app-derived metrics	[54]

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CRH: corticotropin-releasing hormone; CSF: cerebrospinal fluid; DMN: default-mode-network; DTI: diffusion tensor imaging; FA: fractional anisotropy; GH: growth hormone; HPA: hypothalamic-pituitary-adrenal; IFN-γ: interferon-gamma; IGF-1: insulin-like growth factor-1; IL-1β: interleukin-1 beta; ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome; MRI: magnetic resonance imaging; PET: positron emission tomography; POTS: postural orthostatic tachycardia syndrome; VBM: voxel-based morphometry

Declarations

Acknowledgments

AI-Assisted Work Statement: During the preparation of this work, the author utilized DALL·E 3 (OpenAI) to generate illustrative icons featured in Figure 2. Additionally, the author employed ChatGPT-4.5 (OpenAI) to assist with grammar, stylistic refinement, and proofreading of the manuscript. All outputs generated by these tools were critically reviewed and edited by the author to ensure accuracy, coherence, and scholarly integrity. The author takes full responsibility for the content of this publication.

Author contributions

NLA: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing—original draft, Writing—review & editing, Validation.

Conflicts of interest

The author declares that he has no conflicts of interest.

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