The Exhausted Defence Phenotype: A Proposed Psychoneuroimmunoendocrine Subphenotype of Affective Deficiency, Organized Around Failed Nocturnal Autonomic Restoration

Abstract

A recognizable group of patients presents with chronic myofascial pain, stiffness organized along defensive chains, non-restorative sleep, fatigue disproportionate to exertion, paraesthesiae, histamine-related symptoms and a diffuse sense of bodily unsafety, while standard investigation excludes major inflammatory, endocrine, neurological and infectious disease. These patients are commonly assigned several partial labels at once. We propose that a subgroup of them may be described more usefully by a single organizing hypothesis, which we term the Exhausted Defence Phenotype (EDP): a state in which a sustained defensive posture, rather than tissue damage, becomes the principal cost to the organism. We situate the proposal explicitly within the nociplastic pain territory defined by the International Association for the Study of Pain (Kosek, 2024) rather than beside it, and we do not propose a new disease. The model's organizing claim is that the decisive failure is not daytime arousal but the loss of the nightly window of autonomic restoration: sleep, and non-REM sleep in particular, is where parasympathetic predominance is normally recovered, and in this phenotype that window is shortened, fragmented and invaded by arousal. We assemble evidence that experimental sleep deprivation reduces vagally-mediated heart rate variability (Zhang et al., 2025); that trauma may sensitize central arousal systems and produce insomnia through hyperarousal common to both (Sinha, 2016); that people with chronic pain report heightened attention to bodily sensation while showing reduced interoceptive accuracy (Horsburgh et al., 2024); and that acute psychological stress and corticotropin-releasing hormone increase human intestinal permeability through a mast-cell-dependent mechanism blocked by a mast-cell stabiliser (Vanuytsel et al., 2014). We state plainly that the model's proposed developmental root is its weakest link: a meta-analysis of childhood adversity and vagal regulation found no significant overall association, with effects appearing only in specific subtypes and subgroups (Wesarg et al., 2022). We therefore advance the developmental claim as a subgroup hypothesis to be tested, not an established premise, and we propose research phenotyping criteria — explicitly not diagnostic criteria — together with conditions under which the model would fail. The framework is educational and hypothesis-generating; it proposes no treatment and makes no claim to diagnose, treat or cure.