Hierarchical-Circular Model of Biological Memory: an integrative framework for pathogenesis and allostasis in...

Predominant linear and brain-centric models inadequately explain the marked clinical heterogeneity and systemic origins of neurodevelopmental disorders (NDDs). A transformative, integrative framework is needed to capture their complex, non-linear pathogenesis.

We propose a novel theoretical hypothesis-the Hierarchical-Circular Model of Biological Memory-developed through a critical synthesis of multidisciplinary evidence. Organized around the core principle "Signal → Plasticity → Stable State," the model integrates five interacting levels: (1) morphogenetic/genetic, (2) epigenetic, (3) allostatic, (4) the psychoneuroendocrine-immune (PNEI) network, and (5) the interoceptive-neuronal level.

The framework posits that NDDs emerge from disrupted circular causality within biological adaptation systems. Early adverse signals (e.g., genetic risk, prenatal stress) become embedded via epigenetic programming and propagate bidirectionally, establishing a pathological stable state. This state is characterized by high allostatic load, PNEI network dysregulation, and a collapse of predictive interoceptive integration in the brain. The model introduces the constructs of "allostatic integrity" and "circular reserve" to explain individual differences in phenotypic expression and resilience.

This model provides a falsifiable, systems-based paradigm that moves beyond descriptive synthesis. It generates specific predictions: (1) multi-level biomarker dyssynchrony will outperform single-level measures in prognostic stratification, and (2) interventions simultaneously targeting multiple system levels will be most effective. By bridging gene-environment interactions with brain network dysfunction, the framework guides future research toward multi-level biomarker discovery, personalized prevention, and multidimensional interventions, fundamentally redefining NDDs as disorders of circular biological adaptation.