VEN Density Mediates Interoceptive Accuracy and Neurodegenerative Risk Through Mitochondrial‑Inflammatory Coupling

Von Economo neuron (VEN) density in the anterior insula predicts individual differences in interoceptive accuracy, which in turn modulates systemic inflammatory tone and risk of neurodegeneration via mitochondrial‑dependent signaling pathways.

Rationale

• VENs are metabolically costly, rich in mitochondria, and support rapid interoceptive signaling [2].
• Their density remains stable in normal aging, is elevated in SuperAgers, and collapses in AD and FTD [1].
• Interoceptive tasks (e.g., heartbeat detection) reflect insular function but have not been linked to VEN biomarkers in vivo.
• Mitochondrial dysfunction in VENs could increase reactive oxygen species, triggering NF‑κB‑mediated inflammation that accelerates proteinopathy spread.

Mechanistic Insight

VENs express high levels of uncoupling protein 2 (UCP2) and pyruvate dehydrogenase kinase 4 (PDK4), making their ATP production sensitive to intracellular calcium fluxes during interoceptive bursts. When interoceptive signaling is frequent and accurate, calcium‑driven activation of UCP2 limits mitochondrial ROS, preserving VEN integrity. Conversely, poor interoceptive performance leads to sustained calcium overload, ROS burst, and chronic microglial activation via the NLRP3 inflammasome. This creates a feed‑forward loop: inflammation impairs VEN metabolism, further degrading interoceptive signaling and accelerating neurodegeneration.

Testable Predictions

1. Cross‑sectional – In a cohort of adults aged 60‑90, higher VEN density (measured with 7 T MRI using layer‑specific sequences) will correlate with superior heartbeat detection accuracy (r > 0.4, p < 0.001).
2. Mediation – The relationship between VEN density and inflammatory markers (plasma IL‑6, CRP) will be mediated by interoceptive accuracy (indirect effect > 0, bootstrap CI not crossing zero).
3. Longitudinal – Baseline interoceptive accuracy will predict slower increase in neurofilament light (NfL) over 2 years, independent of age and APOE ε4 status; this effect will be attenuated when controlling for VEN density.
4. Intervention – Eight weeks of daily interoceptive training (real‑time biofeedback of heart rate) will increase VEN‑specific metabolic signal (measured by MR spectroscopy of N‑acetyl‑aspartate) and reduce peripheral IL‑6 by ≥15 % compared to active control.

Experimental Approach

• Participants: 120 older adults stratified by cognitive status (CN, MCI, AD).
• Imaging: 7 T MRI with cortical‑layer sequencing to quantify VEN density in anterior insula subregions.
• Interoception: Heartbeat detection task (Schandry protocol) and respiratory‑aware tracking.
• Biomarkers: Plasma IL‑6, CRP, TNF‑α; CSF NfL, p‑tau181; peripheral mitochondrial ROS in isolated monocytes.
• Analysis: Structural equation modeling to test mediation; mixed‑effects models for longitudinal outcomes; RCT for training intervention.

Falsifiability

If VEN density shows no correlation with interoceptive accuracy, or if interoceptive accuracy fails to mediate the VEN‑inflammation link, the hypothesis is refuted. Similarly, a null effect of interoceptive training on VEN‑related metabolic signals or inflammatory markers would falsify the proposed mechanistic pathway.

Translational Implication

Validating this chain would position interoceptive metrics as a low‑cost, scalable proxy for VEN health, enabling early identification of individuals who may benefit from mitochondria‑targeted neuroprotective strategies (e.g., UCP2 activators, NAD⁺ boosters) before clinical neurodegeneration manifests.