Skin-Brain Axis: neural pathways in acupuncture treatment

This scientific review presents a revolutionary conceptual framework for understanding the mechanisms of acupuncture through the 'Skin-Brain Axis' hypothesis. The concept proposes that the skin possesses a dense network of nerve endings, neurotransmitters, and receptors capable of detecting tissue injury with high precision and transmitting signals to the brain via sensory neurons. The research demonstrates that acupoints have unique anatomical characteristics that make them especially responsive to mechanical stimulation. These points have a nerve fiber density 1.4 times higher than non-point regions, in addition to 55% more mast cells and denser vascular networks.

The cellular complexity includes four main functional categories: classical immune cells (mast cells and M2 macrophages), barrier and immune regulatory cells (keratinocytes and fibroblasts), cell populations related to the neural system (peptidergic and non-peptidergic nociceptors), and vascular-immune interface cells. The mechanism of action involves three integrated systems. First, neural activation through multicellular mechanosensory complexes, where Aδ and C fibers detect collagen deformation caused by needle movement. Clinical studies show that low-frequency stimulation (1-10 Hz) selectively activates large-diameter Aβ fibers, while high frequency (50-100 Hz) stimulates small-diameter Aδ/C fibers, correlating with the clinical 'deqi' effect.

Second, immune regulation through mast cell-keratinocyte-fibroblast interactions, where activated mast cells release ATP and histamine that inhibit pain signal transmission, while keratinocytes secrete hormones of the hypothalamic-pituitary-adrenal axis to maintain local immune homeostasis. Third, hemodynamic optimization mediated by neurovascular coupling, where vasoactive substances (CGRP, substance P) induce arteriolar dilation through axonal reflexes, significantly increasing blood flow and tissue oxygen saturation. Signal transmission occurs through somatotopically organized peripheral pathways. Modern neural tracing techniques have confirmed that different points activate specific segments of the spinal cord: head and face points correspond to trigeminal ganglion innervation, upper limbs to C3-T2 dorsal root ganglia, lower limbs to T8-L6 segments, and trunk to T8-L8 segments.

Intervention experiments confirmed the necessity of these pathways, where transection of the common peroneal nerve or subdiaphragmatic vagus completely abolished the analgesic and anti-inflammatory effects of acupuncture at Zusanli (ST-36). Central brain responses demonstrate specific neurodynamic modulation of brain regions and functional networks. In hypertension and migraine, acupuncture activates prefrontal cortical regions, cingulate areas, and hypothalamic nuclei to regulate autonomic balance and pain-processing circuits. For insomnia and cognitive disorders, efficacy arises from improved functional integration in the default mode network, hippocampal formation, and limbic circuits.

Five specific domains explain brain responses: neural network regulation through modulation of neurons, synapses, and neural circuits; cerebrovascular function regulation via vascular permeability and angiogenesis; brain metabolism regulation including mitochondrial energy and nutrient metabolism; central immunity regulation through abnormal glial cell polarization and massive enrichment of inflammatory cytokines; and cell death regulation via apoptosis, autophagy, and ferroptosis. Current limitations include studies focused on isolated aspects of the point microenvironment, peripheral signaling, or central networks, with few investigations holistically dissecting the 'point-peripheral-CNS' signaling cascade. Future directions should prioritize mechanistic clarity to transform acupuncture from empirical practice into precision neuromodulation, including the development of real-time fMRI technologies, AI-guided spatiotemporal maps of point-CNS interactions, and application of single-cell sequencing to delineate point-specific effects on brain networks.