## 4 Mechanisms of Peripheral US Neuromodulation  
The mechanisms of action of US in the modulation of neural activities in the CNS have been systematically reviewed [9; 38]. Here, we focus on US neuromodulation of peripheral nerve endings, axons, and somata in DRG, which, unlike the bone-protected CNS, are tightly wrapped by multiple layers of connective tissues, e.g., the epineurium, perineurium, endoneurium, and nerve extracellular matrix. This might explain why low-intensity US (<1 W/cm\({}^{2}\)) directly activates brain neurons [9] but cannot activate peripheral nerve endings or axons. Another difference between the CNS and the PNS is the lack of inhibitory neurons in peripheral sensory afferents. In the CNS, both activation and suppression effects are reported by US stimulation [38], which can be attributed to the selective activation of excitatory (e.g., glutamatergic) and inhibitory (e.g., GABAergic and glycinergic) neurons, respectively. In the periphery, the suppression effect is generally reflected as inhibition of action potential generation or transmission [50]. Sensory nerve endings can be directly activated by US stimulation, as evidenced by a series of classical clinical studies by [PERSON] et al., which reveal that virtually all the sensory modalities can be activated by US at intermediate and high-intensity [72; 73]. The activation of the low-threshold mechanoreceptors in the skin and cochlear hair cell appears to require the least US intensity and energy [72; 75; 76], indicating that US likely evokes action potentials via mechanotransduction intrinsic to those nerve endings, i.e., opening of mechanosensitive ion channels by the local mechanical force leading to action potential generation in the spike initiation zone [59]. Evoking other sensory modalities requires high-intensity focused US, which can lead to significant local heating (>5 \({}^{\circ}\)C) and inertial cavitation with sudden collapse of the bubble [88]. How high-intensity US activates sensory nerve endings remains undetermined. Putative mechanisms include temperature gating of voltage-sensitive sodium and potassium ion channels, mechanical gating of other transducer molecules like the transient receptor potential (TRP) channels, and indirect effects on surrounding non-neuronal tissues. US neuromodulation to block action potential transmission in peripheral nerve axons has been extensively studied and appears to require the local thermal effect of high-intensity US stimulation [49; 50]. The rise of local temperature reportedly induces a conduction block in peripheral axons by changing the kinetics of voltage-sensitive sodium channels, leading to their inactivation; temperature has a much greater impact on the inactivation kinetic than on the activation kinetic [89]. Non-thermal mechanisms could also contribute to the peripheral nerve block by high-intensity US, e.g., inertia cavitation with strong acoustic forces that directly \"bombs\" the fibers leading to irreversible disruption [49]. Despite the invasiveness, clinical applications of high-intensity US neuromodulation on peripheral nerves show beneficial effects on pain management in painful amputation stump neuromas, phantom limbs [90], and spasticity [91]. Reversible peripheral neuromodulation of peripheral nerve axons implements low- and intermediate-intensity US which does not directly evoke action potentials [43; 47]. Intermediate-intensity US generally causes a negligible thermal effect (<1 \({}^{\circ}\)C) and produces harmless stable cavitation [43; 47], and thus, its neuromodulatory effects on peripheral nerve axons occur likely through local acoustic radiation forces. From analyzing the existing experimental reports in Table 2, intermediate-intensity US likely enhances the neural activity in mammalian peripheral nerves by increasing the nerve conduction velocity. Unlike the nerve endings, the axon may lack the mechanosensitive ion channels tuned to transduce micromechanical forces.