Thermal Effects

Thermal effects constitute perhaps the most experimentally accessible proposed mechanism for LIFU neuromodulation. Ultrasound is attenuated as it propagates through tissue, and a fraction of the absorbed acoustic energy is converted to heat. Even at sub-ablative LIFU intensities, sonication can produce measurable temperature elevations in the target tissue, typically in the range of 0.01 – 2°C for FDA-compliant protocols.

Temperature directly modulates neuronal excitability through multiple well-characterized mechanisms:

• Q₁₀ effects on ion channel kinetics: All voltage-gated and leak channels have temperature-dependent rate constants described by Q₁₀ coefficients. A small temperature rise accelerates channel kinetics, shortening AP duration and refractory period (excitatory at moderate ΔT); larger or sustained rises preferentially upregulate K⁺ conductances, producing net hyperpolarization and inhibition. Badawe et al. (2024) demonstrated that Q₁₀-mediated kinetic shifts at ΔT < 2°C are sufficient to alter firing patterns in HCN and Kv channels under prolonged sonication.
• K2P channel thermal sensitivity: TREK-1, TREK-2, and TRAAK are both mechanosensitive and thermosensitive, with open probability increasing with temperature. This makes K2P channels a mechanistic overlap zone between thermal and mechanical hypotheses — activation under LIFU may reflect both membrane tension and local heating simultaneously.
• NaV channel inactivation: Elevated temperature accelerates NaV inactivation, reducing the available sodium current and raising the effective AP threshold — contributing to silencing at higher thermal loads.

Collins & Mesce (2022) presented a strong empirical challenge to purely mechanical interpretations of LIFU neuromodulation in non-sensory neurons, arguing that at FDA-compliant intensities the observed effects in their preparation were fully accounted for by thermal mechanisms alone, without requiring MS channel activation or cavitation. This remains a significant open debate in the field.

Relevance to this project. Thermal effects are treated as a secondary but non-negligible module in the unified model. Rather than a confound to be eliminated, spatiotemporal heating gradients are modeled as an independent control variable with their own Q₁₀-dependent contribution to channel kinetics, recalibrated for mammalian CNS at T_ref = 37°C. The thermal module is particularly relevant for prolonged sonication protocols and for reconciling the inhibitory effects that membrane-only models underpredict.