Size principles governing selective neuromodulation and recruitment order of nerve fibers

Exogenous electrical stimulation of peripheral nerves preferentially activates the larger diameter fibers due to the lower applied current (or voltage) needed for their activation. However, the ability to selectively stimulate small fibers, and sparing large fibers, would have an important role in clinical applications. This review elucidates the biophysical basis and clinical significance of achieving fiber size-specific recruitment in neuromodulation therapies. We evaluate various methodologies designed to modulate recruitment patterns, including spatial electrical modulation techniques such as electrode configuration and field shaping, temporal modulation strategies involving pulse parameter adjustments. Other neuromodulating technologies are reviewed, including focused ultrasound, optogenetics, and chemogenetics. We discuss the limitations of current techniques and directions for future research to enhance the precision of nerve fiber recruitment, thereby optimizing therapeutic efficacy.