Tuszynski, M. | Search bioRxiv

bioRxiv2026

Adaptive Charge Modulation Enables Focal, Selective Spinal Cord Stimulation

Clinical neuromodulation primarily employs near-field low frequency electrical stimulation to activate neurons in the immediate vicinity of the electrode. We introduce Adaptive Charge Modulation (ACM), a spatiotemporal, charge-balanced stimulation strategy that focuses activation at deep tissue sites distant from the stimulating contacts. We apply ACM to stimulate deep regions of the spinal cord, distant from dorsal root entry zones which are preferentially activated during low frequency stimulation (LFS). ACM applies multipolar, biphasic rectangular pulses to exceed activation thresholds in deeper neuronal populations, with reduced surface activation, potentially due to high-frequency suppression of neural activity. In epidural spinal cord stimulation in rats, ACM achieved single-muscle selectivity among fourteen monitored muscles with minimal co-activation of other muscles. Using simultaneous, high spatiotemporal resolution, 2,112-channel brain-spine recordings, we characterized the response latencies and pathways consistent with focal recruitment at depth. We observed chronic stability of the electrode and ACM in freely behaving animals over 68 days post-implantation. By enabling focal activation with epidural surface electrodes, ACM may expand the reach and precision of neuromodulation and neural interfaces.

bioengineering↗

bioRxiv2024

Disruption of Core Stress Granule Protein Aggregates Promotes CNS Axon Regeneration

Depletion or inhibition of core stress granule proteins, G3BP1 in mammals and TIAR-2 in C. elegans, increases axon regeneration in injured neurons, showing spontaneous regeneration. Inhibition of G3BP1 by expression of its acidic or B-domain accelerates axon regeneration after nerve injury, bringing a potential therapeutic intervention to promote neural repair in the peripheral nervous system. Here, we asked if G3BP1 inhibition is a viable strategy to promote regeneration in injured mammalian central nervous system where axons do not regenerate spontaneously. G3BP1 B-domain expression was found to promote axon regeneration in the transected spinal cord provided with a permissive peripheral nerve graft (PNG) as well as in crushed optic nerve. Moreover, a cell-permeable peptide (CPP) to a subregion of B-domain (rodent G3BP1 amino acids 190-208) accelerated axon regeneration after peripheral nerve injury and promoted regrowth of reticulospinal axons into the distal transected spinal cord through a bridging PNG. G3BP1 CPP promoted axon growth from rodent and human neurons cultured on permissive substrates, and this function required alternating Glu/Asp-Pro repeats that impart a unique predicted tertiary structure. The G3BP1 CPP disassembles axonal G3BP1, G3BP2, and FMRP, but not FXR1, granules and selectively increases axonal protein synthesis in cortical neurons. These studies identify G3BP1 granules as a key regulator of axon growth in CNS neurons and demonstrate that disassembly of these granules promotes retinal axon regeneration in injured optic nerve and reticulospinal axon elongation into permissive environments after CNS injury. This work highlights G3BP1 granule disassembly as a potential therapeutic strategy for enhancing axon growth and neural repair. SIGNIFICANCE STATEMENTThe central nervous system (CNS) axon does not have the capacity for spontaneous axon regeneration, as seen in the peripheral nervous system (PNS). We previously showed that stress granule-like aggregates of G3BP1 are present in uninjured PNS axons, and these slow nerve regeneration. We now report that CNS axons contain G3BP1 granules, and G3BP1 granule disassembling strategies promote axon regeneration in the injured sciatic nerve, transected spinal cord with a peripheral nerve graft, and injured optic nerve. Thus, G3BP1 granules are a barrier to axon regeneration and can be targeted for stimulating neural repair following traumatic injury, including in the regeneration refractory CNS.

neuroscience↗