Infrared neural stimulation (INS) is a promising neuromodulation technique capable of exciting neural tissue without the need for exogeneous agents or genetic modification. Due to its high spatial specificity, INS could improve upon traditional methods of selective neural stimulation in both the laboratory and the clinic. As of yet, no study has compared the efficacy and safety of using different INS parameters such as spot size and wavelength. Moreover, differences in the methods of determining energy deposition and laser spot size make it difficult to compare stimulation parameters used in the current literature. Here, we present results comparing INS efficacy using 1450nm and 1875nm light over a range of spot sizes and radiant exposures. Stimulation thresholds were determined using recorded compound muscle action potentials (CMAPs) and visible muscle contractions in an in vivo rat sciatic nerve model. Overall, 1450nm light required lower radiant exposures to achieve threshold activation as compared to 1875nm. While radiant exposures remained relatively constant across different spot sizes when using 1450nm, the threshold radiant exposures for 1875nm exposures increased with spot size suggesting deeper nerves fibers tend to be activated. Moreover, exposures using a flat-top beam profile yielded less variability in the stimulation threshold than those using a Gaussian profile. As in previous studies, histology confirmed that damaging radiant exposures are several times greater than the stimulation threshold for both 1450nm and 1875nm. Our results provide valuable insight for future studies involving INS and for further developing INS as both a research and clinical tool.
Infrared neural modulation (INM) is a label-free method for eliciting neural activity with high spatial selectivity in mammalian models. While there has been an emphasis on INM research towards applications in the peripheral nervous system and the central nervous system (CNS), the biophysical mechanisms by which INM occurs remains largely unresolved. In the rat CNS, INM has been shown to elicit and inhibit neural activity, evoke calcium signals that are dependent on glutamate transients and astrocytes, and modulate inhibitory GABA currents. So far, in vivo experiments have been restricted to layers I and II of the rat cortex which consists mainly of astrocytes, inhibitory neurons, and dendrites from deeper excitatory neurons owing to strong absorption of light in these layers. Deeper cortical layers (III-VI) have vastly different cell type composition, consisting predominantly of excitatory neurons which can be targeted for therapies such as deep brain stimulation. The neural responses to infrared light of deeper cortical cells have not been well defined. Acute thalamocortical brain slices will allow us to analyze the effects of INS on various components of the cortex, including different cortical layers and cell populations. In this study, we present the use of photoablation with an erbium:YAG laser to reduce the thickness of the dead cell zone near the cutting surface of brain slices. This technique will allow for more optical energy to reach living cells, which should contribute the successful transduction of pulsed infrared light to neural activity. In the future, INM-induced neural responses will lead to a finer characterization of the parameter space for the neuromodulation of different cortical cell types and may contribute to understanding the cell populations that are important for allowing optical stimulation of neurons in the CNS.
Infrared neural stimulation (INS) is a neurostimulation modality that uses pulsed infrared light to evoke artifact-free, spatially precise neural activity with a noncontact interface; however, the technique has not been demonstrated in humans. The objective of this study is to demonstrate the safety and efficacy of INS in humans in vivo. The feasibility of INS in humans was assessed in patients (n=7) undergoing selective dorsal root rhizotomy, where hyperactive dorsal roots, identified for transection, were stimulated in vivo with INS on two to three sites per nerve with electromyogram recordings acquired throughout the stimulation. The stimulated dorsal root was removed and histology was performed to determine thermal damage thresholds of INS. Threshold activation of human dorsal rootlets occurred in 63% of nerves for radiant exposures between 0.53 and 1.23 J/cm2. In all cases, only one or two monitored muscle groups were activated from INS stimulation of a hyperactive spinal root identified by electrical stimulation. Thermal damage was first noted at 1.09 J/cm2 and a 2∶1 safety ratio was identified. These findings demonstrate the success of INS as a fresh approach for activating human nerves in vivo and providing the necessary safety data needed to pursue clinically driven therapeutic and diagnostic applications of INS in humans.
Low-intensity, pulsed infrared light provides a novel nerve stimulation modality that avoids the limitations of traditional electrical methods such as necessity of contact, presence of a stimulation artifact, and relatively poor spatial precision. Infrared neural stimulation (INS) is, however, limited by a 2:1 ratio of threshold radiant exposures for damage to that for stimulation. We have shown that this ratio is increased to nearly 6:1 by combining the infrared pulse with a subthreshold electrical stimulus. Our results indicate a nonlinear relationship between the subthreshold depolarizing electrical stimulus and additional optical energy required to reach stimulation threshold. The change in optical threshold decreases linearly as the delay between the electrical and optical pulses is increased. We have shown that the high spatial precision of INS is maintained for this combined stimulation modality. Results of this study will facilitate the development of applications for infrared neural stimulation, as well as target the efforts to uncover the mechanism by which infrared light activates neural tissue.