Electrical stimulation has been used to restore hearing1-4, vision5,6, and somatosensation7,8 as well as for treating movement disorders9-12, chronic pain13-16, and epilepsy17,18. Today, there are over 1000 neuromodulation clinical trials registered on clinicaltrials.gov utilizing implanted or non-invasive electrodes to activate or inactivate nervous tissue. Although a multitude of studies have examined the impact of stimulation parameters on neuronal activity and/or behavior, the cellular properties of evoked neuronal activity to different electrical stimuli remain elusive. we aimed to bring our new optical technologies to conclusively characterize the relationship between electrical stimulation and evoked neuronal activity. Understanding the complexity of the nervous systems requires the ability to readout detailed measurements from controlled inputs19-22. While many new techniques and technologies are emerging, electrical stimulation remains one of the oldest and most widely used methods for directly interfacing and driving the nervous system23-27. In particular, optogenetics now give us a powerful tool to study mechanisms of electrical stimulation, but there are several underlying issues that limit the use of optogenetics directly in the therapies and basic science studies28,29.
Our lab’s contribution to the field. In our first published stimulation study, we showed that frequency-dependent differences in spatial and temporal somatic neuronal activation occurs during continuous stimulation30. Our data elucidated conflicting results from prior studies31-33 reporting either ‘dense spherical activation of somas biased towards those near the electrode’, or ‘sparse and distributed activation of somas at a distance from the electrode’. These findings published in the Journal of Neuroscience Research indicated that the neural element specific temporal response local to the stimulating electrode changed as a function of applied charge density and frequency30. Next, motivated by non-human primate research34, we asked the simple question of ‘does increasing amplitude and increasing frequency both recruit the same spatiotemporal activation pattern of neurons in the cortex when imaged with 2-photon microscopy?’ We published that the answer was distinctly ‘No, stimulation frequency and amplitude recruit neural activity in different spatiotemporal patterns35,36’ (Fig. 1). Another interesting distinction was that onset neurons (neurons that increased in GCaMP activity at the onset of an electrical stimulation pulse train and then turned off before the end of the pulse train) and steady state neurons (neurons that increased in GCaMP activity throughout the electrical stimulation pulse train) behaved differently between increasing stimulation amplitude and increasing frequency (Fig. 1). The mechanism of onset neuronal cell body activation and cessation of calcium activity under continuous stimulation remains poorly understood. Our analysis suggested that many axons were still entrained to the stimulation despite many somas failing to entrain30,36,37. We saw in our Biomaterials study that glutamate release was only significantly elevated compared to baseline within the first ~20 µm of the electrode, even at high stimulation amplitudes36. In turn, this suggests that the effective direct stimulation radius of ICMS is much smaller than is revealed by the calcium activity, which would indicate that direct electrical stimulation is a very focal event, and well within the region of glial scarring for chronic implants36.
Current and Future Directions. More recently, we have shown that changing waveform shape37 and temporal pattern (in revision) leads to activation of different neurons and neural network activity at the same location. This is presumably due to differences in neuronal subtypes, arborization of different neuronal subtypes, distribution and subtypes of voltage-gated ion channels present, and differences in capacitive charging across the membrane of differentially sized neurites. These findings also further shed light on the identity of onset activity. Traditional neurostimulation assumes we are switching on a single type of axons, and that we engage with these axons in the same way over time. By understanding how altering these stimulation parameters shape neural activity of different neuronal subtypes, it likely that we can begin to more intelligently engineer biomimetic stimulation paradigms38. Moreover, electrical stimulation not only influences neuronal populations, but alters activity of non-neuronal cells39. We aim to study how stimulation can manipulate these non-neuronal cells and understand their downstream influence on neural circuit activity.
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