Feedback control could give optogenetics the specificity it needs to fight neurological disorders like epilepsy, chronic pain and depression. Neural stimulation systems based on electrical inputs already use feedback to control to fine tune their effects, but a device developed at the Georgia Institute of Technology is the first to provide similar control for optical stimulation. Georgia Tech doctoral student Riley Zeller-Townson demonstrates preparation of a cell culture for placement into the optoclamp. Courtesy of Rob Felt/Georgia Tech. "Our work establishes a versatile test bed for creating the responsive neurotherapeutic tools of the future," said Steve Potter, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "Neural modulation therapies of the future, whether they be targeted drug delivery, electrical stimulation or even light-plus-optogenetics through fiber optics, will all be closed loop. That means they will be responsive to the moment-to-moment needs of the nervous system." Optogenetics involves placing genes that express light-sensitive proteins into mammalian cells that normally lack such proteins. When the proteins are illuminated with specific wavelengths of light, they change the behavior of the cells, introducing certain types of ions or pushing ions out of the cells to alter electrical activity. Without a feedback loop, scientists could only assume that the optical signals were having the desired effects or try to confirm at the end of the experiment that those effects had been achieved. To address this shortcoming, the Georgia Tech researchers created an open-source technology called the optoclamp. The technique uses a computer to acquire and process the neuronal response to the optical stimulus in real time and then vary the light input to maintain a desired firing rate. By providing precise optical control of firing in neuronal populations, the technology could help disentangle causally related variables of circuit activation, the researchers said. The full stimulation light train of the optoclamp, which uses a computer to acquire and process the neuronal response to optical stimuli in real time and then vary the light input to maintain a desired firing rate. Courtesy of Georgia Tech. Studying the effects of open-loop optical stimulation on neural systems, the researchers found considerable variation in the responses of neuronal networks grown on multielectrode arrays and in the neurons of animal models. "The same stimulus pattern can produce highly variable levels of activity," said Jon Newman, who built the optoclamp while a doctoral student in Georgia Tech’s Laboratory for Neuroengineering. He is now a postdoctoral researcher at MIT. "The amount of optical stimulation needed to achieve the same level of activity varied by orders of magnitude, depending on the population that was being controlled, or even in the same type of cells and preparation, but within different subjects." With colleagues at Emory University, the researchers also explored homeostatic plasticity, a phenomenon that results from a lack of neural stimulation. Scientists had believed that the effect was controlled by the firing rate of cells, but work with the optoclamp showed instead that neurotransmission levels were responsible. "Effectively, we were able to decouple two things that are normally very closely related," Newman said. "This is potentially a very big deal in terms of developing therapies for aberrant forms of synaptic plasticity." Potential applications include treating chronic pain, epilepsy, tinnitus, phantom limb syndrome and other nervous systems disorders where the brain has overreacted to the loss of normal inputs. Funding came from the National Institutes of Health and the National Science Foundation The research was published in eLife (doi: 10.7554/eLife.07192 [open access]) and Nature Communications (doi: 10.1038/ncomms7339).