Monitor Neural Activity

Summary Neuroscience has an essential requirement for large-scale perturbation tools. Such tools would be transformative in the mapping of brain function, the causal testing of neurotheoretic models, and the diagnosis and treatment of neurological disorders. The proposed five-year project is aimed at uncovering the fundamental mechanisms of US stimulation through the reciprocity of mathematical analysis, computational modeling and experimental validation.

Abstract Magnetogenetics is a recently proposed method for stimulating cells using electromagnetic fields. In one approach, radio-frequency (RF) electromagnetic fields are applied to stimulate membrane channel proteins such as TRPV1 and TRPV4 that are attached to ferritins. The concept is highly attractive as it enables wireless neural stimulation without limitation on penetration depth or the requirement of invasive surgeries.

Microstimulation has been an invaluable tool for neuroscience researchers to infer functional connections between brain structures or causal links between structure and behavior. In recent years, therapeutic microstimulation is gaining interest for the restoration of visual, auditory and somatosensory functions as well as emerging applications in bioelectronic medicine. Current neural stimulation parameters and safety limits need to be revised for microelectrodes using more systematic and advanced methodologies.

Our long-term goals are to better understand the response of neurons to artificial stimulation, and, to use this knowledge to develop new and more effective strategies for stimulating non- or improperly-functioning neurons of the CNS. The development of models that comprehensively and accurately predict the response of neural populations to electric stimulation has proven challenging, in part because of the significant morphological differences that can exist even between nearby cells, and, a lack of understanding as to how such differences shape each cell’s response to stimulation.

Abstract Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method which can alter brain activity in humans in a safe manner. Due its ease of application and ability to target specific brain regions, the repetitive application of TMS (rTMS) has the potential of augmenting or even replacing classic pharmacologic treatment-strategies. However, due to the enormous parameter space concerning its application (amplitude, coil position and orientation), optimal, i.e., personalized stimulation parameters for rTMS are very difficult to determine.

Project Summary Based on the gate-control theory of pain, traditional spinal cord stimulation (SCS) to treat chronic back/leg pain utilizes 40-60 Hz stimulation that activates spinal dorsal columns to elicit paresthesia over a patient’s painful region. This paresthesia-based SCS is only effective for 40-50% of patients with chronic back/leg pain, and the efficacy gradually reduces over time. A recent advance in SCS employs a high-frequency (10 kHz) biphasic stimulation waveform (HF10-SCS) at a subthreshold intensity that is paresthesia-free.

PROJECT SUMMARY/ABSTRACT: Electrical brain stimulation (EBS) is a FDA-approved neuromodulation therapy applied to several neurological disorders. However, the molecular basis of its efficacy remains unclear. Here we propose investigation of a glial mechanism for EBS mediated by astrocytes-derived extracellular vesicles (EVs). We recently discovered from both in vitro and in vivo experiments that electrical stimulation affects the release of EVs from astrocytes.

Project Abstract Electrical stimulation is widely used to activate and/or disrupt neuronal activity. Despite its critical importance in experimental and clinical neuroscience, at present, there is no validated method to predict which neural elements of the brain will be activated by a given stimulation regime. Based on our pilot studies, we propose here to develop a novel computational approach for predicting the specific neurons which will be activated by a given stimulation protocol, based on neuron shape, location, type and connectivity.

PROJECT SUMMARY/ABSTRACT The ability to track electrical activity in genetically defined neurons deep in the brain has long been sought by neuroscientists to unravel the functions of neuronal circuits in health and disease. We seek to address this technical gap by developing genetically encoded voltage indicators (GEVIs), which are fluorescent proteins that report voltage dynamics as changes in brightness. GEVIs would be excellent completements to broadly-used indicators of calcium, another important information carrier in the brain.

Project summary The mammalian brain is remarkably dynamic and can quickly adjust its functional state in response to changes in the environment. For example, when a salient event occurs, the brain enters a mode that enhances memory formation. Such brain state changes occur too rapidly to be due to anatomical rewiring. Instead, they are thought to arise from the action of neuromodulators (NMs) and neuropeptides (NPs).