Circuit Diagrams

Project Summary/Abstract: During the past two decades, functional Magnetic Resonance Imaging (fMRI) has become ubiquitous in studies of the human brain function. Similarly, Transcranial Magnetic Stimulation (TMS) has established its role as one of the most widely used neuromodulation techniques. Both of these methods have gained popularity due to their safe and noninvasive nature in addition to their wide availability.

This project will develop a low-noise transcranial magnetic stimulation (TMS) system. TMS is a technique for non-invasive brain stimulation using strong, brief magnetic pulses. TMS is widely used as a tool for probing brain function and is an FDA approved treatment for depression. A significant limitation of TMS, however, is that the magnetic pulse delivery is associated with a loud clicking sound as high as 140 dB resulting from electromagnetic forces. The loud noise significantly impedes both basic research and clinical applications of TMS.

Abstract This project seeks to develop a wireless, minimally invasive bi-directional deep brain stimulation technology based on remote heating of magnetic nanoparticles. Reliably modulating the activity of specific neuronal populations is essential to establishing causal links between neural firing patterns and observed behaviors. Electrical stimulation, as well as its recent non-invasive alternatives, ultrasound and electromagnetic induction, do not discriminate between cell types and have limited spatial resolution.

Aimed at revolutionizing our understanding of the brain, the BRAIN initiative calls for “improvement of existing non-invasive neuromodulation” techniques.

 DESCRIPTION (provided by applicant): The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has the ambitious goal of elucidating how neuronal ensembles interactively encode higher brain processes.

 DESCRIPTION (provided by applicant): Driver lines that direct Cre protein to specific neuron types have proven to be invaluable tools to not only visualize specific neuron types but also to manipulate their activity through the Cre- mediated activation of optogenetic probes or to assess gene function by Cre-mediated gene knockout. Most Cre driver lines, such as BAC-based Cre drivers or knock-ins of Cre into specific loci, monitor the complete expression pattern of entire genetic loci.

 DESCRIPTION (provided by applicant): A fundamental goal of neuroscience is to understand the function(s) of defined neural populations in a complex organism. We propose to develop and validate a technology for non- invasive modulation of neural activity in vivo. There has been huge progress in developing tools for temporal regulation of neural activity. These techniques, from light activated channels to designer receptors, enable modulation of defined neural populations in vivo to examine their roles in many physiological functions. But current technologies have their limitations.

 DESCRIPTION (provided by applicant): Molecular definitions of neural cell types largely depend on the expression of RNAs or proteins as assessed by in situ hybridization, RNA array and sequencing, and immunohistochemistry. However, recent studies are demonstrating that gene regulatory elements, such as enhancers, can have highly specific spatial and temporal activity patterns in the developing brain. Thus, enhancer activity can be used to define neural cell types, and importantly, also have other broad applications.

 DESCRIPTION (provided by applicant): Significant work is ongoing to reveal how different cell types in the brain contribute to behavior and pathology, and how they change in plasticity and disease, empowered by new genetic, optical, and physiological tools. However, the functional activity and dysregulation of neuronal circuits relies critically on the in situ molecular composition of neuronal synapses.

 DESCRIPTION (provided by applicant): Neurons communicate information through fluctuations in the electrical potentials across their cellular membranes. Whole-cell patch clamping, the gold standard technique for measuring these fluctuations, is something of an art form, requiring great skill to perform on only a few cells per day. Thus, it has been primarily limited to in vitro experiments, a few in vivo experiments, and very limited applications in the awake brain. Dr. Forest (and collaborator Dr.