Modular Device for Wireless Optically Controlled Neuromodulation in Free Behaving Models by Joanna Sands B.S., Massachusetts Institute of Technology (2019) Submitted to the Department of Electrical Engineering and Computer Science in partial fulfillment of the requirements for the degree of Master of Engineering in Electrical Engineering and Computer Science at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY September 2020 ○c Massachusetts Institute of Technology 2020. All rights reserved. Author................................................................ Department of Electrical Engineering and Computer Science August 14,2020 Certified by. Anantha Chandrakasan Professor Thesis Supervisor Accepted by . Katrina LaCurts Chair, Master of Engineering Thesis Committee 2 Modular Device for Wireless Optically Controlled Neuromodulation in Free Behaving Models by Joanna Sands Submitted to the Department of Electrical Engineering and Computer Science on August 14,2020, in partial fulfillment of the requirements for the degree of Master of Engineering in Electrical Engineering and Computer Science Abstract This work presents a modular, light-weight head- borne neuromodulation platform that achieves low-power wireless neuromodulation and allows real-time programma- bility of the stimulation parameters such as the frequency, duty cycle, and intensity. This platform is comprised of two parts: the main device and the optional inten- sity module. The main device is functional independently, however, the intensity control module can be introduced on demand. The stimulation is achieved through the use of energy-efficient 휇LEDs directly integrated in the custom-drawn fiber-based probes. Our platform can control up to 4 devices simultaneously and each device can control multiple LEDs in a given subject. Using the multiple LED channels, the platform can also be used to recording in-vivo temperatures to prevent damage to the couple neuron. Our hardware uses off-the-shelf components and has a plug and play structure, which allows for fast turn-over time and eliminates the need for com- plex surgeries. The rechargeable, battery-powered wireless platform uses Bluetooth Low Energy (BLE) and is capable of providing stable power and communication re- gardless of orientation. This presents a potential advantage over the battery-free, fully implantable systems that rely on wireless power transfer, which is typically direction-dependent, requires sophisticated implantation surgeries, and demands com- plex custom-built experimental apparatuses. Although the battery life is limited to several hours, this is sufficient to complete the majority of behavioral neuroscience experiments. Our platform consumes an average power of 0.5 mW, has a battery life of 12 hours. Thesis Supervisor: Anantha Chandrakasan Title: Professor 3 4 Acknowledgments As this chapter of my life comes to an end, I am so thankful for everyone I met who helped me through these 5 years of MIT. I give all of my thanks to my advisor, Anantha Chandrakasan, for all of his ideas, guidance, and feedback for this project and all other pursuits I’ve attempted during my 18 months in the lab. I’m also so thankful to Sirma Orguc. She was a great research mentor and partner who put countless hours into working with me and others to see these projects through. I’m so happy that we were able to meet and work together, without her I have no idea what I’d have done this year. I also want to thank Anantha Group as a whole for all of their help with circuits, equipment, and staying sane during the late nights in lab, especially Preet, Mohamed, and Vipasha. I really appreciate the coffee breaks we’ve had both pre-COVID and post-COVID and hope we can continue them long into the future! I’m thankful for Polina Anikeeva and Atharva Sahasrabudhe who helped ground this project with in-vivo tests and experimental goals. I want to thank the staff and students of 6.002 (both Fall and Spring) for makingmy teaching experience feel so meaningful and fun. I also want to thank my housemates who put up with my late-night tests on the equipment I brought home during the ramp down as well as my other friends would happily listen to all of my design issues despite not knowing anything about either circuits or biology. Finally, I want to thank my family for all of the support I’ve received. I’m so grateful for my parents’ willingness to listen and give support despite being hundreds of miles away and for my sister’s constant presence through our time together at MIT. 5 6 Contents 1 Introduction 13 1.1 Contributions . 14 1.2 Outline . 14 2 Literature Review 17 2.1 Methods of Optical Stimulation . 17 2.1.1 Laser-Sourced Stimulation . 18 2.1.2 LED-Sourced Stimulation . 18 2.2 Methods of Powering Non-tethered Implantable Devices . 19 2.3 Wireless Communication with Implanted Devices . 19 2.4 In-Vivo Temperature Sensing . 20 3 System Overview 23 3.1 The Physical System . 23 3.2 The Software System . 24 4 Hardware Implementation 27 4.1 Experimental Considerations . 27 4.2 Base Module Implementation . 29 4.3 Optional Intensity Control . 30 4.4 In-Vivo Temperature Sensing . 31 4.4.1 Gain Constraints . 33 4.4.2 Gain Calculations . 34 7 5 Software Implementation 35 5.1 Stimulation Control . 35 5.2 Communication Protocol . 36 5.2.1 Data Rate, Power and Latency Considerations . 37 5.3 User Interface Design . 37 6 Results and Evaluation 39 6.1 Waveforms and Stimulation . 39 6.2 Temperature Sensing . 41 6.3 Power Consumption and Battery Performance . 43 7 Conclusion and Future Work 49 7.1 Future Work . 50 A Tables 51 B Figures 53 8 List of Figures 2-1 Example Temperature Sensing System . 21 3-1 System Components . 24 3-2 System Block Diagram . 25 4-1 Module Hardware . 28 4-2 Temperature Circuit Block Diagram . 31 4-3 Probe Current based on Temperature . 32 5-1 Example User Interface . 38 6-1 Example Stimulation Waveforms . 40 6-2 Intensity Control Diagram . 40 6-3 Stimulation Results . 41 6-4 Real Time Temperature Recordings . 42 6-5 Temperature Recordings . 42 6-6 Input Current . 44 6-7 Battery Behavior . 44 6-8 Input Current . 46 B-1 Additional Input Current Waveforms . 53 9 10 List of Tables A.1 Explanation for each parameter in the stimulation control message . 51 A.2 Average Current for Available Cofigurations . 52 11 12 Chapter 1 Introduction In modern research, studies of the brain and the nervous system often rely on the controlled perturbation of neural behavior in order to better understand the function of individual components [21]. Optogenetics is a technique in which light-sensitive proteins, produced in genetically modified neurons, are exposed to light in order to either promote or inhibit certain neural responses [21]. For the previously mentioned studies, this technique has advantages over classical neuromodulation techniques, such as electrical stimulation, due to the cell type specificity, low electrical disturbance and high temporal resolution [11]. For some types of stimulation, like laser-based systems, the model must be teth- ered to an external system, which can affect the behavior of the model and limit the freedom of movement [11]. The use of energy-efficient 휇LEDs can allow for use of optogenetics alongside wireless devices for tether free behavioral monitoring. The system presented in this work is a head-borne device for optical neuromod- ulation in free behaving mice models. It is made with the goal of being modified to account for variation in the stimulation scenario and to support the additional func- tionalities without requiring changes to the entire system. With this focus in mind, the resulting device requires only one external component, has a simple fabrication scheme, weighs less than 2 grams, and is 14mm in diameter. It can also support intensity control, multiple LED control, and real-time in-vivo temperature recording. 13 1.1 Contributions For this work, a platform for performing wireless optically stimulated neuromodu- lation was developed and tested in full collaboration with Sirma Orguc as well as Atharva Sahasrabudhe, a member of the Bioelectronics Group at MIT. Probe de- sign, creation and implantation as well as all in-vivo measurements were handled by Atharva. All hardware work was done in close collaboration with Sirma. This platform required the creation of four distinct components. The soft, flexible probes containing 휇LEDs were desgined by Atharba Sahasrabudhe. Three stack- able custom PCBs were designed in partnership with Sirma Orguc, one prototype for basic operation, one prototype for temperature sensing operation and an addi- tional intensity module. Additionally, firmware code was developed to run onthe PCB’s embedded microcontroller to handle the creation of stimulation waveforms and communication with other devices. Another file of code was written for the re- ceiving device to act as a BLE-UART adapter. Finally, a MATLAB user interface was designed to allow users to easily send and receive data. This thesis contributes: ∙ A BLE-enabled battery-powered device capable of connecting to pre-implanted probes containing 휇LEDs for both stimulation and temperature recording. ∙ An optional module for the aforementioned device for intensity control ∙ A MATLAB User Interface for sending and receiving data over UART 1.2 Outline Chapter 1 outlines the motivation and contributions made in this work. Chapter 2 contains a review of relevant literature and an exploration of various tech- niques used in creating devices for neuromodulation. Chapter 3 is an overview of the goals of the system and a discussion of the interaction of the different components. 14 Chapter 4 details the implementation of the hardware components of the system, starting with the needs of the initial prototype and moving into the additional func- tionalities. Chapter 5 describes the implementation of the software components including the microcontroller firmware and the user interface.