Luận án tiến sĩ nghiên cứu xây dựng hệ thống kích thích tế bào thần kinh và ứng

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF NATIONAL DEFENCE ACADEMY OF MILITARY SCIENCE AND TECHNOLOGY TA QUOC GIAP RESEARCH ON ESTABLISHING THE NEURAL STIMULATION SYSTEM AND APPLY FOR EVALUATING THE SPATIAL RESPONSE OF HIPPOCAMPAL PLACE CELLS DOCTOR OF ENGINEERING DISSERTATION HANOI - 2020 MINISTRY OF EDUCATION AND TRAINING MINISTRY OF NATIONAL DEFENCE ACADEMY OF MILITARY SCIENCE AND TECHNOLOGY TA QUOC GIAP RESEARCH ON ESTABLISHING THE NEURAL STIMULATION SYSTEM AND APPLY FOR EVALUATING THE SPATIAL RESPONSE OF HIPPOCAMPAL PLACE CELLS Specialization: Electronic engineering Code: 9 52 02 03 DOCTOR OF ENGINEERING DISSERTATION SUPERVISORS: 1. NGUYEN LE CHIEN 2. LE KY BIEN HA NOI - 2020 i DECLARATION I hereby declare that this dissertation is my original work. The data and results presented in the dissertation are honest and have not been published in any other work.

References are fully cited. 10th January, 2020 giả luận án TA Quoc Giap ii ACKNOWLEDGMENTS First and foremost, I would like to express my deep appreciation to my direct supervisors, Dr. NGUYEN Le Chien, Dr. LE Ky Bien and Association Professor TRAN Hai Anh, who enthusiastically guided me during my whole PhD time.

Thank you very much for many meaningful advices and discussion for my work. I learnt from the mentors not only techniques for fulfilling my PhD work, but also methods for solving problems in a lab as well as in the life. Thank you very much for revising my thesis, giving me helpful comments and advices. My sincere appreciations must go to other teachers in the Departments for their encouragement, knowledge sharing, supports and helps in our course and conduct the thesis.

I would like to express my sincere thanks to the Institute of Electronics – Academy of Military Science and Technology; Department of Physiology, Department of Material Equipment – VietNam Military Medical University, where I study, live and work for creating favorable conditions for me to participate in studying and researching during my time as a PhD student. I want to express my special thank to the leader of Academy of Military science and technology and other collaborator centers for their support and help for this work. Finally, I would like to thank my family members for their love, encouragement. And especially, I would thank my wife who have sacrificed a lot of things for supporting me to fulfill my PhD work.

iii TABLE OF CONTENTS Page LIST OF SYMBOL AND ABBREVIATION……………………………….v LIST OF FIGURES AND TABLES…………………………………………ix INTRODUCTION. 1 CHAPTER 1 OVERVIEW ABOUT ELECTRICAL ACTIVITY OF NEURONS. Membrane potential of neurons. Structure of nerve cells membrane.

Resting and action potential. Electrical nerve stimulation and medical significance. The response of cell membranes to electrical stimulation. The recording methods of the neuronal action potential.

Hippocampus and hippocampal place cells. Function of the Hippocampus. Fundamentals of electronic circuit model of neuron. Related research to this dissertation.

29 CHAPTER 2 EQUIVALENT ELECTRICAL CIRCUIT MODEL. AND NEURONAL ELECTRICAL STIMULATION ALGORITHMS. Electronic model of neuron membrane and assessment of electric stimulation parameters. Electronic circuit model of neurons.

Simulation of stimulating parameters on Maeda and Makino models. Simulation results and discussion. The system for stimulation and recording the electrical activity of neurons. Building electrical stimulation algorithm model for neurons.

Model and algorithm of electrical stimulation of neurons with NPT test. Model and algorithm of electrical stimulation of neurons with spatial response tests. 63 CHAPTER 3 EVALUATING THE STIMULATION ALGORITHMS AND. THE SYSTEM BY BEHAVIOURAL RESPONSES AND.

PRACTICAL EXERCISES ON MICE. Materials and methods. Simulation of the NPT task. Response simulation in spatial exercises.

Analyze and evaluate experimental results on mice. Experimental results performed on NPT test. Experimental results performed on the spatial response tests. The results of stimulating and recording experiments of the neuronal electronic activity in the hippocampus on mice………………………………80 3.

Unit isolation and recording………………………………………. Common characteristics of hippocampal place cells………………. The evaluation of the algorithms, stimulation and recording systems for the electrical activity of neurons…………………………………………………83 3. The evaluation of algorithms……………………………………….

The evaluation of stimulating and recording system for the electrical activity of neurons. 100 APPENDICES ………………………………………………………………… v LIST OF SYMBOLS AND ABBREVIATIONS 𝐶 Ions concentration 𝐶𝑚 Capacitance of the membrane per unit plane cr The adjusted response number countInterVal Number of stops to adjust the parameter delayTime The minimum time from when the mouse receives the reward until the new reward area appears deltaTime The time it takes to count from the time the mouse receives the prize until the new reward area appears delta Limits the distance the mouse moves to get the reward 𝑑𝐷𝑀𝑇 The distance the mouse moves over a certain period of time in the DMT test 𝑑𝑅𝑅𝑃𝑆𝑇 The distance the mouse moves over a certain period of time in the RRPST test 𝑑𝑃𝐿𝑇 The distance the mouse moves over a certain period of time in the PLT test 𝑑𝑋 Diameter on the horizontal axis of the virtual environment 𝑑𝑌 Diameter on the vertical axis of the virtual environment 𝐸𝐴 Action potential of cell 𝐸𝐾 Resting potential of cell 𝐸̅ Electric field strength 𝐹 Faraday constant 𝑔𝑁𝑎 Conductivity of Na+ ion channels 𝑔𝐾 Conductivity of K+ ion channels 𝑔𝐿 Conductivity of secondary ion channels Interval Interval to stop for parameter adjustment 𝐼𝑖 Intra-axonal current vi 𝐼𝑘𝑡 Cell membrane stimulated current 𝐼𝑜 Extra-axonal current 𝐼𝑠 Stimulation current per unit of time K IN Intracellular K+ concentration K OUT Extracellular K+ concentration maxT The maximum time of task maxPt The maximum number of rewards maxwidth Radius of mice area moving M50 50 percent of the optimal M70 70 percent of the optimal M80 80 percent of the optimal n Valence of ions Na OUT Extracellular Na+ concentration Na IN Intracellular Na+ concentration 𝑅 Constant 𝑅𝑚 Membrane resistance per unit area 𝑇 Absolute temperature 𝑡 Time to stimulate 𝑡1 Rewarding eligible time 𝑡2 Reward receiving time 𝑡𝐿𝑇 Total amount of exercise time for the mouse 𝑡𝑆 Training time (also the total time of sessions) 𝑡𝐼𝑛 Rest time to adjust the value of the stimulating parameter 𝑉𝑚 Membrane potential Pt Number of rewards. 𝑉𝑚 – 𝑉𝑁𝑎 Transmembrane potential of Na+ channel vii 𝑉𝑚 – 𝑉𝐾 Transmembrane potential of K+ channel 𝑉𝑚 – 𝑉𝐿 Transmembrane potential of secondary channels 𝑉′ Electric membrane charge 𝑣𝑚 ̅̅̅̅ The mean of movement speed of the mouse in the open environment 𝑋𝑚𝑎𝑥 Maximum diameter in the horizontal axis of the virtual environment 𝑋𝑚𝑖𝑛 Minimum diameter in the horizontal axis of the virtual environment x0, y0 Reward coordinates of mouse before t xs, ys The coordinates of the mice at the time t is assigned with x0, y0 which is the original position of the mice xt ,yt Reward coordinates of mouse at 𝑡 xz1, yz1 The x and y coordinates of the center of the reward area 1 xz2, yz2 The x and y coordinates of the center of the reward area 2 xzt, yzt x, y coordinates of the center of the current reward area 𝑌𝑚𝑎𝑥 Maximum diameter in the vertical axis of the virtual environment 𝑌𝑚𝑖𝑛 Minimum diameter in the vertical axis of the virtual environment 𝑧1 Reward region 1 𝑧2 Reward region 2 wz Radius of the reward area 𝛥𝑡 System latency 𝛥𝑡𝐷𝑀𝑇 System latency in DMT test 𝛥𝑡𝑁𝑃𝑇 System latency in NPT test 𝛥𝑡𝑅𝑅𝑃𝑆𝑇 System latency in RRPST test viii 𝛥𝑡𝑃𝐿𝑇 System latency in PLT test 𝜙𝑖 Inner membrane potential 𝜙0 Outer membrane potential Membrane time constant 𝜃0 Response threshold 𝜃cr Correction threshold AD Alzheimer’s disease BSR Brain stimulation reward CCD Charge coupled device DAC Digital analog converter DC Direct current DMT Distance movement task EBS Electrical brain stimulation EF Extracellular field FPS Frames per second HNM Hippocampal network model ICSS Intracranial self – stimulation MCI Mild cognitive impairment MFB Medial forebrain bundle MTLE Mesial temporal lobe epilepsy NPT Nose – poking task OF Open – field PLT Place learning task RND, RRPST Random task, random reward place search task SPF Spike potential field SNR Signal to noise ratio ix LIST OF FIGURES page Figure 1. Basic structure of nerve cell…………………………………….

Concentration and potential of ions at rest………………………. Direction of potential field lines around a neuron……………. Changes in membrane potential under the effect of stimulation pulses……………………………………………………………………. Dopamine transmission pathways of mesolimbic……………… 14 and mesocortical systems…………………………………………………… 14 Figure 1.

Cell membrane’s response to stimulus signals………………… 16 Figure 1. Demonstration of extracellular potential recording technique and the data form. Diagram of rodent brain and the location of the hippocampus… 21 Figure 1. Experimental equipment for the formation of the axon cable equation………………………………………………………………… 23 Figure 1.

Electronic circuit model and voltage chart of neurons…………24 Figure 2. Electric model of neron and the theory of action potential………32 Figure 2. Electrical neuron model according to Maeda and Makino………34 Figure 2. Electric model of a neuron under the stimulation of direct current………………………………………………………………….

One-dimensional stimulation pulse form with specified parameter………………………………………………………………. The voltage response pattern of the model……………………. Voltage change by stimulating intensity at 80Hz……………… 38 Figure 2. Change in voltage by stimulation frequency, at the intensity of 70μA…………………………………………………………………….

Model of stimulating and recording the potential of neurons…. The integrated control pulse pattern of the system and the neuron stimulation pulse………………………………………………………. Model of system for stimulating and responding to nose-poke behavior………………………………………………………………… 42 Figure 2. Flow chart of the NPT test…………………………………….

Stimulating algorithm flowchart for DMT test………………. The system for stimulation and recording the action potential of neurons on mice………………………………………………………… 53 Figure 2. Algorithm flowchart for the RRPST test……………………. Flowchart of electric stimulation algorithm for PLT test…….

The recording chamber for the ICSS response and………………. nose-poking behaviors of mice………………………………………………66 Figure 3. The illutration of the model and the arrangement of the spatial tasks……………………………………………………………………. Program interface in DMT test………………………………….

Program interface in RRPST test………………………………. Program interface in PLT test…………………………………. Relationship between nasal poking behavioral response and intensity of stimulation…………………………………………………. The dependence of nose-poking response on the stimulating frequency………………………………………….

Experimental results are analyzed for the spatial response tests………………………………………………………………………80 Figure 3. The neuron activity are recorded and isolated using an offline- sorter program (Plexon)………………………………………………… 81 Figure 3. Electrical activity of neurons recorded at hippocampus……… 82 xi Figure 3. Model of evaluating the stability and latency of the system for NPT task by labchart Pro v8.

The illustration for pulses of the reward condition, reward delivery, and the delay time of the system……………………………… 87 Figure 3. The evaluation of the stability and delay of the system for the DMT, RRPST and PLT tasks……………………………………………87 Figure 3. Program to evaluate the stability and latency of DMT test…… 88 Figure 3. Graph of system latency time in DMT test…………………… 89 Figure 3.

Program to evaluate systemic stability and latency in RRPST test………………………………………………………………………. Graph of system latency time in RRPST test…………………. Program to evaluate systemic stability and latency in PLT test. Graph of system latency time in PLT test…………………….

The necessity of the dissertation Biomedical engineering is an applied science field, which connects different sciences from physics, chemistry, and biology to electrical, control, information, micro and nano technologies in order to provide biomedical solutions for improving human health. Neural engineering is an important subfield of biomedical engineering, which uses engineering techniques to treat, replace, or restore the functions of the neural system. One of the central field of neurophysiology is the study of the mechanisms of memory and information storage in the brain [8], [48], [73], [87 - 89]. It requires a device possessed controllable and stable properties for studying the mechanism of memory storing in the brain.

This plays an important role in a comprehensive understanding of physiological neural system. Therefore, the development of systems that allow studying the physiology of the nervous system has highly practical applications. Based on the available but functionally limited equipments and programs, many supportive equipment and programs is needed for the system to be functionally competent. In this dissertation, a neural stimulation and recording sytem is developed for evaluating behavioral and spatial responses of mice from electrical stimulations with proper algorithms.