electroceuticals in neurologic and psychiatric disorders · professor and chair of neurology dell...
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David Paydarfar, MDProfessor and Chair of Neurology Dell Medical School and Mulva Clinic for the NeurosciencesThe University of Texas at AustinAustin, TX
Electroceuticals in Neurologic and Psychiatric Disorders
David Paydarfar, MD
●Research/Grants: Clayton Foundation; Merck & Co., Inc.; National Institutes of Health (NIH); National Science Foundation (NSF); Texas Alzheimer’s Research and Care Consortium
●Advisory Board: Prapela, Inc.
Disclosures
Identify the role of electroceutical treatment in neurologic and psychiatric disorders.
Learning Objective1
How can we normalize dysfunctional circuitsusing external stimuli?
Central question in neuroscience: How do neural circuits determine behavior?
Zamora-Lopez G, et al. Front Neuroinform. 2010;19:4:1.
Ancient Egyptian and Roman physicianstreated a range of painful conditions.Scribonius Largus published use of torpedo fish to treat headache.
Spinal cord stimulatorCochlear implantsRetinal implantsDeep brain stimulators
Benjamin FranklinLuigi GalvaniGiovanni AldiniG.B.C. Duchenne
Ugo CerlettiLucio BiniFriedrich Meggendorfer
2500 BC 45 AD 1750 - 1850 1934 - 1944 1960 - present
Medicinal Electric Fish Electrotherapy Electroconvulsive Therapy Implanted Stimulators
Steemit.com
jstor.org
Rosicrucian Egyptian Museum San Jose, California
wellcomecollection.org https://en.wikipedia.org/wiki/Electric_bath_(electrotherapy)
https://commons.wikimedia.org/wiki/File:Electroconvulsive_Therapy.png
https://www.nidcd.nih.gov/https://www.ninds.nih.gov/
Electricity in Medicine
Trigeminal NervesMigraine
Cardiac Conduction NervesArrhythmias, Heart Failure
Carotid Sinus NerveHypertension
Dorsal Column of Spinal CordIntractable Pain
Phrenic NervesParalysis of the Diaphragm
Vagus NerveEpilepsy, Immune Modulation
curetoday.comninds.nih.gov
Transcranial Magnetic Stimulation (TMS)
Transcranial Direct CurrentStimulation (TDCS)
Tumor Treating Fields(TTF)
GliomaBrain Metastasis
Obsessive Compulsive DisorderDepressionMigraine PainAddictionStroke Rehabilitation
ninds.nih.gov
Deep Brain Stimulation(DBS)
Movement DisordersEpilepsyDepressionComaCognitive Impairment
What have we learned in 4,500 years?
2500 BCMedicinal Electric Fish
2020 ADImplanted Electric Stimulators
What are the mechanisms of action?
What are the spatial and temporal scales of effect?
How is optimal dose profile determined?
Zamora-Lopez G, et al. Front Neuroinform. 2010;19:4:1.
Electroceutical Science
Charge-Sensitive Biological Switches
Organism
Network
Cellular
Molecular
Protein Activation,
Signal Transduction
Action Potentials,
Immune Cell Activation
Sleep / Wake
Cell Maturation, Apoptosis,
DivisionMigration
Voltage-sensitive membrane proteins regulate ion fluxes and generate the action potential
Na+
channels open, Na+
enters cell
K+ channelsopen, K+
begins to leave cell
N=Na+ channelsclose
K+ leavescell
K+ channels close
The Action Potential
Depolarization & HyperpolarizationMicrotubule AssemblyActin Filaments/Adhesion Voltage-Sensitive Ionic Channels
Mitotic Inhibition & ApoptosisAlignment & Migration
Constant Voltage (DC) 1 Hz – 1 KHz (AC) 100 KHz – 500 KHz (AC)+
−
Electric field effect on cells is highly dependent on stimulus frequency
Cell/Circuit Scale Gyri/Lobar Scale Multilobar Scale
Temporal and spatial scales of neural stimulation techniques
Polanía R, et al. Nat Neurosci. 2018;21(2):174-187.
Flexible electrode (red)
Vascular network (green)
50µm
Stable in vivo recording from individual neurons long-term (> 1 year)
Neurons (yellow)
d1 d2 d3 d4 d5 d6 d7 d8 d9 d10 d11 d12 d13 d14
0.1
mV
1 ms
6 Mon +20
0 µV
1 ms
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Chong Xie, PhD Rice University
A new class of micro-electrodes – ultra-flexible & biocompatible
Luan L, et al. Sci Adv 2017;3(2):e1601966.
What are the mechanisms of action?
What are the spatial and temporal scales of effect?
How is optimal dose profile determined?
Electroceutical Science - Main Questions
Zamora-Lopez G, et al. Front Neuroinform. 2010;19:4:1.
State 1 Stimulation State 2Cardiac
arrhythmiasCardiac Conduction
SystemNormal sinus
rhythmParkinsonian
tremorsSubthalamic
Nucleus No tremors
Epileptic seizures ThalamocorticalCircuits
Normal brain activity
Migraine Trigeminal Nerves No headache
Electrical stimulation can induce switching between pathological and healthy states
State 1 State 2
Stimulus Intensity Time
State switching
Stimulus Energy
Too Much Energy§ Decreased
battery life
§ Off target effects§ Damaged tissue
Just Right
Too Little Energy§ Failed outcome§ Wasted energy
Goldilocks Principle
Prevalence (US):• 2.3 million adults and over 450,000
children• Diagnose roughly 150,000 new cases
each year• Financial burden - $9.6 billion in 2009
Treatments for Epilepsy• Drug therapies• Surgery• Electrical Stimulation
Epilepsy
Neuronal synchronization underlying epilepsy
Crunelli V, Leresche N. Nat Rev Neurosci. 2002;3(5):371-382.
Desynchronized ActivitySynchronized Activity
Responsive Neural Stimulation (RNS)
NeuroPace RNS System
1 secondneuropace.com
How can we optimize the stimulus waveforms?
• Efficacy ~50%
• Off target effects
• Battery life
RNS suppression of seizure
Black Box System
Input Output
Stochastic Search Algorithm§ Stochastic Hill-Climbing§ Simulated Annealing§ Genetic Algorithms§ Particle Swarm Optimization
Search Algorithms
Optimized stimulus: 24.43 μJ/cm2
Rectangular pulse: 154.88 μJ/cm2
Optimal stimulus to desynchronize five coupled neurons
Chang J. Paydarfar D Sci Rep 2018;8:1-13.
Bistable Single Cell
Bistable Population
Desynchronization
Computed optimal stimulus waveforms
System Response
Stimulus
Illustration of counterbalancing mechanism
-20
0
20
40
60
80
100
120
10 20 30 40
Waveform shape Stimulus timing
Tailoring therapy to the dysfunctional circuit
• Mechanisms of action
• Spatial and temporal scales of effect
• Optimal dose profile
Electroceutical Principles
Special Thanks!
Joshua Chang, MD/PhDAssistant Professor
UT Austin
Machine Learning in Health Care
Varun Sridhar, BSEngComputational Research Fellow
Clayton Foundation
Software Engineering
Sara Hackett, BSEngResearch Engineer
UT Austin
Biomedical Instrumentation
Don’t forget to fill out your evaluations to collect your credit.
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