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

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Questions Answers &