Scientific Symposium The Neurobiology of Brain Stimulation ......Neurofeedback Clinic at the University of Colorado Hospital. Initially a research tool, QEEG has now been well Initially

Scientific Symposium The Neurobiology of Brain Stimulation in Epilepsy:

Targets, Networks, and Cascades

Symposium Chair: Kevin Graber, M.D.

Tuesday, December 6, 2016 Convention Center – Ballroom A

8:45 – 10:45 a.m.

Accreditation The American Epilepsy Society is accreditedby the Accreditation Council for ContinuingMedical Education (ACCME) to providecontinuing medical education for physicians.

AMA Credit Designation StatementThe American Epilepsy Society designates this live activity for amaximum of 29.50 AMA PRA Category 1 Credits™. Physiciansshould claim only the credit commensurate with the extent oftheir participation in the activity.

International Credits: The American Medical Association hasdetermined that non-U.S. licensed physicians who participate inthis CME activity are eligible for a maximum of 29.50 AMA PRACategory 1 Credits™.

Physician Assistants: AAPA accepts certificates of participationfor educational activities certified for AMA PRA Category 1Credits™ from organizations accredited by ACCME or arecognized state medical society. Physician assistants mayreceive a maximum of 29.50 hours of Category 1 credit forcompleting this program.

Continuing Education for Nurses andPharmacists

Jointly provided by AKH, Inc.,Advancing Knowledge in Healthcare,and the American Epilepsy Society.

Nurses:Advancing Knowledge in Healthcare is accredited as aprovider of continuing nursing education by the AmericanNurses Credentialing Center’s Commission on Accreditation.This activity is awarded 29.50 contact hours.

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Select portions of this Annual Meeting are approved forpharmacy CE credit. Specific hours of credit for approvedpresentations and the Universal Activity Numbers assigned tothose presentations are found elsewhere in the programmaterials. Criteria for success: credit is based on documentedprogram attendance and online completion of a programevaluation/assessment.

If you have any questions about this CE activity relative tonursing and/or pharmacy CE, please contact AKH Inc [email protected].

The American Board of Psychiatry and Neurology has reviewedthe 70th Annual Meeting — American Epilepsy Society and hasapproved this program as part of a comprehensive epilpesyprogram, which is mandated by the ABMS as a necessarycomponent of maintenance of certification.

Claiming CME Credit and CME CertificatesAttendees who registered in the following categories may claimCME or CE for the meeting: physician, health care provider,trainee, one-day and two-day. Meeting registration includescredit claiming: there is no separate fee to claim CME/CE.

Attendees will receive an emailed notification to access theonline evaluation and credit claim system.

The evaluation and credit claim system will remain openthrough Tuesday, February 28, 2017. Evaluations and creditclaims must be completed by this date in order to record andreceive your CME/CE certificate.

Attendance Certificate/International AttendeesA meeting attendance certificate will be available at theregistration desk for international meeting attendees onTuesday, December 6.

Resolution of Conflicts of InterestIt is the policy of the American Epilepsy Society to ensurebalance, independence, objectivity and scientific rigor. Allpersons involved in the selection, development andpresentation of content are required to disclose any real orapparent conflicts of interest. In accordance with the ACCMEStandards for Commercial Support of CME, AES implementedthe mechanism of prospective peer review of this CME activity,to identify and resolve any conflicts. Additionally, the content ofthis activity is based on the best available evidence.

Unapproved Use DisclosureAES requires CME authors to disclose to learners whenproducts or procedures being discussed are off-label,unlabeled, experimental and/or investigational (not FDAapproved); and any limitations on the information that ispresented, such as data that are preliminary or that representongoing research, interim analyses and/or unsupportedopinion. This information is intended solely for continuingmedical education and is not intended to promote off-label useof these medications. If you have questions, contact themedical affairs department of the manufacturer for the mostrecent prescribing information. Information aboutpharmaceutical agents/devices that is outside of U.S. Food andDrug Administration approved labeling may be contained inthis activity.

DisclaimerThis CME activity is for educational purposes only and does notconstitute the opinion or endorsement of, or promotion by, theAmerican Epilepsy Society. Reasonable efforts have been takento present educational subject matter in a balanced, unbiasedfashion and in compliance with regulatory requirements.However, each activity participant must always use his or herown personal and professional judgment when consideringfurther application of this information, particularly as it mayrelate to patient diagnostic or treatment decisions including,without limitation, FDA-approved uses and any off-label,investigational and/or experimental uses.

EDUCATION CREDITS

American Epilepsy Society | www.AESnet.org | Houston, Texas 70th Annual Meeting | 6th Biennial North American Regional Epilepsy Congress 23

OVERVIEW Brain stimulation is an evolving treatment for medically refractory epilepsy. This session will convey the basic antiseizure mechanisms of brain stimulation. The history of brain stimulation will be presented as well as a discussion of the sites of stimulation in animal models. How electrical current spreads through brain tissue will be explained. Conceptualization of brain stimulation paradigms as ablative forces will be discussed, and information on how stimulation of a network can modulate an epileptogenic focus will be addressed. Examples of how chronic stimulation can modulate protein pathways and lead to neuroplastic changes will be presented; potential mechanisms of improved efficacy over time will be covered. Clinical studies have sometimes proceeded with only limited understanding of the basic mechanisms. As competing and complementary technologies emerge, new treatment algorithms should be developed to direct patients to the best treatment options. Understanding of the neurobiology and mechanisms of brain stimulation may illuminate clinical trials and treatment decisions, contributing to the development of anti-seizure therapeutic best practices utilizing this approach. LEARNING OBJECTIVES Following participation in this symposium, learners should be able to: • Discuss the anti-seizure mechanisms of brain stimulation for medically refractory epilepsy. • Provide an overview of empirical observations of various sites of anti-seizure stimulation. • Describe how anti-seizure stimulation can both disrupt and drive local neuronal circuits. • Delineate the network effects of anti-seizure stimulation. • List chronic the neuronal changes that may drive long term benefits of brain stimulation for epilepsy.

TARGET AUDIENCE Intermediate: Epilepsy fellows, epileptologists, epilepsy neurosurgeons, and other providers with experience in epilepsy care (e.g., advanced practice nurses, nurses, physician assistants), neuropsychologists, psychiatrists, basic and translational researchers. Advanced: Address highly technical or complex topics (e.g., neurophysiology, advanced imaging techniques or advanced treatment modalities, including surgery.) PROGRAM Chair: Kevin Graber, M.D. Introduction and Overview of Brain Stimulation in Models and Patients: Targets and Empirical Effects Kevin Graber, M.D. Mechanisms of Seizure Control with Local Circuit Stimulation Dominique Durand, Ph.D. Modulation of Epileptic Networks with Electrical Stimulation Kristl Vonck, M.D., Ph.D. Positive Cascades: Improving Efficacy and Outcomes Esther Krook-Magnuson, Ph.D. Conclusions Kevin Graber, M.D.

Education Credit 2.0 CME Credits Nurses may claim up to 2.0contact hours for this session. Nurse Practitioners may claim 2.0 hours of pharmacology for this session.

Pharmacy Credit Pharmacists: AKH Inc., Advancing Knowledge in Healthcare approves this knowledge-based activity for 2.0 contact hours (0.2 CEUs). UAN 0077-9999-16-093-L01-P. Initial Release Date: 12/6/16.

FACULTY/PLANNER DISCLOSURES It is the policy of the AES to make disclosures of financial relationships of faculty, planners and staff involved in the development of educational content transparent to learners. All faculty participating in continuing medical education activities are expected to disclose to the program audience (1) any real or apparent conflict(s) of interest related to the content of their presentation and (2) discussions of unlabeled or unapproved uses of drugs or medical devices. AES carefully reviews reported conflicts of interest (COI) and resolves those conflicts by having an independent reviewer from the Council on Education validate the content of all presentations for fair balance, scientific objectivity, and the absence of commercial bias. The American Epilepsy Society adheres to the ACCME’s Essential Areas and Elements regarding industry support of continuing medical education; disclosure by faculty of commercial relationships, if any, and discussions of unlabeled or unapproved uses will be made. FACULTY / PLANNER BIO AND DISCLOSURES Kevin Graber, MD, Chair and Faculty Associate Professor Stanford University Kevin Graber, MD, is an associate professor of neurology and neurological sciences at Stanford University, and is director of the clinical epilepsy fellowship program at the Stanford Comprehensive Epilepsy Center. He has a long standing interest in basic mechanisms of post traumatic epilepsy, and has participated in clinical studies using vagus nerve stimulation. Dr. Graber discloses he has no financial relationships to disclose relevant to this activity. Dominique Durand, PhD, Faculty Professor Case Western Reserve University Dominique M. Durand is Professor of Biomedical Engineering and Director of the Neural Engineering Center at Case Western Reserve University in Cleveland, Ohio. He received an engineering degree from France, M.Sc. degree in Biomedical Engineering from CWRU in Cleveland OH., and a Ph.D. in Electrical Engineering from the University of Toronto. He is an IEEE Fellow, also Fellow of the AIMBE, Institute of Physics and AAAS. He serves on several editorial boards of peer-reviewed scientific journals and he is the editor-in-chief and founding editor of the Journal of Neural Engineering. His research interests are in neural engineering, neurophysiological mechanisms of epilepsy, neuromodulation for the control of epilepsy, neural interfacing with the somatic and autonomic nervous system Dr. Durand discloses he has no financial relationships to disclose relevant to this activity.

Esther Krook-Magnuson, PhD, Faculty Assistant Professor University of Minnesota Esther Krook-Magnuson, PhD, is an Assistant Professor in the Department of Neuroscience at the University of Minnesota. Dr. Krook-Magnuson uses neuromodulation techniques such as in vivo optogenetics to study neuronal circuitry in rodent models of epilepsy. Dr. Krook-Magnuson discloses she has no financial relationships to disclose relevant to this activity. Kristl Vonck, MD, PhD, Faculty Assistant Professor of Neurology Ghent University Hospital Kristl Vonck is Assistant Professor of Neurology at Ghent University Hospital, Ghent, Belgium. Her medical training was carried out at Ghent University and her PhD thesis was entitled ‘Neurostimulation for refractory epilepsy, clinical efficacy and mechanism of action’. She has held international training positions at Guy’s Hospital, London, UK; Yale University School of Medicine, New Haven, Connecticut, USA and the University of Stellenbosch, South Africa. Her research interests include neurostimulation and neurophysiological homemonitoring of neurological disorders. Dr. Vonck discloses receiving support for Consulting Fees (e.g., advisory boards): LivaNova, Medtronic; Honoraria: LivaNova, Medtronic CME REVIEWERS Lauren Frey, MD, Reviewer University of Colorado Lauren Frey, MD Associate Professor, Department of Neurology University of Colorado Dr. Frey specializes in the care of adults living with epilepsy. She has an outpatient clinic at the University of Colorado Hospital and is the MedicalDirector of the Epilepsy Monitoring Unit and an active participant in the Epilepsy Surgery program there. Dr. Frey is also the Director of the Quantitative EEG (QEEG) Laboratory and the Neurofeedback Clinic at the University of Colorado Hospital. Initially a research tool, QEEG has now been well-studied in multiple clinical settings and has a number of clinical uses in neurology, psychiatry and rehabilitation. Neurofeedback is a form of biofeedback that uses EEG to follow the brain’s electrical activity in real time. Dr. Frey discloses receiving support for Stockholder/Ownership Interest (excluding diversified mutual funds): Glaxo-Smith-Kline, Johnson and Johnson PHARMACY/NURSE PLANNERS Gigi Smith, PhD, RN, CPNP-PC: No financial relationships to disclose relevant to this activity. Dorothy Duffy, PharmD: No financial relationships to disclose relevant to this activity. AKH STAFF / AES STAFF AKH staff and planners: No financial relationships to disclose relevant to this activity. AES staff and planners: No financial relationships to disclose relevant to this activity. CLAIMING CREDIT: PHYSICIANS

Attendees who registered in the following categories may claim CME or CE for the meeting: physician, health care provider, trainee, one-day and two-day. Meeting registration includes credit claiming: there is no separate fee to claim CME/CE. Attendees will receive an emailed notification to access the online evaluation and credit claim system. The evaluation and credit claim system will remain open through Tuesday, February 28, 2017. Evaluations and credit claims must be completed by this date in order to record and receive your CME/CE certificate. Physicians can claim CME credit online at https://cme.experientevent.com/AES151/ This Link is NOT Mobile-friendly! You must access it from a laptop, desktop or tablet. How to Claim CME Credit To claim CME credits online, please follow the on-screen instructions at the above url. Log in using your last name and zip code, OR your last name and country if you’re not from the United States. All CME credits must be claimed by February 28, 2017. Questions? Contact Experient Customer Service at: 800-974-9769 or [email protected] NURSING & PHARMACY PLEASE NOTE: Providing your NABP e-profile # is required. The National Association of Boards of Pharmacy (NABP) requires that all pharmacists and pharmacy technicians seeking CE credit have an ID number issued by NABP. Pharmacy CE providers, such as AKH Inc., Advancing Knowledge in Healthcare, are required to submit participant completion information directly to NABP with your ID number and birth information to include month and date (not year) as a validation to this ID number. If you do not have an ID number (this is not your license #), go to: www.MyCPEmonitor.net

Nursing and Pharmacy credit (per session) is based on attendance as well as completion of an online evaluation form available at: WWW.AKHCME.COM/2015AES THIS MUST BE DONE BY JANUARY 15, 2017 TO RECEIVE YOUR CE CREDIT. We cannot submit credit to NABP after this date. If you have any questions, please contact AKH at [email protected].

DISCLAIMER Opinions expressed with regard to unapproved uses of products are solely those of the faculty and are not endorsed by the American Epilepsy Society or any manufacturers of pharmaceuticals.

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11/28/2016

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Introduction & Overview of Brain Stimulation in Models

and Patients: Targets and Empirical Effects

Kevin Graber, MD

Stanford University

Disclosure

None

Learning Objectives

• Understand an overview of research sites for anti-seizure stimulation and some empirical effects

• Be aware of efficacy of vagus nerve stimulation, responsive stimulation of the seizure focus, and stimulation of the anterior nucleus of the thalamus

• Only vagus nerve stimulation and responsive neural stimulation are approved by the FDA

Disclaimer

• Focal currents applied to the cortical surfacecaused involuntary movements in dogs

Fritsch G, Hitzig E. International Classics in Epilepsy and Behavior: 1870. Electric excitabilityof the cerebrum Epilepsy Behav 2009;15:123-30.

• High intensity stimulation in motor cortices of monkeys and dogs produced repetitive movementsFerrier D. Experimental Researches in Cerebral Physiology and Pathology. J Anat Physiol 1873;8:152-155

Electrical Stimulation and the Nervous systemEarly Studies: 1860’s

O1-P3-C3-F3-Fp1

O2-P4-C4-F4-Fp2

RefGnd

Undercut/Cortical Isolation Model of Posttraumatic Epileptogenesis

Graber K, Prince DA, 1999; 2006

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Partially isolated mid-marginal gyrus in cats - develops low threshold for electrically-induced after discharges (AD) and seizures

20 subthreshold stimulations/day after injury, greatly reduces chronic hyperexcitability-80% of non-stim. group have AD > 6 weeks (n=15);

threshold = 1.5 mA, 50 Hz, 1 msec pulse width-18% of subthreshold stim group have AD (n=17),

Treated with 50 Hz, 1 msec x 2 sec~400 treatments at 0.6 mA, ~400 treatments at 0.8 mA~200 treatments at 1 mA

Stimulation of the focus

Patients: Brief electrical pulses can sometimes stop after discharges, spikes and fast frequencies in patients with intracranial electrodesLesser R. et al. Neurology 1999;53:2073-81Kinoshita et al Epilepsia 2004;45:787-91.

Hippocampal Stimulation: mixed results; some positiveSee review: Sprengers et al. Cochrane Database Syst Rev 2014

Animal Studies: Examples:

Hippocampus and Amygdala: low vs. high frequency stim?-100 Hz stim to Schaffer collateral can temporarily block bicuculline induced seizures (slices)-1 Hz stim of to Schaeffer collaterals or dentate are seizure suppressive in several models-50 Hz stim suppresses spikesAlbensi et al. Brain Res 2004;998:56-4 and 2008;1226:163-3; Bragin et al. Epilepsia 2002;43suppl5:81-5; others

Piriform and Entorhinal CortexLow frequency stimulation may delay rodent kindlingYang et al. Neuroscience 2006;138:1089-96; Ghorbani et al. Neurosci Lett 2007;425:162-6; Xu et al. Epilepsia 2010;51:1861-4.

Trend toward improvementover time?

Responsive Neural Stimulation Mean disabling seizures by month

.

Martha J. Morrell Neurology 2011;77:1295-1304

Responsive Neural Stimulation

~2/3 seizure reductionsustained over time

Gregory K. Bergey et al. Neurology 2015;84:810-817

Vagus Nerve Stimulation(FDA Approved 1997)

Panebianco et al. Cochrane Database Syst Rev. 2015 Apr 3;(4):CD002896

Mechanisms of action via afferents to brain stem nuclei?• Locus Coeruleus:

e.g. direct stim reduces PTZ seizures in rats (adrenergic), delays amygdala kindling• Raphe Nuclei:

mixed results: pro- and anti-seizure (rodent PTZ and amygdala kindled seizures)• Nucleus of the Solitary Tract

Reduced seizure severity and delayed kindling in cats

Hypothalamic projections?mixed pro- and anti-seizure effects; stim of mammillary bodies increased PTZ threshold

See Graber and Fisher in Jasper’s Basic Mechanisms of the Epilepsies 2012 for review

Vagus Nerve StimulationImproved efficacy over time?

Ching et al Brit J Neurosurg 2012

95% Error Bars

Years

Englot and colleagues: Meta-analysis of 74 clinical studies, 3321 patients • Average seizure frequency was 45%; • 36% reduction at 3–12 months after surgery; 51% reduction after > 1 year of therapyJ Neurosurg 2011 Dec;115(6):1248-55

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Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy (SANTE)

Fisher et al. Epilepsia 2010;51:899-908

Cerebellum

Animal studies provide a mixed picture (pro- and anti-seizure, or ineffective), depending on site and type of stimulation (deep nuclei vs. cerebellar cortex), but some are positive.See reviews of Kroush and Koubessi Neurochir Suppl 2007;97:347-56; Fountas et al. Neurosurg Focus 2010 29:E8

In small clinical studies, mean seizure frequency reduction was -12.4% across several trials (-35% to +10.6%) but n is small.Sprengers et al Cochrane Database Syst Rev 2014

A small trial suggested generalized tonic clonic seizures continued to reduce after six months Velasco et al. 2005: 46:1071-81

Other sites for Stimulation—Animal Studies*

Caudate—mixed pro and anti-seizure (animal studies)

Globus pallidus externus – low frequency stim reduces MES and PTZ seizures; high frequency stim facilitates kindling

Substantia nigra pars reticulata: mixed results

Subthalamic nucleus: stim may reduce absence in GAERS, and clonic seizures induced by flurothyl

Centromedian nucleus of the thalamus (*small clinical studies)—nonsignificant seizure reduction (small n)

Nucleus reticularis of the thalamus—reduced hippocampal kindling

See reviews: Graber and Fisher in Jasper’s Mechanisms of the Epilepsies, 2012 and Wyckhuys at al Acta Neurol Belg 2009;109:63-80; Also: Cheng et al. Acta Pharm of Sin 2015;36:957-65; Lado et al Epilepsia 2003;44157-64; Nanobashvili et al. Neurol 2003;181:224-30.

Year pubmed.com searched 10/16/16

Questions

How does it work: is it driving, inhibiting or simply disrupting circuits and networks?

Why does stimulation seem to have better efficacy over a few months of time?

Can understandings of mechanisms yield insights that may translate into improved therapies and identification of the best targets?

Learning Objectives

• Discuss anti-seizure mechanisms of brain stimulation for medically refractory epilepsy

• Understand examples of how anti-seizure stimulation can both disrupt and drive neuronal circuits

• Become familiar with some network effects of anti-seizure stimulation

• Entertain some hypotheses of how neuronal and network changes might drive long term benefits of brain stimulation for epilepsy

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Impact on Clinical Care and Practice

• Being informed of potential anti-seizure mechanisms of brain stimulation may assist you with use of these treatment modalities for patients with medically refractory epilepsy.

The Neurobiology of Brain Stimulation in Epilepsy

Mechanisms of Seizure Control with Local Circuit StimulationDominique Durand, PhDCase Western Reserve University

Modulation of Epileptic Networks with Electrical StimulationKristl Vonck, MD, PhDGhent University

Positive Cascades: Improving Efficacy and OutcomesEsther Krook-Magnuson, PhDUniversity of Minnesota

#AES2016

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Mechanisms of seizure controlwith local circuit mechanisms

Dominique M. DurandNeural Engineering Center

Biomedical engineering Department Case Western Reserve University

Disclosure

none

Learning Objectives

• Understand the mechanisms of low frequency stimulation for seizure control

• Learn the effect of spike activity on local circuits

DBS for Epilepsy

NeuroPace.com Close loop stimulation/detection system.

Target variable.

191 patients

44% reduction and 53% after 2 years

Heck et al, Epilepsia. 2014 Mar;55(3):432-41

Recently approved by the FDA

Medtronic OpenLoop (110 patients)

Target : Anterior Nucleus of the Thalamus

40 to 50% reduction in seizure frequency

14 patients became seizure free for at least 6 months

Fisher et al, 2010 Epilepsia

Approved in Europe and conditional approval by FDA

White Matter Tract as a TARGET

Ventral Hippocampal commissure (VHC) is prominent in rats

Hypothesis: Fiber tract stimulation can inhibit seizures in rats and in humans

Effect of LFS on Seizure Frequency

• 100% responders• 90% seizure frequency reduction• Significant after-effect

Rashid S, Pho G, Czigler M, Werz MA, Durand DM Low Frequency Stimulation of Hippocampal Commissures Reduces Seizures in Chronic Rat Model of Temporal Lobe Epilepsy, 53(1):147-56, Epilepsia, 2011, PMID: 22150779

0 20 40 60 80 100 120-5

0

5

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plitu

de (

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Clinical Trial

• LFSF resulted in a significant reduction of hippocampal interictal epileptiform discharges (p = 0.001, Generalized estimating equations [GEE]-Identity Link Function)

• Seizure likelihood was reduced by 87% in 1-2 days following each 4-hr LFSF session (p = 0.001, GEE-Logit Link Function), without changes in anti-epileptic medications

• There were no complications, and hourly mini-mental status examination during stimulation showed no deviation from the baseline.

Koubeissi MZ, Kahriman E, Syed TU, Miller J, Durand DM. Low Frequency electrical stimulation of a fiber tract in temporal lobe epilepsy. Ann Neurol. 74(2):223-31 2013 23915

Slice Preparation 12-21 day-old axial rat brain slices 350 or 750 µm Consisting of:

bilateral hippocampi, HC, EC

Epilepsy Model100 µM 4-AP in warm, oxygenated ACSF

Electrical Recording (CA3, CA1)Interface chamberGlass microelectrodesExtracellular:

1-4 MΩ filled with 150mM NaCl

Intracellular: 100-140 MΩ filled with 1M KCl

Signal Acquisition100 x total signal amplificationLow-pass filtering (5 kHz)44.1 kHz sampling rate

Toprani, S and Durand DM. Fiber Tract Stimulation Can Reduce Epileptiform Activity in an in-vitro Bilateral Hippocampal Slice Preparation, Experimental Neurology, 240:28-43, 2013, PMID: 23123405

In-vitro Tests

Effect of Stimulation at1Hz (100us)

• Paired t (4) = 14.6, p < 0.0001• 100% suppression bilaterally

3 mV

1 s

Spontaneous activity from 100 µM 4-AP bath application to a combined hippocampal-EC slice of a 14 day old SD rat in vitro

Mechanisms of effect: ChannelsGABAB IPSP m/s Afterhyperpolarization

Timing

GABAA: fast IPSP, ~50 ms

GABAB: Delayed onset of 20 ms lasting hundreds of milliseconds

Fast: 1-10 ms

Medium: 50-100 ms

Slow: 1-2 s

Description

Metabotropic receptors that open GIRK channels

High receptor concentration in areas of repetitive, synchronous activity

Extrasynaptic location activated by “spillover”

Activated by calcium influx during depolarization

Limit firing frequency

Spike-frequency adaptation to sustained or repetitive depolarization

AntagonistGABAA: Bicuculline methiodine (BMI)GABAB: 2-OH-saclofen; CGP 55845

m/s AHP: clotrimazole; UCL 2077

Antagonisteffect

Nicoll, Biochemical Pharmacology, 68:1667-1674. 2004

GABAB

antagonism

Lancaster et al, J Physiol 536, 809-823, 2001

sAHPantagonism

Mechanism of Action

LTD is not involved

Slice health is maintained throughout LFS

P = 1, ANOVA

P = 0.999, ANOVA

0

20

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60

80

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Average

% of Seizure Red

uction During LFS

4‐AP

100 uM BMI

Low magnesium

450 uM saclofen

10 uM clotrimazole

LFS is not effective in seizure models that inhibit long-lasting post-stimulus hyperpolarization

Mechanisms of action: Pharmacology

3

Mechanisms of action: Electrophysiology

P < 0.005, ANOVA

P < 0.01, Tukey P < 0.01, Tukey

Key features of the “protective”

hyperpolarization

Induced by electrical stimulation

Long-lasting (~500 ms)

Recovery from hyperpolarization seems to occur at stimulus frequencies below 1 Hz

Toprani, S and Durand DM. Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation, 591(Pt 22):5765-90, J. Physiology (London), 2013, PMID: 23981713

Optical and electrical stimulation produce similar entrainment effects

TP Ladas, CC Chiang, LE Gonzalez Reyes, TS Nowak, and DM Durand, Seizure Reduction through Interneuron-mediated Entrainment using Low Frequency Optical Stimulation, j.expneurol.2015.04.001. Epub 2015 Apr 8.PMID: 25863022

Seizures

> 10 Hz

> 1 s

Variable amplitude

Evolving

Mean interictal frequency = 1.2 +/- 0.7

Mean ictal frequency = 46 +/- 34

N = 19 slices

Toprani, S and Durand DM. Experimental Neurology, 240:28-43,

2013, PMID: 23123405

Why LFS?

Kibler, A.B., et al, J Neuroscience Methods, 2012.

Zhang. M. M., et al, J Neuroscience, 2014.

Each spike: 20 µm in diameter and 200 µm high, resistance 1-2MΩ.

band-pass filter from 1 Hz to 4kHz. Gain:1000.

Sampling frequency: 10kHz.

Kindlmann, G. and et al, NIH Symposoium on Biocomputation & Bioinformation 2003.

Mapping Spontaneous activity

Axonal conduction + synaptic transmissionLow Calcium aCSF + EGTA.

Zhang. M. M., et al, J Neuroscience, 2014.

Longitudinal direction: 0.12 ± 0.03 m/s.

Transverse direction: 0.08 ± 0.04 m/s.

Propagation is non-synaptic

Gap junctionConnexin 36 (Cx36) proteins in gap junctionsare present in the area of CA3 and potentiallysensitive to mefloquine. Behrens C.J., et al, Neuroscience,

2011. Cruikshank S.J., et al, PNAS, 2004.

Mefloquine applied to the unfolded tissue at 50 µM.

Zhang M., Ladas TP, Qiu C., Shivacharan RS, Luis E. Gonzalez-Reyes, Dominique M. Durand. Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions or diffusion and is consistent with electrical field transmission, J Neuroscience, 22;34(4):1409-19, 2014.

Propagation is independent of gap junction

4

Could ionic diffusion explain it?

Zhang M., Ladas TP, Qiu C., Shivacharan RS, Luis E. Gonzalez-Reyes, Dominique M. Durand. Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions or diffusion and is consistent with electrical field transmission, J Neuroscience, 22;34(4):1409-19, 2014.

……

Cell#5

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Cell i=5

Cell i=4

6

……

Cell i=6

……

Nodei 6,jj 1

j 2

j 3

j 4

…

j 33j 34j 35

Ephaptic Field Effect

Qiu C, Shivacharan RS, Zhang M, Durand DM. Can Neural Activity Propagate by Endogenous Electrical Field? J Neurosci. 2015 Dec 2;35(48):15800-11. PMID: 26631463

30mV

50ms

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30mV

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Row B Middle Cell

Row C Middle Cell

Cell #

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Propagation across three layers (4-AP)


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Speed

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Speed vs. Factor (Mean and STD)

d=2um

d=3um

d=4um

Physiological SF Range

Mean Distance Mean Speed (WithinPhysiological SF Range)

0.23±0.096 m/s

0.10±0.048 m/s

0.05±0.020 m/s

0.12 ± 0.097 m/s

Effect of distance


(A)

(B)

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Control Group

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In‐Vitro Speed vs. Osmolarity (4‐AP) *

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2μm 3μm 4μm

Speed (% of 3μm speed)

dc‐c

In‐Silico Speed Change vs. Cell‐to‐cell distance (4‐AP/ Ca‐free channel kinetics)

Model predictions on osmolarity


Zhang. M. M., et al, unpublished data, 2014.

Source of the propagating spikes

Zhang M., Shivacharan RS, Chiang CC, , Luis E. Gonzalez-Reyes, Dominique M. Durand. Propagating Neural Source Revealed by Doppler Shift of Population Spiking Frequency, J Neuroscience, Mar 23;36(12):3495-505, 2016 PMID: 27013678

5


Source itself is moving

Zhang. M. M., et al, unpublished data, 2014.

Average speed: 0.017 ± 0.006 m/s22 sample groups from 6 different tissue.

Doppler estimated speed


Conclusions•LFS applied in-vitro and -vivo animal preparations a fiber tract shows significant reduction in interictal and ictal activity in several models of epilepsy

•LFS mechanism involve entrainment of neural activity, hyperpolarization of the membrane. Both optical and electrical stimulation produce similar effects

•LFS applied to the DHC of human patients with mesial temporal lobe epilepsy also produced significant reductions in both inter- and ictal activity

•Mechanisms involve long lasting hyperpolarizing potentials and neural entrainment at low frequency

• 4-AP-induced spontaneous propagating events move diagonally across the entire flat unfolded hippocampus at a speed of ~0.1m/s

•The source of the spikes is also moving but more slowly at ~0.01 m/s

•Both speeds are similar to what was recorded in human brain with electrode arrays

•The propagation is best explained by electrical field effect.

•Propagating spikes could be protective of seizures by inducing low frequency stimulation effects.

Collaborators and Funding

FacultyCWRU_UHZhouyan Feng Biomedical Engineering

(Zhejiang U)MaryAnn Werz (Neurology, UH)Robert Maciunas (Neurosurgery)Mohamad Koubeissi, (Neurology, UH)Hand Luders, (Neurology, UH)Jonathan Miller, (Neurology, UH)

Neural Engineering Center Staff/StudentsSaifur Rashid, MD, Research Associate, NECTina Goetz, Animal Technician, NECGerald Pho Undergraduate studentMingming Zhang, Graduate studentsSheela Toprani, MSTP studentThomas Ladas, MSTP studentLuis Gonzales, Research Associate

University Hospital HealthSystem_Goerge Washington University

Funding: NIH-NIDS, Coulter Foundation

Location of the Source Varies with Spiking Order

First spike (single spike): originates in temporal side.

Remainder of the spikes: originate in the septal side.This is true bilaterally.

Zhang. M. M., et al, J. Neuroscience, 2016.

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MODULATION OF EPILEPTICNETWORKS WITH ELECTRICAL

STIMULATIONKRISTL VONCK

Department of NeurologyReference Center for Refractory Epilepsy

Laboratory for Clinical and Experimental Neurophysiology, -biology and -psychologyGhent University Hospital, Belgium

Disclosure

Livanova, Medtronic, Cerbomed, Neurosigma

Learning Objectives

• At the end of the presentation, the learner will be able to • understand the rationale and various potential

strategies of neurostimulation for epilepsy

• discuss challenges of neurostimulation for epilepsy

Neurostimulation in epilepsy

Neurostimulation issues Neurostimulation modalities

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Vonck & Boon,Nature Rev Neurol 2015

Neurostimulation in epilepsy

Vagus nerve stimulationKV4

Vagus nerve stimulation

Cheyuo et al. J Cerebral Blood Flow & Metab 2011

KV13

Vagus nerve stimulation

www.us.livanova.cyberonics.com

KV14

Vagus nerve stimulationKV15

Slide 9

KV4 Kristl Vonck, 11/22/2016

Slide 10


Slide 11


Slide 12


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VNS implantation procedure

pictures courtesy from Ghent University Hospital

KV16

VNS KV17

VNS mechanism of action KV18

VNS incuded changes in NTKV19

VNS P3KV20

tVNS

Colzato LS et al. 2015; Wei He et al. 2012

KV21

Slide 13


Slide 14


Slide 15


Slide 16


Slide 17


Slide 18


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Deep brain stimulation and Cortical stimulation

medtronic.com

KV5

DBS and CS in epilepsy strategiesKV12

ANT DBS

Wikipedia.org

KV11

ANT DBS

Salanova et al. 2015

KV10

RNS

Bergey et al. Neurology 2015

KV9

Neurostimulation in epilepsyKV8

Slide 19


Slide 20


Slide 21


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Slide 24


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Neurostimulation ConclusionKV7

Neurostimulation ConclusionKV6

Impact on Clinical Care and Practice

• several neurostimulation therapies already available for refractory epilepsy• efficacy not dramatically different in long-term• invasiveness/side effects

• more neurostimulation therapies will soon become available• MOA investigation and biomarker identification may improve

outcome • prestimulation evaluation protocol

A prestimulation evaluation protocol for patients with drug resistantepilepsy. Carrette et al. Seizure2016

#AES2016

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Slide 26


11/28/2016

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Positive Cascades: Improving efficacy and outcomes

Esther Krook‐MagnusonUniversity of Minnesota

Department of Neuroscience

Scientific SymposiumThe Neurobiology of Brain Stimulation in Epilepsy: Targets, Networks and Cascades

Disclosures

• I have no financial conflicts of interest to disclose

Objectives

• Assess the long‐term benefits of electrical stimulation

• Consider potential mechanisms for slowly improving outcomes

• Recognize current limitations

• Discuss how optogenetics can help

Question:

Why do improvements in seizure frequency grow overtime with therapies involving electrical stimulation (VNS, DBS, ANT)?

Question:

Is this true?

Are there improvements in outcome over time?

A: Not always.

Valentin et al, Epilepsia (2013). Deep brain stimulation of the centromedian thalamic nucleus for the treatment of generalized and frontal epilepsies

Additional major caveat: drop outs

“therapeutic product ineffective”

Fisher et al, Epilepsia (2010) Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy

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Additional major caveat: drop outs

Black: Data taken from Bergey et al, 2015

Red: Very rough recalculation I made re: drop outs(assumes those include in values reported all showed median responseand all that those dropped out showed 0% sz freq change.) Black is median, Red is mean

Black data extracted from Bergey et al, Neurology (2015) Long‐term treatment with responsive brain stimulation in adults with refractory partial seizures

The point

The point is not that improvements over time is an artifact of people dropping out of the study. The point is that people dropping out of a study has to be considered. You cannot take a percent decrease at 3months and a percent decrease at 3 years and assume the same population of participants.

Question:

Is this true?


A: Yes, sometimes!

Example 1: RNS

Heck et al, Epilepsia (2014) Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trialReproduced with permission from the authors.

Example 2: SANTE


Note that downward is better in this graph.

Example 3: VNS

Pakdaman et al, Neurol Sci (2016) Vagus nerve stimulation in drug‐resistant epilepsy: the efficacy and adverse effects in a 5‐year follow‐up study in Iran

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Different time frames in each of these examples

From 6 to 26 months(0.5‐2.2years)

Upto to 4months 1‐5 years

Already flat‐lining?

Heck et al, Epilepsia (2014) Fisher et al, Epilepsia (2010) Pakdaman et al, Neurol Sci (2016)

Benefits may flat line at some point

Heck et al, Epilepsia (2014) Morrell & Halpern, Neurosurg Clin N Am (2016)

Question:

Is this true?


A: Yes, sometimes!

Question:

Why do improvements in seizure frequency grow overtime with therapies involving electrical stimulation (VNS, DBS, ANT)?

That’s a good, and unanswered, question…

Relatively Boring Possibilities

• Changes in drugs (unrelated to the stimulation itself)

• Changes in detection or stimulation (directly improving therapy)

• Natural changes in the progression not due to therapy(there’s no sham/control group for open label period)

• Maybe there’s increasing tissue damage (consider insertional effects)

It’s worth noting that it isn’t clear if the patient is getting better over time or if the effect of stimulation is improving over time.

It’s also not clear to me if it is an increase at the individual or group level.

Individual responses over time

Insertional effect, stimulation never turned on

N=1 N=8 N=2

Decreased frequency with start of stimulation Delayed benefit (6‐12mo after implantation)

Krishna et al, Neurosurgery (2016) Anterior Nucleus Deep Brain Stimulation for Refractory Epilepsy: Insights Into Patterns of Seizure Control and Efficacious Target

NB: This delayed benefit individual also shows a slow further improvement over time.

(11 of 16 considered responders)

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Additional possibilities:

• Breaking a bad loop (fewer seizures mean fewer seizures bad cascades)

• Allowing positive rewiring (fewer seizures mean positive plasticity might have a better chance)

• Direct rewiring / ‘anti‐kindling’ (maybe stimulation itself is producing LTD‐like phenomone, or strengthening of inhibitory components)

For improvements over months/years, a slow incremental process seems most likely.

If slow increase at the individual level Such a long time frame could allow larger anatomical changes to take place

Wang et al, J Neurosci (2008)

Stimulation of the anterior thalamic nucleus (in non‐epileptic mice) increases neurogenesis.

Image from: Encinas et al, J Comp Neurol (2011)Neurogenic hippocampal targets of deep brain stimulation

See also: Toda et al, J Neurosurg (2008)The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation

4 days of thalamic stimulation induces motor cortex axonal sprouting (Keller et al, J Neurophysiol (1992))

Altering activity levels and growth factors could have many downstream effects

For example, altered mTOR signaling can have non‐cell autonomous effects, alter K+ channel expression, or effect axonal sprouting.

Crino, Nature Reviews Neurology (2016)

There’s a lot we don’t know

Ultimately, the mechanisms behind any long term effects are likely to be specific to the type and location of stimulation and the type of epilepsy.

Long term benefits beyond reducing seizure frequency

• Improved quality of life

• Improved cognitive outcomes

• Improved mood

NB: these outcomes can vary by treatment strategy & epilepsy type

Room for (further) improvement

• Not all patients are helped. For some, seizure frequency gets worse.


Heck et al, Epilepsia (2014) Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial

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Room for (further) improvement

• Side effects (depending on the stimulation used)• Depression• Hoarseness, throat discomfort, coughing, etc

• Infection (battery replacement)

• Improve our understanding of stimulation mechanism of action acutely and chronically

• Improve and extend our interventions (identify new targets, improve specificity of intervention, improve knowledge of best stimulation parameters, etc)

• Improve our basic understanding of epilepsy and circuits

How do we move forward?

Optogenetics is a technique which one day may enter the clinic, but is right now useful as a tool towards answering major unresolved questions

Mini Optogenetics PrimerOptogenetics uses light sensitive proteins called opsins.

There are different types of opsins ‐‐

Excitatory channels

ChR2, ReaCh, SSFO

Inhibitory channels Inhibitory pumps G‐protein coupled and many more!

iC1C2 Arch, HR Opto‐XRs Opto‐SOS, LITEs, VP‐EL222

One can use transgenic animals and/or viral vectors to get expression of the opsin(s) of choice in select cell populations.And then use light to control them on‐demand.

Krook‐Magnuson & Soltesz, Nature Neuroscience (2015)

Optogenetics has already been successfully used experimentally in vivo• To stop seizures

• To induces seizures

• To examine what parameters matter

• To test new locations for stimulation & better understand previous locations

• To refine potential interventions

• To better understand the role of specific circuits and cell typesExample relevant references: Wykes et al (2012), Krook‐Magnuson et al (2013), Sukhotinsky et al (2013), Paz et al (2013), Krook‐Magnuson et al (2014), Berglindet al (2014), Krook‐Magnuson et al (2015), Kros et al (2015), Ladas et al (2015), Furman et al (2015), Weitz et al (2015), Lu et al (2016), Soper et al (2016)

For a review, see Krook‐Magnuson and Soltesz, Nature Neuroscience, 2015

Optogenetics example 1: Granule CellsInhibiting granule cells is sufficient to stop IHKA TLE seizures

Krook‐Magnuson, Armstrong et al. J Physiol (2015)

Optogenetics example 1: Granule Cells

Krook‐Magnuson, Armstrong et al. J Physiol (2015)

Kainate Naïve Animal:

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Optogenetics example 2: Cerebellum

Scale bars: 5s, 0.05mV

Krook‐Magnuson et aI. eNeuro (2014)Optogenetic excitation of the cerebellum.

Optogenetics example 2: Cerebellum

Krook‐Magnuson et aI. eNeuro (2014)

Optogenetic inhibition of the cerebellum was also an effective strategy!

Ivan Soltesz

Entire Soltesz Lab, including

• Caren Armstrong

• Gergely Szabo

• Mikko Oijala

• Anh Bui

• Hannah Kim

• Csaba Varga

• Judit Vargane

• Rose Zhu

• Cecilia Lozoya

Acknowledgements

Special thanks also to •Dr. Hongkui Zeng

and the Allen Brain Institute •Dr. Karl Deisseroth•Dr. Ed Boyden

Previous Funding: •Citizens United for Research in Epilepsy (CURE) Taking Flight Award (to EKM)•US National Institutes of Health grant K99NS087110 (to EKM)•the George E. Hewitt Foundation for Medical Research (to EKM & GS)•the Epilepsy Foundation (to CA)•US National Institutes of Health grant 1F31NS086429‐01 (to AB)•US National Institutes of Health grant NS074702 (to IS)

Undergraduates• Sean Lew• Dhrumil Vyas• Kyle Pendergast Current Lab Volunteers & Undergrads

‐Bin Huang‐Katerina Hoffman‐Mikaela Brandt‐Fontaine‐Joshua Cadavez‐Casey Xamonthiene‐Chris Krook‐Magnuson‐Yaroslav Pochinka‐Haruna Gutierrez‐Samuel Nelson

K‐M Lab

Funding: •MnDRIVE Neuromodulation•US National Institutes of Health grant R00NS087110, NIH R03NS098015•IETF (International Essential Tremor Foundation)Check out more at: krookmagnusonlab.com

Wilson YuPostdoc

Shane AllenProgrammer

Zach ZeidlerGrad student

Zoé Christenson WickGrad student

Caara HirschResearcher II

Jennifer ChmuraResearcher I

References• Valentin et al, Epilepsia (2013). Deep brain stimulation of the centromedian thalamic nucleus for the treatment of generalized and frontal epilepsies• Fisher et al, Epilepsia (2010). Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy• Bergey et al, Neurology (2015). Long‐term treatment with responsive brain stimulation in adults with refractory partial seizures• Heck et al, Epilepsia (2014). Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS

System Pivotal trial• Pakdaman et al, Neurol Sci (2016). Vagus nerve stimulation in drug‐resistant epilepsy: the efficacy and adverse effects in a 5‐year follow‐up study in Iran• Morrel & Halpern, Neurosurg Clin N Am (2016). Responsive Direct Brain Stimulation for Epilepsy• Krishna et al, Neurosurgery (2016). Anterior Nucleus Deep Brain Stimulation for Refractory Epilepsy: Insights Into Patterns of Seizure Control and Efficacious Target • Encinas et al, J Comp Neurol (2011). Neurogenic hippocampal targets of deep brain stimulation• Toda et al, J Neurosurg (2008). The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation• Wang et al, J Neurosci (2008). Chronic fluoxetine stimulates dendritic maturation and synaptic plasticity of newborn granule cells, a possible mechanism for antidepressant action• Crino, Nature Reviews Neurology (2016). The mTOR signalling cascade: paving new roads to cure neurological disease• Krook‐Magnuson & Soltesz, Nature Neuroscience (2015). Beyond the hammer and the scalpel: selective circuit control for the epilepsies• Wykes et al, (2012). Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy• Krook‐Magnuson, Armstrong et al, (2013). On‐demand optogenetic control of spontaneous seizures in temporal lobe epilepsy• Sukhotinsky et al, (2013). Optogenetic delay of status epilepticus onset in an in vivo rodent epilepsy model• Paz et al, (2013). Closed‐loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury• Krook‐Magnuson et al, (2014). Cerebellar Directed Optogenetic Intervention Inhibits Spontaneous Hippocampal Seizures in a Mouse Model of Temporal Lobe Epilepsy.• Berglind et al, (2014). Optogenetic inhibition of chemically induced hypersynchronized bursting in mice• Krook‐Magnuson, Armstrong et al, (2015). In vivo evaluation of the dentate gate theory in epilepsy• Kros et al, (2015). Cerebellar output controls generalized spike‐and‐wave discharge occurrence• Ladas et al, (2015). Seizure reduction through interneuron‐mediated entrainment using low frequency optical stimulation• Furman et al, (2015). Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures: Effects on cortical physiology• Weitz et al, (2015). Optogenetic fMRI reveals distinct, frequency‐dependent networks recruited by dorsal and intermediate hippocampus stimulations• Lu et al, (2016). Optogenetic dissection of ictal propagation in the hippocampal‐entorhinal cortex structures• Soper et al, (2016). Optogenetic activation of superior colliculus neurons suppresses seizures originating in diverse brain networks

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Scientific Symposium The Neurobiology of Brain Stimulation ......Neurofeedback Clinic at the University of Colorado Hospital. Initially a research tool, QEEG has now been well Initially