Where Neuromodulation and Neuropsychology Meet: Promoting Plasticity for Brain Health Sarah H

Where Neuromodulation and Neuropsychology Meet: Promoting Plasticity for Brain Health Sarah H. Lisanby, MD Director, NIMH Translational Research Division Chief, Noninvasive Neuromodulation Unit, NIMH Intramural Research Program Co-Lead, Team B, NIH BRAIN Initiative

• Patent on TMS technology, licensed to university, no royalties • Unlabeled/unapproved uses of drugs or products in this presentation – Transcranial magnetic stimulation (TMS) – Transcranial direct current stimulation (tDCS) – Magnetic Seizure Therapy (MST)

• Neuromodulation and Neuropsychology can interact by – Testing causal hypotheses about neural origins of cognitive/affective processes in health and disease – Discovering mechanisms of action of cognitive/ behavioral interventions – Developing paired interventions targeted to specific domains of function

• Neuromodulation in Brain Health • Transcranial Magnetic Stimulation (TMS) • Brain Plasticity – How to measure it – How to modulate it • Pairing Neuromodulation with Cognitive Interventions

ECT Electroconvulsive Therapy

UltraSound TMS LIFUS Watch This Space

MST Therapy Therapy Electroconvulsive ECT waves, waves, Millimeter InfraRed Near Light, Level – Low THz Stimulation Optical, RF and Therapy Seizure Magnetic TeraHz ,

Neuromodulation Neuromodulation Promoting Brain Health

Correlation Causation TreatmentCure

• Complementary to Neuropharm and Psychosocial Interventions • 3rd pillar of modern mental health practice • Promise to turn knowledge of circuitry into therapeutic targets

Pharmacology Pharmacology Psychosocial Int. PsychosocialInt. Neuromodulation

• Complementary to Neuropharm and Psychosocial Interventions • 3rd pillar of modern mental health practice • Promise to turn knowledge of circuitry into therapeutic targets

TMS

• Noninvasive – Uses magnetic fields – No anesthesia or seizure • Neuromodulation – Stimulates circuits • Neuroscience tool – Test brain-behavior relationships • Treatment tool – FDA cleared for depression

ECT circa 1938 TMS today

• Direct electrical stimulation of the cortex under local anesthesia • Discovery of the mapping of cortical areas - homonculus • Advance in surgical treatment of epilepsy by localizing seizure focus • Breakthrough, but invasive

Wilder Penfield 1891 - 1976

• Relationship between electricity and magnetism • Electro-magnetic induction

Wilder Penfield 1891 - 1976 James Maxwell 1831-1879

Wilder Penfield 1891 - 1976 James Maxwell Anthony Barker 1831-1879 Circa 1985

• Measuring plasticity – Pre/post intervention • To inform mechanisms of action – Differences between patient groups and healthy volunteers • To inform pathophysiology of disease • Modulating plasticity – Therapeutic potential as monotherapy, and – Paired with cognitive/beh intervention to achieve synergistic effects

AllPlasticity Rights Reserved, Duke Medicine 2007 TMS Measures Plasticity induced by Plasticity Motor Skill Learning

“Play it again, Sam”

Pascual-Leone 1995 Casablanca • Expansion of motor map following manual practice – evidence of neuroplasticity

AllPlasticity Rights Reserved, Duke Medicine 2007 TMS Measures Motor Map Expansion with Plasticity Hand-Arm Bimanual Intensive Therapy in CP

EMG: Motor Evoked EMG: Motor Evoked Potential (MEP) Potential (MEP)

Synaptic coincidence: Hebbian plasticity S1 M S2

AllPlasticity Rights Reserved, Duke Medicine 2007 Stefan et al. 2000; Ridding et al. 2001 TMS Measures Plasticity Deficit in Plasticity Schizophrenia & Depression

• Deficient PAS enhancement

Schizophrenia Depression

EMG: Motor Evoked EMG: Motor Evoked Potential (MEP) Potential (MEP)

EEG: TMS-Evoked EEG: TMS-Evoked Potentials (TMS-EP) Potentials (TMS-EP) Homo-synaptic plasticity

Plasticity Plasticity Repetitive TMS (rTMS) Induces Plasticity

Neuronetics Brainsway Magstim Magventure Neurosoft 2008 2013 2015 2015 2016

• FDA Cleared for Depression • Evidence in off-label conditions – Level A evidence (Definite effect) for neuropathic pain – Level B evidence (Probable effect) for negative symptoms schizophrenia – Level C evidence (Possible effect) PTSD, auditory hallucinations, cigarette craving and consumption Lefaucheur et al. Clinical Neurophysiology 2014 George, Lisanby, Avery, McDonald et al. Arch Gen Psychiatry. 2010 All Rights Reserved, Duke Medicine 2007 Neuromodulation TMS Plasticity Paired Intervention Outline

• TMS effects are state dependent – Muscle tone

Resting

Facilitated

• TMS effects are state dependent – Muscle tone – Eyes open/closed Eyes Open

Eyes Closed

Chen and Huang. NeuroReport 2018

• TMS effects are state dependent – Muscle tone – Eyes open/closed – Sleep/wake

TMS-Evoked Potential

• TMS effects are state dependent – Muscle tone – Eyes open/closed – Sleep/wake

• TMS effects are state dependent – Muscle tone – Eyes open/closed – Sleep/wake – Attention

• TMS effects are state dependent Motor Imagery (MI) • Brain state can be controlled by Instruction: – Instruction “stop contracting your thumb and just imagine the feel and sensation of the contraction”

• TMS effects are state dependent • Brain state can be controlled by – Instruction – Stimulation • Paired Pulse (ppTMS)

Intracortical facilitation (ICF)

Intracortical inhibition (ICI)

• TMS effects are state dependent • Brain state can be controlled by – Instruction – Stimulation • Paired Pulse (ppTMS)

Inter-hemispheric inhibition

• TMS effects are state dependent • Brain state can be controlled by – Instruction – Stimulation • Paired Pulse (ppTMS) • Paired Associative Stimulation (PAS)

Synaptic coincidence: Hebbian plasticity S1 M S2

• TMS effects are state dependent • Brain state can be controlled by – Instruction – Stimulation • Paired Pulse (ppTMS) • Paired Associative Stimulation (PAS) • 2-Coil Paired Associative Stimulation (PAS)

Fronto-Parietal

Parieto-Frontal

AllCasula Rights Reserved, Dukeet Medicine al. 2007NeuroImage 2016;143:204 Spike-Time Dependent Plasticity in Paired Intervention Prefrontal Cortex

Pre Fronto-Parietal

Dif

Parieto-Frontal Post GlobalMean Field Power

• Fronto-parietal PAS potentiates frontal response (consistent with LTP) • Parieto-frontal PAS depresses frontal response (consistent with LTD) • FP-PAS increases gamma oscillations in PFC • Change in GMFP correlates with inc gamma activity (p’s<0.03) • Represents a tool to sculpt plasticity with therapeutic potential

AllCasula Rights Reserved, Dukeet Medicine al. 2007NeuroImage 2016;143:204 Paired Intervention Rationale for Paired Intervention

• TMS effects are state dependent • Brain state can be controlled by – Instruction – Stimulation – Task performance

Stimulus Retention Probe Q A K + m Delayed Match Y R P to Sample Task

• TMS effects are state dependent • Brain state can be controlled by – Instruction – Stimulation – Task performance – Cognitive/Behavioral intervention

• TMS effects are state dependent • Brain state can be controlled by various means • Pairing TMS with intervention to control brain state On-line Stimulation

Computer Cognitive Paired task Response Associative keys Stimulation (C-PAS) leverages spike-time dependent plasticity to enhance potency

• TMS effects are state dependent • Brain state can be controlled by various means • Pairing TMS with intervention to control brain state Strengthen connectivity within the circuit via Hebbian Plasticity Cognitive Paired Associative Stimulation (C-PAS) Stimulate leverages spike-time A C D the circuit dependent plasticity F S G while it’s to enhance potency activated Cognitive Activate task- Task related circuit All Rights Reserved, Duke Medicine 2007 Paired Intervention Paired Intervention Targeting Working Memory • Domain of Function – Working Memory

* * * Stimulus (3 s) + * H * Retention (7 s)

Probe (3 s) h

ITI (5.5 s)

K S Z + R M C Time Sternberg Delayed- Match-to-sample p task All Rights Reserved, Duke Medicine 2007 Paired Intervention Paired Intervention Targeting Working Memory • Domain of Function – Working Memory • Target – Neural Reserve & Compensation Circuit

All Rights Reserved, Duke Medicine 2007 Paired Intervention Paired Intervention Targeting Working Memory • Domain of Function – Working Memory • Target – Neural Reserve & Compensation Circuit • Intervention – TMS + WM-training – TMS Neuronavigated to WM-resilience network (fMRI) – Simultaneous WM-Training + TMS paired delivery paradigm

fMRI-Guided TMS Working Memory Training

Simultaneous

All Rights Reserved, Duke Medicine 2007 Paired Intervention Paired Intervention Targeting Working Memory • Domain of Function – Working Memory • Target – Neural Reserve & Compensation Circuit • Intervention – TMS + WM-training • Demonstration of target engagement – Compensation Circuit expression – Predicted shift in fMRI network expression during WM task performance

All Rights Reserved, Duke Medicine 2007 fMRI Targeted, Stereotaxic Paired Intervention Neuronavigation, Time-locked Working Memory task Individual fMRI- Targeted Frameless Stereotaxy TMS now Neuro-navigation to individualized target

Stimulus Retention Probe Q A K + m Y R P

Time-locked to specific phase of task

Network associated with better task performance

• Dose-finding, within-subject cross- over, n=44 • Improved cognition (reduced RT by 50 ms, p<0.002) • Frequency-dependent (5Hz) • Site-specific (precuneus) • Context-specific (retention phase of the task) Luber et al Brain Research

All Rights Reserved, Duke Medicine 2007 2007;1128:120-129 TMS + Simultaneous Working Memory Paired Training Remediates Cognitive Performance • Site-specific cognitive enhancement with 5 Hz TMS to sleep deprivation resilience network • Degree of improvement correlated with degree of network expression

r = - 0.58, p < 0.025

Luber et al. Cereb. Cortex 2008;18:2077-85 All Rights Reserved, Duke Medicine 2007 Luber et al Cerebral Cortex 2008;18:2077-85 TMS + Simultaneous Working Memory Paired Training Prevents Cognitive Deficits Number of Lapses in Active and Sham Groups Post Sleep Deprivation*

*There are no lapses pre-sleep 9 deprivation 8

6 5

4 p<.03 3

2 Mean Number of Lapses NumberMeanof 1 Sleep Deprivation x 60 hr 0 Active Sham Tues 8 AM Thurs 12 PM TMS TMS TMS TMS • RCT of TMS+Task to resilience target (2/day x 2 days) • Prevented memory decrement and memory lapses a full 18 hrs after the last TMS • Change in fMRI network localized under TMS coil Luber et al Sleep 2013;36:857-71 All Rights Reserved, Duke Medicine 2007 Paired Intervention Paired TMS + CBT Targeting Depression

Individualized task-activated targeting for simultaneous TMS + CBT

rTMS

rTMS • dTMS to mPFC-ACC after symptom provocation more effective than sham • Sequential paradigm may work if effects of exposure persist during rTMS session Carmi et al. Brain Stimulation. 2018 All Rights Reserved, Duke Medicine 2007 Paired Intervention Paired TMS + Exposure Therapy in PTSD • dTMS to mPFC after exposure to trauma narrative cues to block reconsolidation of trauma memory • Active dTMS+exposure showed efficacy TMS + TMS + Sham + Trauma Neutral Trauma Exposure Exposure Exposure • Both studies used non-focal dTMS coil • Exposure may “functionally” localize the site of action Isserles et al. Brain Stimulation 2013 All Rights Reserved, Duke Medicine 2007 Paired TMS+Behavioral Activation Paired Intervention to Functionally Localize Effects

neural ensemble neural ensemble at “rest” activation via behavior

Represents means Neurostim effects maximized at activated neurons of providing a “functional focality” to nonfocal interventions, such Stimulate the circuit as tDCS or dTMS while it’s activated All Rights Reserved, Duke Medicine 2007 Paired Intervention tDCS During Group CBT for Depression

2017

• Study underway

Thomas Radman, PhD Valeria Martinez-Kaigi, PhD Melbaliz Velez Afanador Kevin Akhlaghi Bruce Luber, PhD Zhi-De Deng, PhD Jeena Thomas, MS

Not pictured: Will Altekruse Lori Shora, NP Yumi Yu, NP

Experimental Therapeutic & NIMH Noninvasive Pathophysiology Branch: Neuromodulation Unit (NNU), Carlos Zarate, MD Lawrence Park, MD NIMH Clinical and Nursing staff of 7SE and OP4

All Rights Reserved, Duke Medicine 2007 • April 9-11, 2018, Rockville, Maryland • http://www.cvent.com/events/4th-annual-brain-initiative- investigators-meeting/event-summary- ea10ec991a1f4e87a4f97f6eb8b38045.aspx • Target audience – BRAIN Initiative investigators; leadership from NIH, NSF, DARPA, IARPA, FDA, and non-federal organizations; members of the media, public, and Congress • Forum for discussing exciting scientific developments and potential new directions, and to identify areas for collaboration and research coordination.

• April 8, 2018, Bethesda, Maryland • https://www.eventbrite.com/e/brain-behavior-quantification- meeting-tickets-42916073130 • Goals – determine how neural circuit activity leads to complex behavior by linking precisely measured behavior with high-temporal resolution neural recordings in humans – bring researchers involved in “deep phenotyping” and invasive human recordings together to “discover how the human brain produces cognition and behavior” (BRAIN 2025 report)

• Want to influence the future scientific priorities of NIMH? • Positions now available • Apply now, through Kelly Services, at these links: • Human Subjects Program Analyst, Division of Translational Research, NIMH – https://kelly.secure.force.com/CandidateExperience/ CandExpJobDetails? id=a7V80000000TnmJEAS&searchFlag=true&tid= • Scientific Program Manager, Division of Translational Research, NIMH – https://kelly.secure.force.com/CandidateExperience/ CandExpJobDetails? id=a7V80000000TQBJEA4&searchFlag=true&tid=