Where Neuromodulation and Neuropsychology Meet: Promoting Plasticity for Brain Health

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 THE BRAIN INITIATIVE

Disclosures 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)

Take Home Points 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

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

Neuromodulation Neuromodulation ECT Electroconvulsive Therapy

Magnetic Transcranial Magnetic Stimulation TMS MST Magnetic Seizure Therapy Electrical TDCS/TACS Transcranial Direct or Alternating Current ECT Electroconvulsive Therapy Other LIFUS Low Intensity Focused UltraSound Watch This Space Optical, RF and THz Stimulation Low Level Light, Near InfraRed, Millimeter waves, TeraHz

Neuromodulation Neuromodulation Promoting Brain Health Correlation Causation Treatment Cure

Neuromodulation Neuromodulation Promoting Brain Health Complementary to Neuropharm and Psychosocial Interventions 3 rd pillar of modern mental health practice Promise to turn knowledge of circuitry into therapeutic targets Psychosocial Int. Neuromodulation Pharmacology

Transcranial Magnetic Stimulation (TMS) TMS Noninvasive Uses magnetic fields No anesthesia or seizure Neuromodulation Stimulates circuits Neuroscience tool Test brain-behavior relationships Treatment tool FDA cleared for depression

From Rome ECT to to Focal Sheffield Neuromodulation TMS ECT circa 1938 TMS today

From Rome to Sheffield by way of Montreal TMS 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

TMS From Rome to Sheffield by way of Edinburgh Relationship between electricity and magnetism Electro-magnetic induction Wilder Penfield 1891-1976 James Maxwell 1831-1879

From Rome to Sheffield TMS Wilder Penfield 1891-1976 James Maxwell 1831-1879 Anthony Barker Circa 1985

From Sheffield to a TMS Clinic near you TMS

TMS and Plasticity Plasticity 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

Plasticity

All Plasticity Rights Reserved, Duke Medicine 2007 Motor Training

TMS Measures Plasticity induced by Motor Skill Learning Plasticity Play it again, Sam Pascual-Leone 1995 Casablanca Expansion of motor map following manual practice evidence of neuroplasticity

All Plasticity Rights Reserved, Duke Medicine 2007 Hand-Arm Bimanual Intensive Therapy: HABIT

TMS Measures Motor Map Expansion with Hand-Arm Bimanual Intensive Therapy in CP Plasticity Friel et al. Neurorehabil Neural Repair 2016

Paired Associative Stimulation (PAS) EMG: Motor Evoked Potential (MEP) EMG: Motor Evoked Potential (MEP) Synaptic coincidence: Hebbian plasticity Plasticity S1 S2 M Stefan et al. 2000; Ridding et al. 2001

TMS Measures Plasticity Deficit in Schizophrenia & Depression Plasticity Deficient PAS enhancement Schizophrenia Depression Frantseva et al Cerebral Cortex 2008 Player et al. Neuropsychopharm 2013

5 Hz rtms to motor cortex EMG: Motor Evoked Potential (MEP) EMG: Motor Evoked Potential (MEP) EEG: TMS-Evoked Potentials (TMS-EP) Homo-synaptic plasticity EEG: TMS-Evoked Potentials (TMS-EP) Plasticity

Repetitive TMS (rtms) Induces Plasticity Plasticity Esser et al., Brain Res Bul 2006;69:86-94

Plasticity Therapeutic Value of rtms-induced Plasticity Neuronetics 2008 Brainsway 2013 Magstim 2015 Magventure 2015 Neurosoft 2016 FDA Cleared for Depression Evidence in off-label conditions Lefaucheur et al. Clinical Neurophysiology 2014 George, Lisanby, Avery, McDonald et al. Arch Gen Psychiatry. 2010 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

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Muscle tone Resting Facilitated

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Muscle tone Eyes open/closed Eyes Open Eyes Closed Chen and Huang. NeuroReport 2018

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Muscle tone Eyes open/closed Sleep/wake TMS-Evoked Potential Massimini et al. Cogn Neurosci 2011

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Muscle tone Eyes open/closed Sleep/wake Massimini et al. Cogn Neurosci 2011

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Muscle tone Eyes open/closed Sleep/wake Attention

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Brain state can be controlled by Instruction Motor Imagery (MI) Instruction: stop contracting your thumb and just imagine the feel and sensation of the contraction Chong & Stinear J Neurophysiol 2017

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Brain state can be controlled by Instruction Stimulation Paired Pulse (pptms) Intracortical facilitation (ICF) Intracortical inhibition (ICI)

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Brain state can be controlled by Instruction Stimulation Paired Pulse (pptms) Inter-hemispheric inhibition

Rationale for Paired Intervention Paired Intervention 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 S2 M

Spike-Time Dependent Plasticity in Prefrontal Cortex Fronto-Parietal Paired Intervention Pre Global Mean Field Power Dif Parieto-Frontal Post 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 Casula et al. NeuroImage 2016;143:204

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Brain state can be controlled by Instruction Stimulation Task performance Stimulus Retention Probe Delayed Match to Sample Task Q A K + Y R P m

Rationale for Paired Intervention Paired Intervention TMS effects are state dependent Brain state can be controlled by Instruction Stimulation Task performance Cognitive/Behavioral intervention

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

Rationale for Paired Intervention Paired Intervention 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 A C D F S G Cognitive Task Activate taskrelated circuit Stimulate the circuit while it s activated Cognitive Paired Associative Stimulation (C-PAS) leverages spike-time dependent plasticity to enhance potency

Domain of Function Working Memory Paired Intervention Paired Intervention Targeting Working Memory * * * + * H * Stimulus (3 s) Retention (7 s) h Probe (3 s) ITI (5.5 s) Time Sternberg Delayed- Match-to-sample task K S Z + R M C p

Domain of Function Working Memory Target Neural Reserve & Compensation Circuit 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 Paired Intervention Paired Intervention Targeting Working Memory fmri-guided TMS Working Memory Training Simultaneous

Domain of Function Working Memory Target Neural Reserve & Compensation Circuit Paired Intervention Paired Intervention Targeting Working Memory Intervention TMS + WM-training Demonstration of target engagement Compensation Circuit expression Predicted shift in fmri network expression during WM task performance

fmri Targeted, Stereotaxic Neuronavigation, Time-locked Working Memory task TMS now Paired Intervention Individual fmri- Targeted Frameless Stereotaxy Neuro-navigation to individualized target Stimulus Retention Probe Q A K + Y R P m Time-locked to specific phase of task

TMS + Simultaneous Working Memory Training Improves Cognitive Performance Paired Network associated with better task performance Dose-finding, within-subject crossover, 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 2007;1128:120-129

TMS + Simultaneous Working Memory 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 Paired r = - 0.58, p < 0.025 Luber et al. Cereb. Cortex 2008;18:2077-85 Luber et al Cerebral Cortex 2008;18:2077-85

TMS + Simultaneous Working Memory Training Prevents Cognitive Deficits Paired Number of Lapses in Active and Sham Groups Post Sleep Deprivation* 9 8 *There are no lapses pre-sleep deprivation Mean Number of Lapses 7 6 5 4 3 2 1 p<.03 Sleep Deprivation x 60 hr Tues 8 AM Thurs 12 PM TMS TMS TMS TMS Luber et al Sleep 2013;36:857-71 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 0 Active Sham

Paired TMS + CBT Targeting Depression Paired Intervention Individualized task-activated targeting for simultaneous TMS + CBT

Paired TMS + Exposure Therapy in OCD Paired Intervention 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 rtms

Paired TMS + Exposure Therapy in PTSD Isserles et al. Brain Stimulation 2013 TMS + Trauma Exposure TMS + Neutral Exposure Sham + Trauma Exposure Paired Intervention dtms to mpfc after exposure to trauma narrative cues to block reconsolidation of trauma memory Active dtms+exposure showed efficacy Both studies used non-focal dtms coil Exposure may functionally localize the site of action

Paired TMS+Behavioral Activation to Functionally Localize Effects Paired Intervention neural ensemble at rest neural ensemble activation via behavior Represents means of providing a functional focality to nonfocal interventions, such as tdcs or dtms Neurostim effects maximized at activated neurons Stimulate the circuit while it s activated

tdcs During Group CBT for Depression Paired Intervention 2017 Study underway

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

April 9-11, 2018, Rockville, Maryland http://www.cvent.com/events/4th-annual-brain-initiativeinvestigators-meeting/event-summaryea10ec991a1f4e87a4f97f6eb8b38045.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. THE BRAIN INITIATIVE

Brain-Behavior Quantification Workshop April 8, 2018, Bethesda, Maryland https://www.eventbrite.com/e/brain-behavior-quantificationmeeting-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) THE BRAIN INITIATIVE

Join Us Job Opportunities at NIMH 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=