NeuromodulationNeuromodulation

Professor Tung-Ping Su, MDProfessor Tung-Ping Su, MD

Department of Psychiatry, Faculty of MedicineDepartment of Psychiatry, Faculty of Medicine

National Yang-Ming UniversityNational Yang-Ming University

Taipei-Veterans General HospitalTaipei-Veterans General Hospital

Dec. 2, 2014 for IBS teachingDec. 2, 2014 for IBS teaching

• Major depressive disorder: Unipolar depression A chronic illness With many relapses/recurrences

Background

• Relapse/Recurrence in depression: Frequent observations Residual symptoms in remission: poorer outcome

Higher rate of relapse or recurrence

Recurrence ratesUp to 50% : unremitting or recurrence

(Eaton. AGP, 2008)

Background

(Judd et al., JAD, 1998; Fava. Biol Psychiatry, 2003)

• Long-term antidepressants treatment : Reduce the odd of relapse by 70% (vs. placebo)Reduce recurrence and to prolong the time to recurrence (Lepine et al., AJP, 2004) (Montgomery et al., JCP, 2004)

Remission or Response

Depression

Normal Mood

Responders

Medication Started

Non-responders

Remission/Recovery

Time

Partial responders

Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991;48(9):851-5.

50 %50 %

The fact…• In clinical practice: (25-32% remission)

Few could achieve complete remission (Moller H. J. et al., World J Biol Psychiatry, 2008)

• Approximately one third of patients do not respond to antidepressants

• Up to another one third of patients show only a partial response

(Bschor. Therapy-Resistant Depression Review. Expert Rev. Neurother, 2010)

Switching rates over time (Cohort 2000)

History of NeuromodulationHistory of Neuromodulation

• ECT: electroconvulsive therapyECT: electroconvulsive therapy

• rTMS: repetitive transcranial rTMS: repetitive transcranial magnetic stimulationmagnetic stimulation

• VNS: vagus nerve stimulationVNS: vagus nerve stimulation

• DBS: deep brain stimulationDBS: deep brain stimulation

• MST: magnetic seizure therapyMST: magnetic seizure therapy

Electro-chemical communicationElectro-chemical communication

100 billion Neurons with100 trillionconnection sense,analysis and respond to theenvironment.

It all boil down to electrical and chemicalcommunication.

Electrical brain:

Excitatory (glutamate) and Inhibitory (GABA)neurons

OutlineOutline• ECTECT• MSTMST• TMSTMS• VNSVNS• DBSDBS• ConclusionsConclusions

Introduction to TMSIntroduction to TMS(Transcranial Magnetic (Transcranial Magnetic

Stimulation)Stimulation)

First Patent of TMS First Patent of TMS

for Depression--1902for Depression--1902

• The 1902 patent was issued The 1902 patent was issued to Pollocsek and Beer for an to Pollocsek and Beer for an electromagnetic device to electromagnetic device to treat depression and treat depression and neuroses.neuroses.

• Source: Library of Mark S. GeorgeSource: Library of Mark S. George

Early TMS Early TMS

• Sylvanius Sylvanius P.Thompson and his P.Thompson and his apparatus to produce apparatus to produce phosphenes using phosphenes using magnetic stimulationmagnetic stimulation

Modern TMSModern TMS

• A.T barker with his A.T barker with his TMS machine in TMS machine in 1985, which set the 1985, which set the stage for much of stage for much of todaytoday’’s work with s work with TMSTMS

TMS HistoryTMS History

• 19951995 –– First therapeutic cases reported in First therapeutic cases reported in depression depression (Mark George et al, Neuroreport)(Mark George et al, Neuroreport)

Transcranial Magnetic Stimulation (TMS)

Time-Varying Electrical Current in a Coil Produces

Focal 2 Tesla Magnetic FieldPasses Unimpeded ThroughSkull

Induces Current in Neurons

Behavioral Change

TMS is TMS is ‘‘ElectrodelessElectrodeless’’ Electrical Stimulation Electrical Stimulation

1) Electrical Energy in CoilInduces2) Magnetic Field (right handRule, Maxwell’s Equations)3) Passes unimpeded through theSkull4) Induces an electrical current inThe brainFrom TMS Review in Science, June 18, 2001

Understanding TMS Effects on NeuronsUnderstanding TMS Effects on Neurons

Critical Variables Include:• fiber orientation• intensity (submotor likely more inhibitory interneurons)• frequency• region• Distance into cortex

Using Phase Maps to Determine The Using Phase Maps to Determine The Exact Magnetic FieldExact Magnetic Field

Structural Scan with TMS Coil Phase Map of Exact Magnetic Field

Approximate Depth Limit of Direct Approximate Depth Limit of Direct Stimulation with Current TMS CoilsStimulation with Current TMS CoilsApproximate Depth Limit of Direct Approximate Depth Limit of Direct Stimulation with Current TMS CoilsStimulation with Current TMS Coils

TMS as a Brain Circuit ProbeTMS as a Brain Circuit Probe• ProsPros

– Relatively non-invasive– Good spatial and temporal resolution

• ConsCons– Unclear knowledge of effects on neurons (local

or secondary), especially as a function of• Frequency,• Duration• Brain region• Intensity

Hughlings Jackson - “Is TMS irritative (augment) or ablative?”

Applications of TMSApplications of TMS• Anticonvulsant(<1 HZ) or proconvulsant (fast: 5-20 Hz)

• Mapping the cortex of the brain

• Probing neural networks by stimulation or inhibition at different places and times

• Measuring cortical excitability in health and in disease, and in response to drugs

• Modulating brain function to study the pathophysiology of a variety of neuropsychiatric conditions, and possibly treat them

• Sadness Induction in Healthy Adults, O15 PET, Sadness Induction in Healthy Adults, O15 PET, (George et al, Am J Psych, (George et al, Am J Psych, 1995)1995)

– Historical Recollection, Viewing Faces– Bilateral Anterior Paralimbic Activation

• Unclear Unclear – What’s causal and true to the emotion, – what’s due to the method, and – what’s epiphenomenal?

Possible mechanism of action of Possible mechanism of action of TMSTMS

• Step 1: Creation of a transmembrane Step 1: Creation of a transmembrane potentialpotential

• Step 2: Spatial derivative of the electric field Step 2: Spatial derivative of the electric field along the nervealong the nerve

• Step 3: Electric field distribution and Step 3: Electric field distribution and transmembrane potentialtransmembrane potential

Observable effects of TMSObservable effects of TMS

• Magnetic field of TMS coilMagnetic field of TMS coil

• Electric field induced by TMS coilElectric field induced by TMS coil

• Local response to TMS stimulationLocal response to TMS stimulation

TMS as TherapyTMS as Therapy

• Clear and convincing data for depressionClear and convincing data for depression– Approved in Canada, Israel– US FDA approved in 2008 for NeuroStar – Taiwan Not approved yet for Magstium

• Need much more work on use Need much more work on use parameters, mechanisms of action, parameters, mechanisms of action, maintenancemaintenance

How does TMS treat depression?How does TMS treat depression?

• HormonalHormonal - hits HPA circuit, resets - hits HPA circuit, resets thryoid, CRH, cortisolthryoid, CRH, cortisol

• Cortical Governing - Cortical Governing - rebalances rebalances relationship between relationship between cortex and limbiccortex and limbic

• AnticonvulsantAnticonvulsant - mimics brain - mimics brain’’s s antiseizure surveillance mechanism with antiseizure surveillance mechanism with local transmitter changes (gaba) local transmitter changes (gaba)

Prefrontal TMS Effects on Prefrontal TMS Effects on Blood FlowBlood Flow

TMS in other mental disordersTMS in other mental disorders

• ManiaMania

• CatatoniaCatatonia

• SchizophreniaSchizophrenia

• Obsessive-compulsive disorderObsessive-compulsive disorder

• PTSDPTSD

• Panic disorderPanic disorder

• AutismAutism

TMS - ConclusionsTMS - Conclusions

• Pros - Great potentialPros - Great potential– Non-invasive– Potential for pushing and pulling circuits

• Therapeutics - Therapeutics - – Still Experimental– Repeated stimulation over 2-3 weeks treats depression

• Problems - Problems - basic effectsbasic effects on neuronal function are on neuronal function are largely unknownlargely unknown– Intensity, frequency, location, trains, dose– Currently limited to cortex

Safety Concerns of Safety Concerns of Transcranial Magnetic StimulationTranscranial Magnetic Stimulation

Conclusions: side effectsConclusions: side effects

• Both Single-pulse TMS / rTMSBoth Single-pulse TMS / rTMS can cause can cause• Headache:Headache:

local discomfortlocal discomfort

muscle tension headachemuscle tension headache• Temporary Temporary increase in auditory thresholdincrease in auditory threshold without without

earplugsearplugs• Heating of metallic objectsHeating of metallic objects within head,on scalp within head,on scalp• Malfunction Malfunction of very close electronic/magnetic devicesof very close electronic/magnetic devices

NeuroStar

Setting for Repetitive transcranial stimulation, r-TMSusing Brainsight(MRI DLPFC localization)

Magstim

The five major regions of dysfunction in depressed brains

and Nu. Accumbens are underactivity and HPA axis: overactivity

Frontal-subcortical circuit

governance

• Lt frontal: positive emotion

• Rt frontal: negative emotion

Acute depression (transient sadness)Lt PFC activity increase

Chronic depressionLt PFC activity decrease

• Similar to seizure:

Cingulate:Attention& mood

Amygdala:Emotional recognition of facesLt Amygdala activated during sadness

• Personality change

• ResultsResults

Hamilton Depressive Rating Scale

0

5

10

15

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25

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35

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Baseline 1st week 2nd week 3rd week 4th week

Time

Add-on rTMS for medication-resistant Add-on rTMS for medication-resistant depression:depression:

a randomized, double-blind, sham-a randomized, double-blind, sham-controlled trial in Chinese patientscontrolled trial in Chinese patients

Tung-Ping Su, Chih-Chia HuangTung-Ping Su, Chih-Chia Huang

J of Clinical Psychiatry 2005:66:930-937J of Clinical Psychiatry 2005:66:930-937

Significant improvement in HAMD-17 score with

2-week active rTMS (20Hz&5Hz) VS. sham Tx

ANOVA-R GPx time F=4.8, p<0.01

Effect of Age, Gender, Menopausal Status, and Ovarian Hormonal Level

on rTMS in Treatment-Resistant Depression

Chih-Chia Huanga, I-Hua Weid, Yuan-Hwa Chou, Tung-Ping Su

Psychoneuroendocrinology, 2007

post-menopausal women

Age

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N=47

Responder: 23

Non-responder: 24

N=17

Responder: 12

Non-responder: 5

N=14

Responder: 0

Non-responder: 14

N=16

Responder: 11

Non-responder: 5

N=31

Responder: 12

Non-responder: 19

Pearson’s correlation test

r = -0.276

P = 0.061

Pearson’s correlation test

r = -0.322

P = 0.207

Pearson’s correlation test

r = 0.35

P = 0.184

Pearson’s correlation test

r = 0.117

P = 0.691

Pearson’s correlation test

r = -0.646

P < 0.001

men

Age

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Fig. 1 Relationship of reduction of percent HAM-D Score with Age in the Whole Group of Depressed Patients, between Genders, and Premenopausal and Postmenopausal Females

all subjects

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Fig. 2 Percentage HAM-D reduction vs. E2/P ratio

N=16

r = -0.11

P = 0.968

N=17

r = 0.563

P = 0.019

N=14

r = 0.158

P = 0.590

N=31

r = 0.527

P = 0.002

men

E2/P ratio

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Table 3 Stepwise Multiple Linear Regression Analysis of Factors Correlated to Percentage HAM-D Reduction After rTMS in Female Patients

Variables

Percentage HAM-D reduction

β t P Adjusted r2

Menopausal status(pre=1; post = 0)

0.728 6.334 <0.001 0.525

P -0.266 -2.350 0.026 0.630

E2/P ratio 0.257 2.248 0.033 0.677

LOCF was applied.E2, estradiol; P, progesterone; pre, premenopausal status; post, postmenopausal status.

Prediction of antidepressant efficacy of a 2-week add-on trial rTMS

in Medication-Resistant Depression: a 18F-FDG PET study

Tung-Ping Su, MDDepartment of Psychiatry

National Yang-Ming UniversityTaipei Veterans General Hospital

2nd WCAP, Taipei, Nov. 9, 2009

Introduction

• Impaired reciprocal function relationship of limbic amygdala &

hippocampus - cortical dorsolateral, medical and ventral prefrontal circuit—thought to correlate with emotional dysregulation and depression– Inconsistent results from imaging studies (PET or SPECT) in exact

location and direction of regional cerebral metabolism in depression, suggesting possible roles of using pre-Tx regional metabolic activities in various parts of the brain to predict tx response from antidepressants (Mayberg 2000, Little 2005,Milak, 2009)

– Medication-resistant depression (MRD) is a unique model for study as if underlying pathophysiology is different from pharmaco-responsive major depression (MDD).

Hypotheses and Aims

• Responders are different from non-responders in resting brain metabolism– Differences may account for core antidepressant mechanism of

rTMS

• Pre-rTMS regional brain glucose uptake in DLPFC, ACC, hippocampus and brainstem may – Predict rTMS effectiveness in medicated TRD patients.

• Is underlying pathophysiology of TRD different from other depressives ?– Compare with previous hypothesis of depression

Methods• Criteria for MRD (N=20)

– MDD dx through MINI and history taking– MRD dx, a hx of failing to respond to at least 2 different antidepressant trials and

with severity of scores >=18 of Hamilton Depression Rating Scale (HRDS-17)– No alcohol or substance abuse history, no major medical and neurological

disorders, no comorbidity of schizophrenia, bipolar disorder, OCD, PTSD or cluster–B personality d/o

• A 2-week of daily rTMS administration with continuation of the current antidepressant medications

• Responders (HDRS-17 score >= 50% reduction) vs. non-responders• PET and MRI procedures

– Healthy control subjects (N=20)

Setting for Repetitive transcranial stimulation, r-TMSm using Brainsight(MRI DLPFC localization)

Study designStudy design

ResultsResults

Treatment-Resistant MDD (20) vs. NC (20)Treatment-Resistant MDD (20) vs. NC (20)at baseline at baseline

NC < MDDNC > MDD

•Global variance across scans: removed by analysis of covariance (ANCOVA)•Btw-gp comparison: ANCOVA, Controlling for age and gender•Cluster level, corrected p <0.001

Treatment-Resistant MDD (20) vs. NC (20) Treatment-Resistant MDD (20) vs. NC (20) A cortico-limbal dysregulation (baseline)A cortico-limbal dysregulation (baseline)

• MDDMDDBil DLPFCBil DLPFCBil OFCBil OFCBil Med. PFC Bil Med. PFC Bil Ant. Insula - IFABil Ant. Insula - IFAAnterior CingulumAnterior CingulumMiddle CingulumMiddle Cingulum

Bil AmygdalaBil AmygdalaBil Putamen/GP Bil Putamen/GP Bil InsulaBil InsulaHippo/ParahipHippo/ParahipRaphe nu. Raphe nu. CerebellumCerebellum

Responder(13) Responder(13) vs.vs. Non-Responder(7)Non-Responder(7)at baselineat baseline

• RespondersResponders

Bil DLPFC (BA 9)Bil DLPFC (BA 9)

Bil OFCBil OFC

Bil Med. PFC (BA 6d)Bil Med. PFC (BA 6d)

Anterior CingulumAnterior Cingulum

Middle CingulumMiddle Cingulum

Bil Uncus/FusiformBil Uncus/Fusiform

Bil Srtiatum Bil Srtiatum

Bil InsulaBil Insula

Hippo/ParahipHippo/Parahip

Raphe nu. Raphe nu.

Cerebellum Cerebellum

•voxel level, k=300, uncontrolled p <0.05

Less hypoactive in ACC, bilateral medial prefrontal Less hypoactive in ACC, bilateral medial prefrontal gyrus at baselinegyrus at baseline

Responder > Non-responder

•Global variance across scans: removed by analysis of covariance (ANCOVA)•Btw-gp comparison: ANCOVA, Controlling for age and gender•Using NC vs. MDD mask•Cluster level, k=2000,uncorrected p <0.05

Less hyperactive in Less hyperactive in left hippocampus and fusiform gyrus left hippocampus and fusiform gyrus

at baselineat baselineResponder < Non-responder

•Global variance across scans: removed by analysis of covariance (ANCOVA)•Btw-gp comparison: ANCOVA, Controlling for age and gender•Using MDD vs NC mask•Cluster level, k=1000,uncorrected p <0.10

Pre-tx areas predicting treatment responses Pre-tx areas predicting treatment responses (≥50% decreases in HDRS)(≥50% decreases in HDRS)

•Higher pre-tx metabolism in ACC •Cluster level, k=1000, uncorrected, p = 0.089 (trend-significance)

•Lower pre-tx metabolism in Left fusiform/hippo/parahippocamcal gyri •Cluster level, k=1000, uncorrected, p = 0.004

ACC Left fusiform/hippocamcal gyri

(Paper in submission, 2009)

SummarySummary• Medicated M-R MDD patients vs. normal subjectsMedicated M-R MDD patients vs. normal subjects

– Lower metabolism in both L and R DLPFC

– Also in the status of limbic-cortical dysregulation

• Patients who responded well to rTMS Patients who responded well to rTMS – Not that severe in limbic-corticol dysregulation

– Higher pre-tx ACC and lower left Hippocampal/Fusiform activities could predict rTMS responses

• rTMS mechanism: stimulate L DLPFCrTMS mechanism: stimulate L DLPFC– By reverse metabolism of L DLPFC activities only ?

– Might have an effect of normalizing limbal-cortical dysregulation

Responder Non-Responder

ResponderTMS治療前和 Normal做比較

Normal>MDD_Responder Normal<MDD_Responder

ResponderTMS治療後和 Normal做比較

Normal>MDD_Responder Normal<MDD_Responder

Remark:1. TMS 治療後， Responder 和 Normal 在大腦前方的活性差異消失。2. Responder 和 Non-responder 在 TMS 治療前，差異度最大的地方是在大腦前區的活性 ( 和Normal 比較 ) 。

Non-responderTMS治療前和 Normal做比較

Normal>Non-responder Normal<Non-responder

Non-responderTMS治療後和 Normal做比較

Normal>Non-responder Normal<Non-responder

Remark:1. Non-Responder 在 TMS 治療後，和 Normal 比較的 pattern 更接近 Responder 。 (??)

Non-responder (Paired t test)TMS 治療前 >TMS 治療後 TMS 治療前 <TMS 治療後

Remark: Non-responder 在 TMS 治療前後， cortex 活性差異不大。

Important PointsImportant Points

There is an explosion of new There is an explosion of new techniques for stimulating the brain techniques for stimulating the brain (TMS, MST, VNS and DBS)(TMS, MST, VNS and DBS)

These new tools will drastically change These new tools will drastically change neuropsychiatry researchneuropsychiatry research and and therapies in the therapies in the next 20 yearsnext 20 years

OutlineOutline• ECTECT• MSTMST• TMSTMS• VNSVNS• DBSDBS