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Repetitive Transcranial Magnetic Stimulation (rTMS)
Tung-Ping Su, MD Department of Psychiatry Taipei-Veterans General Hospital National Yang-Ming University Dec. 09, 2009 for IBS
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History of Neuromodulation
ECT: electroconvulsive therapy rTMS: repetitive transcranial magnetic stimulation VNS: vagus nerve stimulation DBS: deep brain stimulation MST: magnetic seizure therapy
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Electro-chemical communication
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Electrical brain: Excitatory (glutamate) and Inhibitory (GABA) neurons
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Introduction to TMS (Transcranial Magnetic Stimulation)
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First Patent of TMS for Depression--1902
The 1902 patent was issued to Pollocsek and Beer for an electromagnetic device to treat depression and neuroses. Source: Library of Mark S. George
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Early TMS Sylvanius P.Thompson and his apparatus to produce phosphenes using magnetic stimulation
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Modern TMS A.T barker with his TMS machine in 1985, which set the stage for much of today’s work with TMS
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TMS History 1995 – First therapeutic cases reported in depression (Mark George et al, Neuroreport)
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Rapid increase in publications concerning rTMS
1985: 1 1987: 7 1989: 21 1991: 97 1993: 87 1995: 134 1997: 192
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Brain Stimulation Laboratory Specialty Division, MUSC Psychiatry Dept.
• Brain Behavior Research • Translation to Therapies • Interface with CAIR Started in 1995, Assembled grant by grant
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Transcranial Magnetic Stimulation (TMS)
Time-Varying Electrical Current in a Coil Produces Focal 2 Tesla Magnetic Field Passes Unimpeded Through Skull Induces Current in Neurons Behavioral Change
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TMS is ‘Electrodeless’ Electrical Stimulation
1) Electrical Energy in Coil Induces 2) Magnetic Field (right hand Rule, Maxwell’s Equations) 3) Passes unimpeded through the Skull 4) Induces an electrical current in The brain From TMS Review in Science, June 18, 2001
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Understanding TMS Effects on Neurons
Critical Variables Include: • fiber orientation • intensity (submotor likely more inhibitory interneurons) • frequency • region • Distance into cortex
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Using Phase Maps to Determine The Exact Magnetic Field
Phase Map of Exact Magnetic Field Structural Scan with TMS Coil
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Approximate Depth Limit of Direct
Stimulation with Current TMS Coils
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TMS as a Brain Circuit Probe
Pros Relatively non-invasive Good spatial and temporal resolution Cons 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?”
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Applications of TMS Anticonvulsant(<1 HZ) or proconvulsant (fast)
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
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Sadness Induction in Healthy Adults, O15 PET, (George et al, Am J Psych, 1995)
Historical Recollection, Viewing Faces Bilateral Anterior Paralimbic Activation Unclear What’s causal and true to the emotion, what’s due to the method, and what’s epiphenomenal?
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George et al, 2000 Bio Psych
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Summary of 5 Published RCT TMS Antidepressant Trials n=86 active, 83 placebo, 2 Weeks, Prefrontal
Hamilton Depression Score Percent Improvement in
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We need to treat For more than 2 weeks
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Possible mechanism of action of TMS
Step 1: Creation of a transmembrane potential Step 2: Spatial derivative of the electric filed along the nerve Step 3: Electric field distribution and transmembrane potential
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Observable effects of TMS
Magnetic field of TMS coil Electric field induced by TMS coil Local response to TMS stimulation
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TMS as Therapy Clear and convincing data for depression
Approved in Canada, Israel US FDA approved in 2008 Need much more work on use parameters, mechanisms of action, maintenance
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How does TMS treat depression?
Hormonal - hits HPA circuit, resets thryoid, CRH, cortisol Cortical Governing - rebalances relationship between cortex and limbic Anticonvulsant - mimics brain’s antiseizure surveillance mechanism with local transmitter changes (gaba)
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Prefrontal TMS Effects on Blood Flow
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TMS in other mental disorders
Mania Catatonia Schizophrenia Obsessive-compulsive disorder PTSD Panic disorder
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TMS - Conclusions Pros - Great potential Therapeutics -
Non-invasive Potential for pushing and pulling circuits Therapeutics - Still Experimental Repeated stimulation over 2-3 weeks treats depression Problems - basic effects on neuronal function are largely unknown Intensity, frequency, location, trains, dose Currently limited to cortex
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Safety Concerns of Transcranial Magnetic Stimulation
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rTMS Parameters Important for safety
Intensity (strength of voltage; %MT) versus Frequency (how fast; Hz) Train duration (how long; sec) Intertrain interval (spacing)
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Current rTMS safety guidelines : maximum safe duration (seconds) for single trains of rTMS based on the National Institute of Neurological Disorders and Stroke experience(NINDS)
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Conclusions: side effects
Both Single-pulse TMS / rTMS can cause Headache: local discomfort muscle tension headache Temporary increase in auditory threshold without earplugs Heating of metallic objects within head,on scalp Malfunction of very close electronic/magnetic devices
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Department of Psychiatry Taipei-Veterans General Hospital
Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on Mood and Cognition Tung-Ping Su, MD Department of Psychiatry Taipei-Veterans General Hospital April, 23, 2002
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The five major regions of dysfunction in depressed brains
and Nu. Accumbens are underactivity and HPA axis: overactivity
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Frontal-subcortical circuit
Personality change Rt frontal: negative emotion governance Cingulate: Attention & mood Lt frontal: positive emotion Amygdala: Emotional recognition of faces Lt Amygdala activated during sadness Similar to seizure: Acute depression (transient sadness) Lt PFC activity increase Chronic depression Lt PFC activity decrease
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Results
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Tung-Ping Su, Chih-Chia Huang J of Clinical Psychiatry 2005:66:930-937
Add-on rTMS for medication-resistant depression: a randomized, double-blind, sham-controlled trial in Chinese patients Tung-Ping Su, Chih-Chia Huang J of Clinical Psychiatry 2005:66:
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Effect of Age, Gender, Menopausal Status, and Ovarian Hormonal Level
on rTMS in Treatment-Resistant Depression Chih-Chia Huanga, I-Hua Weid, Yuan-Hwa Choua, Tung-Ping Su Psychoneuroendocrinology, 2007
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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 N=47 Responder: 23 Non-responder: 24 Pearson’s correlation test r = P = 0.061 N=16 Responder: 11 Non-responder: 5 N=31 Responder: 12 Non-responder: 19 Pearson’s correlation test r = 0.35 P = 0.184 Pearson’s correlation test r = P < 0.001 N=17 Responder: 12 Non-responder: 5 N=14 Responder: 0 Non-responder: 14 Pearson’s correlation test r = 0.117 P = 0.691 Pearson’s correlation test r = P = 0.207
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Fig. 2 Percentage HAM-D reduction vs. E2/P ratio
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Percentage HAM-D reduction
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 -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.
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Prediction of antidepressant efficacy of a 2-week add-on trial rTMS in Medication-Resistant Depression: a 18F-FDG PET study Tung-Ping Su, MD Department of Psychiatry National Yang-Ming University Taipei Veterans General Hospital 2nd WCAP, Taipei, Nov. 9, 2009 54
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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).
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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 MRD patients. Is underlying pathophysiology of MRD different from other depressives ? Compare with previous hypothesis of depression 56
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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)
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Setting for Repetitive transcranial stimulation,
r-TMSm using Brainsight (MRI DLPFC localization)
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Study design 59
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Results 60
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Treatment-Resistant MDD (20) vs. NC (20)
NC > MDD NC < MDD ACC bilaterl 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 61
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Treatment-Resistant MDD (20) vs. NC (20) A cortico-limbal dysregulation
Bil DLPFC Bil OFC Bil Med. PFC Bil Ant. Insula - IFA Anterior Cingulum Middle Cingulum Bil Amygdala Bil Putamen/GP Bil Insula Hippo/Parahip Raphe nu. Cerebellum Compatible with prior hypothesis of depression 62
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Responder(13) vs. Non-Responder(7)
Responders Bil DLPFC (BA 9) Bil OFC Bil Med. PFC (BA 6d) Anterior Cingulum Middle Cingulum Bil Uncus/Fusiform Bil Srtiatum Bil Insula Hippo/Parahip Raphe nu. Cerebellum 在voxel-level下,responder跟nonresponder比較起來,responder表現出來的都來得比較沒那麼差 (在前一張slide中所指出MDD vs NC所不同的點) voxel level, k=300, uncontrolled p <0.05 63
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Less hypoactive in ACC, bilateral medial prefrontal gyrus
Responder > N-R Stricter threshold using cluster level, only ACC and bilateral medial PFC has significant between-group differences. 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 64
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Less hyperactive in left hippocampus and fusiform gyrus
Responder < N-R Stricter threshold using cluster level, only left hippocampus and left fusiform gyrus have significant between-group differences. 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 65
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Pre-tx areas predicting treatment responses (≥50% decreases in HDRS)
ACC Left fusiform/hippocamcal gyri Correlation analysis: Hamilton rating scale improvement 50% decreases with ACC and Left hippocampus/fusiform gyrus. Higher pre-tx metabolism in ACC Cluster level, k=1000, uncorrected, p = (trend-significance) Lower pre-tx metabolism in Left fusiform/hippo/parahippocamcal gyri Cluster level, k=1000, uncorrected, p = 0.004 (Paper in submission, 2009) 66
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Summary Medicated 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 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 DLPFC By reverse metabolism of L DLPFC activities only ? Might have an effect of normalizing limbal-cortical dysregulation Non-Responder Responder 67
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Responder TMS治療前和Normal做比較 Responder TMS治療後和Normal做比較 Remark:
Normal>MDD_Responder Normal<MDD_Responder 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)。
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1. Non-Responder 在 TMS治療後,和Normal比較的pattern更接近Responder。(??)
Normal>Non-responder Normal<Non-responder 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。(??)
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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。
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Important Points There is an explosion of new techniques for stimulating the brain (TMS, MST, VNS and DBS) These new tools will drastically change neuropsychiatry research and therapies in the next 20 years
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Outline ECT MST TMS VNS DBS Conclusions
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Ascending Vagal projections
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Vagus nerve Afferent connections
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Effects of vagus Nerve stimulation on the brain
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Thank you for your attention
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