1. 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

2. History of Neuromodulation
ECT: electroconvulsive therapy
rTMS: repetitive transcranial magnetic stimulation
VNS: vagus nerve stimulation
DBS: deep brain stimulation
MST: magnetic seizure therapy

3. Electro-chemical communication

4. Electrical brain:
Excitatory (glutamate)
and
Inhibitory (GABA)
neurons

5. Introduction to TMS (Transcranial Magnetic Stimulation)

6. 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

7. Early TMS
Sylvanius P.Thompson and his apparatus to produce phosphenes using magnetic stimulation

8. Modern TMS
A.T barker with his TMS machine in 1985, which set the stage for much of today’s work with TMS

9. TMS History
1995 – First therapeutic cases reported in depression (Mark George et al, Neuroreport)

10. Rapid increase in publications concerning rTMS
1985: 1
1987: 7
1989: 21
1991: 97
1993: 87
1995: 134
1997: 192

11. Brain Stimulation Laboratory Specialty Division, MUSC Psychiatry Dept.
• Brain Behavior Research
• Translation to Therapies
• Interface with CAIR
Started in 1995,
Assembled grant by grant

12. 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

17. 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

19. Understanding TMS Effects on Neurons
Critical Variables Include:
• fiber orientation
• intensity (submotor
likely more inhibitory
interneurons)
• frequency
• region
• Distance into cortex

20. Using Phase Maps to Determine The Exact Magnetic Field
Phase Map of Exact Magnetic
Field
Structural Scan with TMS Coil

21. Approximate Depth Limit of Direct
Stimulation with Current TMS Coils

23. 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?”

24. 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

25. 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?

26. George et al, 2000 Bio Psych

28. Summary of 5 Published RCT TMS Antidepressant Trials n=86 active, 83 placebo, 2 Weeks, Prefrontal
Hamilton Depression Score
Percent Improvement in

29. We need to treat
For more than 2 weeks

30. 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

31. Observable effects of TMS
Magnetic field of TMS coil
Electric field induced by TMS coil
Local response to TMS stimulation

32. 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

33. 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)

34. Prefrontal TMS Effects on Blood Flow

35. TMS in other mental disorders
Mania
Catatonia
Schizophrenia
Obsessive-compulsive disorder
PTSD
Panic disorder

36. 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

37. Safety Concerns of Transcranial Magnetic Stimulation

38. rTMS Parameters Important for safety
Intensity (strength of voltage; %MT)
versus
Frequency (how fast; Hz)
Train duration (how long; sec)
Intertrain interval (spacing)

39. 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)

40. 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

41. 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

42. The five major regions of dysfunction in depressed brains
and Nu. Accumbens are underactivity
and HPA axis: overactivity

43. 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

44. Results

45. 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:

50. 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

51. 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

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

53. 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.

54. 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

55. 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).

56. 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

57. 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)

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

59. Study design 59

60. Results 60

61. 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

62. 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

63. 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

64. 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

65. 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

66. 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

67. 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

68. 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)。

69. 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。(??)

70. 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。

71. 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

72. Outline
ECT
MST
TMS
VNS
DBS
Conclusions

75. Ascending
Vagal
projections

76. Vagus nerve
Afferent
connections

77. Effects of vagus
Nerve stimulation on
the brain

88. Thank you for your attention