Neuromodulation
Professor Tung-Ping Su, MD
Department of Psychiatry, Faculty of Medicine
National Yang-Ming University
Taipei-Veterans General Hospital
Dec. 2, 2014 for IBS teaching
Background
• 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
(Judd et al., JAD, 1998; Fava. Biol Psychiatry, 2003)
 Recurrence rates
Up to 50% : unremitting or recurrence
(Eaton. AGP, 2008)
• 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
Normal Mood
Remission/Recovery
Responders
Medication
Started
Partial responders
50 %
Non-responders
Depression
Time
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.
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)
四組用藥情況從MDD->BPD的改變率
30
25
改變率
20
沒用藥
15
好治療
難治療
換一次
10
5
0
0
2000
2001
2002
2003
門診年
2004
2005
2006
2007
History of Neuromodulation
• ECT: electroconvulsive therapy
• rTMS: repetitive transcranial
magnetic stimulation
• VNS: vagus nerve stimulation
• DBS: deep brain stimulation
• MST: magnetic seizure therapy
Electro-chemical communication
100 billion
Neurons with
100 trillion
connection sense,
analysis and
respond to the
environment.
It all boil down to
electrical and
chemical
communication.
Electrical brain:
Excitatory (glutamate)
and
Inhibitory (GABA)
neurons
Outline
•
•
•
•
•
•
ECT
MST
TMS
VNS
DBS
Conclusions
Introduction to TMS
(Transcranial Magnetic
Stimulation)
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
Early TMS
• Sylvanius
P.Thompson and his
apparatus to produce
phosphenes using
magnetic stimulation
Modern TMS
• A.T barker with his
TMS machine in
1985, which set the
stage for much of
today’s work with
TMS
TMS History
• 1995 – First therapeutic cases reported in
depression (Mark George et al, Neuroreport)
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
TMS is
‘Electrodeless’ Electrical Stimulation
From TMS Review in Science, June 18, 2001
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
Understanding 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
Exact Magnetic Field
Structural Scan with TMS Coil
Phase Map of Exact Magnetic
Field
Approximate Depth Limit of Direct
Stimulation with Current TMS Coils
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?”
Applications 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,
(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?
Possible mechanism of action of
TMS
• Step 1: Creation of a transmembrane
potential
• Step 2: Spatial derivative of the electric field
along the nerve
• Step 3: Electric field distribution and
transmembrane potential
Observable effects of TMS
• Magnetic field of TMS coil
• Electric field induced by TMS coil
• Local response to TMS stimulation
TMS as Therapy
• Clear 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
parameters, mechanisms of action,
maintenance
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)
Prefrontal TMS Effects on
Blood Flow
TMS in other mental disorders
•
•
•
•
•
•
•
Mania
Catatonia
Schizophrenia
Obsessive-compulsive disorder
PTSD
Panic disorder
Autism
TMS - Conclusions
• Pros - Great potential
– 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
Safety Concerns of
Transcranial Magnetic Stimulation
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
NeuroStar
Magstim
Setting for Repetitive
transcranial
stimulation,
r-TMS
using Brainsight
(MRI DLPFC localization)
The five major regions of dysfunction in depressed brains
and Nu. Accumbens are underactivity
and HPA axis: overactivity
Frontal-subcortical circuit
• Rt frontal:
negative emotion
governance
• Personality
change
Cingulate:
• Lt frontal:
positive emotion
• Similar to seizure:
Acute depression (transient sadness)
Lt PFC activity increase
Chronic depression
Lt PFC activity decrease
Attention
& mood
Amygdala:
Emotional
recognition
of faces
Lt Amygdala
activated during
sadness
Hamilton Depressive Rating Scale
40
35
30
• Results
25
20
15
10
5
0
Baseline
1st week
2nd week
Time
3rd week
4th week
Add-on rTMS for medication-resistant
depression:
a randomized, double-blind, shamcontrolled trial in Chinese patients
Tung-Ping Su, Chih-Chia Huang
J of Clinical Psychiatry 2005:66:930-937
Significant improvement in HAMD-17 score with
2-week active rTMS (20Hz&5Hz) VS. sham Tx
HAMD -17
30
26.5
25
23.2
22.7
20
19
18.8
20 Hz (N=10)
15.5
15
5 Hz (N=10)
13.2
10
12.3
sham (N=10)
9.8
5
0
Baseline
Week1
Week2
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
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
percentage HAM-D reduction
100
80
N=47
60
Responder: 23
Non-responder: 24
40
20
Pearson’s correlation test
r = -0.276
0
P = 0.061
-20
20
30
40
50
60
70
80
Age
men
women
Responder: 11
Non-responder: 5
Pearson’s correlation test
r = 0.35
P = 0.184
100
percentage HAM-D reduction
N=16
percentage HAM-D reduction
100
80
60
40
20
0
-20
20
30
40
50
N=31
80
Responder: 12
60
Non-responder: 19
40
Pearson’s correlation test
20
r = -0.646
0
60
70
80
P < 0.001
-20
20
30
40
Age
100
80
80
r = -0.322
P = 0.207
80
N=14
60
40
20
0
-20
20
30
40
50
Age
60
percentage HAM-D reduction
percentage HAM-D reduction
Pearson’s correlation test
70
post-menopausal women
100
Responder: 12
Non-responder: 5
60
Age
pre-menopausal women
N=17
50
Responder: 0
60
Non-responder: 14
40
Pearson’s correlation test
20
r = 0.117
0
70
80
-20
20
P = 0.691
30
40
50
Age
60
70
80
Fig. 2 Percentage HAM-D reduction vs. E2/P ratio
women
men
100
percentage HAM-D reduction
100
80
N=16
r = -0.11
P = 0.968
60
40
20
0
80
r = 0.527
40
P = 0.002
20
0
-20
0
N=31
60
1000
2000
3000
-20
-2000
0
2000
E2/P ratio
P = 0.019
60
40
20
0
-2000
10000
post-menopausal women
percentage HAM-D reduction
r = 0.563
8000
50
100
80
6000
E2/P ratio
pre-menopausal women
N=17
4000
N=14
40
r = 0.158
30
P = 0.590
20
10
0
-10
0
2000
4000
E2/P ratio
6000
8000
10000
0
1000
2000
E2/P ratio
3000
Table 3 Stepwise Multiple Linear Regression Analysis of Factors
Correlated to Percentage HAM-D Reduction After rTMS in Female
Patients
Percentage HAM-D reduction
Variables
β
t
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
Menopausal status
(pre=1; post = 0)
Adjusted r2
P
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, MD
Department of Psychiatry
National Yang-Ming University
Taipei 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 design
Results
Treatment-Resistant MDD (20) vs. NC (20)
at baseline
NC > MDD
NC < 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)
A cortico-limbal dysregulation (baseline)
• MDD
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
Responder(13) vs. Non-Responder(7)
at baseline
• 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
•voxel level, k=300, uncontrolled p <0.05
Less hypoactive in ACC, bilateral medial prefrontal
gyrus 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
left hippocampus and fusiform gyrus
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 MDD vs NC mask
•Cluster level, k=1000,uncorrected p <0.10
Pre-tx areas predicting treatment responses
(≥50% decreases in HDRS)
ACC
•Higher pre-tx metabolism in ACC
•Cluster level, k=1000, uncorrected,
p = 0.089 (trend-significance)
Left fusiform/hippocamcal gyri
•Lower pre-tx metabolism in Left
fusiform/hippo/parahippocamcal gyri
•Cluster level, k=1000, uncorrected,
p = 0.004
(Paper in submission, 2009)
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
Responder
Non-Responder
Responder
TMS治療前和Normal做比較
Normal>MDD_Responder
Normal<MDD_Responder
Responder
TMS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-responder
TMS治療前和Normal做比較
Normal>Non-responder
Normal<Non-responder
Non-responder
TMS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 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
Outline
•
•
•
•
•
ECT
MST
TMS
VNS
DBS