8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 1/49
Laboratory for
Magnetic
Brain
Stimulation
Felipe Fregni, MD, PhD
Assistant Professor
Harvard Medical School
Neuromodulation for chronic pain
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 2/49
• Why neuromodulation for the
treatment of chronic pain?
• What do we know about
chronic pain?
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 3/49
• Chronic pain has a different
pathophysiology as compared to acute
pain syndromes
• It is associated with plastic changes in the
nervous system - leading to the
phenomenon of central and peripheral
sensitization
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 4/49
Development of spontaneous activity in primary afferents
Increase of mechanosensitiviy
Activation of protein kinase C facilitates the response to sensory
neurons to capsaicin
Inflammation -
production of
multiple mediators -
bind to G-protein
receptors - activation
of second
messengers
(alterations in gene
expression andreceptors
Primary nociceptors mostly terminate in the spinal
cord - second-order neurons exhibit plasticity
dependent activity - repetitive activity induces long-
lasting facilitation in the output system
Brain activation - SI, SII -
discrimation and intensity
of pain; anterior cingulate
cortex, insula and frontal
cortex - emotional aspects
of pain
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 5/49
• In chronic pain, usually, there is no (or
little) peripheral damage, injury or
inflammation - it is a result of nervous
system dysfunction
• Chronic pain is a result of maladaptive
plasticity
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 6/49
Clinical examples
• Clinical conditions of chronic pain in which
the pathophysiology is maladaptive plastic
mechanisms
- Phantom limb pain
- Fybromyalgia
- Pain in spinal cord injury- Pain in stroke
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 7/49
How to revert
nervous system
dysfunction
associated with
chronic pain?
TENS
Melzack and
Wall - gate
theory
Spinal cord
stimulation
Vagal nerve
stimulation?
Deep Brain
Stimulation
Cortical
stimulation -
noninvasive
and invasive
techniques
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 8/49
Cortical Stimulation for the
treatment of pain
• Initial experience with invasive stimulation - epidural
stimulation of motor cortex is effective to reduce chronic
pain (Tsubokawa, 1993)
• Animal study - the spinal cord was transected -hyperactivity in the thalamus that was decreased by
motor cortex stimulation, but not sensory stimulation
(Tsubokawa, 1991)
• Neuroimaging study - thalamic modulation associatedwith M1 stimulation (Garcia-Larrea, 1999)
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 9/49
PET scan after MCS
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 10/49
M1 stimulation for chronic pain
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 11/49
Noninvasive techniques of
cortical stimulation
• Repetitive transcranial magnetic
stimulation
• Transcranial direct current stimulation
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 12/49
Transcranial magnetic stimulation
basic principles
Magnetic field
TMS coil
Electric current
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 13/49
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 14/49
Transcranial Direct Current
Stimulation
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 15/49
tDCS model
Wagner & Fregni, 2007
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 16/49
Clinical studies
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 17/49
Initial experience - rTMS
• Cross-over study in which60 patients withneuropathic pain receiveda single session of activeand sham rTMS
• 10Hz (1000 pulses) rTMSof the primary motor
cortex - single session
Lefaucheur et al., JNNP, 2004
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 18/49
Khedr et al. - JNNP - 2005
Long-lasting effects
• 48 patients - post-stroke pain andtrigeminalneuralgia
• 20Hz rTMS of theprimary motorcortex - 5
consecutivesessions
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 19/49
rTMS for chronic visceral pain
• Initial study - site and
parameters of stimulation
(1Hz - right and left SII
(secondary somatosensory
area; 20 Hz - right and left
SII; sham rTMS)
• Main outcome = %VAS
reduction + % Medicationreduction
Fregni et al., Annals of Neurology, 2005
1-Hz vs. 20-Hz
-100
-80
-60
-40
-20
0
20
40
60
P a i n c h a n g e s ( % ) f r o m b a s e l i n e
1-Hz
20-Hz
Right vs. Left
-100
-80
-60
-40
-20
0
20
40
60
1
P a i n c h a n g e s ( % ) f r o m
b a s e l i n e
Right
Left
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 20/49
18 10019 100
20 100
21 100
22 200
23 200
24 200
25 200
26 200
27 200
28 10029 100
30 200
31 200
32 200
33 200
34 200
35 200
36 200
37 200
38 200
39 200
40 200
41 200
42 200
Mean Fentanyl use (mcg
0
50
100
150
200
250
- 7 - 5 - 3 - 1 1 3 5 7 9 1 1 1 3 1 5 1 7 1 9 2 1 2 3 2 5 2 7 2 9 3 1 3 3 3 5 3 7 3 9 4 1
Days
Baseline L-1Hz R-1Hz R-Sham L-20Hz L-sham R-20Hz
Opioid use during treatment
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 21/49
2 weeks of rTMS for chronic
visceral pain
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 22/49
Other strategies
• rTMS for migraine - site of stimulation (leftDLPFC ) - preliminary studies withsignificant reduction of migraine attacks
and medication use (Brighina, 2004)• Other sites of stimulation - comparison of
M1, SI, SMA and PM - pain reduction onlyafter M1 stimulation (Hirayama, 2006)
• Prediction tool for epidural stimulation(Andre-Obadia, 2006)
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 23/49
Pooled analysis - meta-analysis
• Studies
investigating M1
stimulation for
chronic pain (rTMS
and tDCS)
• 12 studies using
nonivasive brain
stimulationrisk ratio noninvasive studies
.1 1 10
Combined
Fregni _2006(tdcs2)
Fregni _2006(tdcs1)
Hir ayama_2006
André-Obadi a_2_2006
André-Obadi a_1_2006
Khedr_2005
Pleger_2004
Lefauc heur_2004
Canav er o_2002
Rollnik_2002
Lefaucheur_2_2001
Lefaucheur_1_2001
Lefauc heur_2001
Risk ratio (responders rate) - active vs. sham rTMS - 2.64, 95% C.I., 1.63 – 4.30
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 24/49
Invasive vs. noninvasive brain
stimulation
• 12 studies using non-invasive brainstimulation and 22 for invasive brainstimulation (open studies)
• Weighted responders rate:
– 72.6% (95% C.I., 67.7 – 77.4) invasive stimulation studies
– 45.3% (95% C.I., 39.2 –
51.4) noninvasive stimulation studies
( 36.8% (95% C.I., 30.5 – 43.0) for the rTMS studies and71.4% (95% C.I., 52.1 – 90.7) for tDCS studies)
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 25/49
Find a marker for pain changes
- glutamate levels?
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 26/49
0
1
2
3
4
5
6
7
8
9
10
Right SII Left SII
G l u t a m a t e ( m m o
l / l )
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Before rTMS After rTMS
G l u t a m a t e (
m m o l / l )
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 27/49
Study design
• 17 patients with spinal cord injury and refractory chronicpain
• Randomized (1:2) to receive sham and active tDCS
• Baseline evaluation (2 weeks before)
• Treatment (5 days of treatment)
• Follow-up evaluation (after 2 weeks of treatment)
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 28/49
Site of stimulation
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 29/49
tDCS of the primary motor cortex for the treatment of central pain due
to spinal cord injury - Fregni et al., Pain, 2006
0
1
2
3
4
5
6
7
8
9
Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Follow-up
M e a n p a i n s c o r e
s ( V A S )
Active tDCS Sham tDC
*
*
***
**
*
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 30/49
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 31/49
tDCS and fibromyalgia
• Extensive evidence suggests that fibromyalgia is associated with a central
nervous system dysfunction:
• Recent evidence has shown that fibromyalgia is associated with specific brain
activity changes. In a recent SPECT study, patients with fibromyalgia as
compared to healthy controls showed a decrease in the regional cerebral bloodflow in the thalamus, caudate nucleus and pontine tegmentum (1). I
• In addition it has long been demonstrated that antidepressants, such as
tricyclics, improve pain in fibromyalgia (2) and recent studies suggest that
centrally acting drugs such as dopaminergic drugs are effective in alleviating
the symptoms of fibromyalgia as compared with placebo (3).
• Finally, this disorder is extremely refractroctory to peripheral treatments such
as non-steroidal anti-inflamatory drugs 31
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 32/49
Methods
• Thirty-two patients (females only – mean age of 53.4 ±
8.9 years) participated in this study.
• The following assessments were made: pain
measurement, quality-of-life/other domains offibromyalgia, psychiatric symptoms, cognitive and
safety evaluation and adverse events.
• Sleep assessment - polysomnography
• Stimulation - a constant current of 2mA intensity for 20minutes - 3 groups:
• Anodal M1
• Anodal DLPFC
• Sham tDCS
32
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 33/49
Results - main outcome (pain)
The type 3 test of fixed effects revealed a significant effect of time
(p<0.0001), group (p=0.007) and interaction term time vs. group (p<0.0001)
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 34/49
Results - sleep (1)
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 35/49
Results - sleep (2)
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 36/49
Questions
• Long-lasting effect?
• Efficacy of stimulation to other, non-
sensorimotor cortical targets?
• Optimum timing of the brain stimulation?
• Brain stimulation for acute pain?
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 37/49
What we don’t know about
chronic pain?• Individual variability - why some
individuals develop chronic pain - naturevs. nurture
• Is there specific neural circuits associatedwith different chronic pain syndromes -resolution of neuroimaging tools are notsuficient
• Is it possible to cure chronic pain
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 38/49
Is it the perfect therapy for
chronic pain?• Far from it…
• Effects sizes are still modest
• Adverse effects associated with long-termuse
• Loss of efficacy
• Is there a tolerability for brain stimulation?
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 39/49
Challenges for the future
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 40/49
Redesigning TMS technology
• Coils that can induce an electric current in deep areas -e.g. cone coils
• Changing pulse configuration - unidirectional
square pulse might improve the efficacy of thismethod
• Continuous vs. variable frequency
• Modeling the electrical current
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 41/49
Methods of monitoring TMS treatment
• Neuroimaging techniques (SPECT, PET,fMRI) - “on-line”Bestmann et al., Neuroimage. 2005
• “off -line” (immediate response or long-term treatments such as depressiontreatment)
Fregni et al. Neurology. 2006 (in press)
• Spectroscopy to measure metabolitechanges
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 42/49
EEG-guided TMS system
EEG system to control TMS parameters Analysis of the TMS response - comparisonbetween motor vs. prefrontal cortex(Kahkonen et al., Psychopharmacology (Berl), 2005)
Klimesch et al showed that stimulation
at alpha +1Hz frequency induces a
larger cognitive performance gain
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 43/49
Enhancing rTMS effects
- Effects of rTMS might be due to
synaptic strengthening
(LTP/LTD).
- Baseline cortical activity would be
an important predictor of thesubsequent effects of rTMS
Iyer et al., J Neurosci. 2003
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 44/49
Preconditioning rTMS with tDCS
Siebner et al., Journal of Neuroscience, 2004
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 45/49
Theta burst stimulation
Theta burst stimulation of the motor cortex produces a long-lasting and powerful effect
on motor cortex physiology
Huang et al., Neuron, 2005
M i t th h t t d ft
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 46/49
Maintenance therapy - what to do after
the induction phase?
• Recent studies showing that rTMS if applied once every
1 or 2 weeks is effective to maintain the beneficial
therapeutic effectsO'Reardon JP, Blumner KH, Peshek AD, Pradilla RR, Pimiento PC. Long-term maintenance therapy
for major depressive disorder with rTMS.J Clin Psychiatry. 2005 Dec;66(12):1524-8.
Li X, Nahas Z, Anderson B, Kozel FA, George MS. Can left prefrontal rTMS be used as a
maintenance treatment for bipolardepression?Depress Anxiety. 2004;20(2):98-100.
• Our experience shows that it is possible to maintainpatients in remission for several years using rTMS
B i ti l ti f th
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 47/49
Brain stimulation for the
treatment of pain is not new…
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 48/49
• Although there are some encouraging
results, neuromodulation for chronic pain
is still a relatively unexplored field and
conclusions regarding its clinical effects atthis stage are not yet possible.
8/12/2019 tDCS y tMS en dolor crónico
http://slidepdf.com/reader/full/tdcs-y-tms-en-dolor-cronico 49/49
Thank you
Top Related