tDCS y tMS en dolor crónico

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Laboratory for

Magnetic

Brain

Stimulation

Felipe Fregni, MD, PhD

Assistant Professor

Harvard Medical School

Neuromodulation for chronic pain



• Why neuromodulation for the

treatment of chronic pain?

• What do we know about

chronic pain?



• 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



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



• 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



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



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



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)



PET scan after MCS



M1 stimulation for chronic pain



Noninvasive techniques of

cortical stimulation

• Repetitive transcranial magnetic

stimulation

• Transcranial direct current stimulation



Transcranial magnetic stimulation

basic principles

Magnetic field

TMS coil

Electric current



Transcranial Direct Current

Stimulation



tDCS model

Wagner & Fregni, 2007



Clinical studies



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



Khedr et al. - JNNP - 2005

Long-lasting effects

• 48 patients - post-stroke pain andtrigeminalneuralgia

• 20Hz rTMS of theprimary motorcortex - 5

consecutivesessions



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



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



2 weeks of rTMS for chronic

visceral pain



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)



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



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)



Find a marker for pain changes

- glutamate levels?



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 )



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)



Site of stimulation



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

*

*

***

**

*



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



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



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)



Results - sleep (1)



Results - sleep (2)



Questions

• Long-lasting effect?

• Efficacy of stimulation to other, non-

sensorimotor cortical targets?

• Optimum timing of the brain stimulation?

• Brain stimulation for acute pain?



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



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?



Challenges for the future



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



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



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



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



Preconditioning rTMS with tDCS

Siebner et al., Journal of Neuroscience, 2004



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



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



Brain stimulation for the

treatment of pain is not new…



• 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.



[email protected]

Thank you

tDCS y tMS en dolor crónico

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