Laboratory for

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Neuromodulation for chronic pain
Felipe Fregni, MD, PhD Assistant
Professor Harvard Medical School
Laboratory for Magnetic Brain
Stimulation
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• Why neuromodulation for the treatment of chronic
  pain?
• What do we know about chronic pain?

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• 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

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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
and receptors
Brain activation - SI, SII - discrimation and
intensity of pain anterior cingulate cortex,
insula and frontal cortex - emotional aspects of
pain
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
Development of spontaneous activity in primary
afferents Increase of mechanosensitiviy
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• 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

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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

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How to revert nervous system dysfunction
associated with chronic pain?
Cortical stimulation - noninvasive and invasive
techniques
Deep Brain Stimulation
Vagal nerve stimulation?
Spinal cord stimulation
TENS Melzack and Wall - gate theory
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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
  associated with M1 stimulation (Garcia-Larrea,
  1999)

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PET scan after MCS
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M1 stimulation for chronic pain
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Noninvasive techniques of cortical stimulation

• Repetitive transcranial magnetic stimulation
• Transcranial direct current stimulation

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Transcranial magnetic stimulation basic
principles
Magnetic field
Electric current
TMS coil
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Transcranial Direct Current Stimulation
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tDCS model
Wagner Fregni, 2007
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Clinical studies
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Initial experience - rTMS

• Cross-over study in which 60 patients with
  neuropathic pain received a single session of
  active and sham rTMS
• 10Hz (1000 pulses) rTMS of the primary motor
  cortex - single session

Lefaucheur et al., JNNP, 2004
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Long-lasting effects

• 48 patients - post-stroke pain and trigeminal
  neuralgia
• 20Hz rTMS of the primary motor cortex - 5
  consecutive sessions

Khedr et al. - JNNP - 2005
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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 Medication
  reduction

Fregni et al., Annals of Neurology, 2005
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Opioid use during treatment
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2 weeks of rTMS for chronic visceral pain
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Other strategies

• rTMS for migraine - site of stimulation (left
  DLPFC ) - preliminary studies with significant
  reduction of migraine attacks and medication use
  (Brighina, 2004)
• Other sites of stimulation - comparison of M1,
  SI, SMA and PM - pain reduction only after M1
  stimulation (Hirayama, 2006)
• Prediction tool for epidural stimulation
  (Andre-Obadia, 2006)

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Pooled analysis - meta-analysis

• Studies investigating M1 stimulation for chronic
  pain (rTMS and tDCS)
• 12 studies using nonivasive brain stimulation

Risk ratio (responders rate) - active vs. sham
rTMS - 2.64, 95 C.I., 1.63 4.30
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Invasive vs. noninvasive brain stimulation

• 12 studies using non-invasive brain stimulation
  and 22 for invasive brain stimulation (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 and 71.4 (95 C.I., 52.1 90.7) for tDCS
  studies)

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Find a marker for pain changes - glutamate levels?
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Study design

• 17 patients with spinal cord injury and
  refractory chronic pain
• Randomized (12) to receive sham and active tDCS
• Baseline evaluation (2 weeks before)
• Treatment (5 days of treatment)
• Follow-up evaluation (after 2 weeks of treatment)

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Site of stimulation
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tDCS of the primary motor cortex for the
treatment of central pain due to spinal cord
injury - Fregni et al., Pain, 2006








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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 blood
  flow 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

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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 of
  fibromyalgia, psychiatric symptoms, cognitive and
  safety evaluation and adverse events.
• Sleep assessment - polysomnography
• Stimulation - a constant current of 2mA intensity
  for 20 minutes - 3 groups
• Anodal M1
• Anodal DLPFC
• Sham tDCS

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Results - main outcome (pain)
The type 3 test of fixed effects revealed a
significant effect of time (plt0.0001), group
(p0.007) and interaction term time vs. group
(plt0.0001)
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Results - sleep (1)
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Results - sleep (2)
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Questions

• Long-lasting effect?
• Efficacy of stimulation to other,
  non-sensorimotor cortical targets?
• Optimum timing of the brain stimulation?
• Brain stimulation for acute pain?

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What we dont know about chronic pain?

• Individual variability - why some individuals
  develop chronic pain - nature vs. nurture
• Is there specific neural circuits associated with
  different chronic pain syndromes - resolution of
  neuroimaging tools are not suficient
• Is it possible to cure chronic pain

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Is it the perfect therapy for chronic pain?

• Far from it
• Effects sizes are still modest
• Adverse effects associated with long-term use
• Loss of efficacy
• Is there a tolerability for brain stimulation?

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Challenges for the future
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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 this
  method
• Continuous vs. variable frequency
• Modeling the electrical current

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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 depression treatment)
• Fregni et al. Neurology. 2006 (in press)
• Spectroscopy to measure metabolite changes

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EEG-guided TMS system
Klimesch et al showed that stimulation at alpha
1Hz frequency induces a larger cognitive
performance gain
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Enhancing rTMS effects

• - Effects of rTMS might be due to synaptic
  strengthening (LTP/LTD).
• - Baseline cortical activity would be an
  important predictor of the subsequent effects of
  rTMS
• Iyer et al., J Neurosci. 2003

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Preconditioning rTMS with tDCS
Siebner et al., Journal of Neuroscience, 2004
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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
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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 effects
• O'Reardon JP, Blumner KH, Peshek AD, Pradilla RR,
  Pimiento PC. Long-term maintenance therapy for
  major depressive disorder with rTMS.J Clin
  Psychiatry. 2005 Dec66(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.
  200420(2)98-100.
• Our experience shows that it is possible to
  maintain patients in remission for several years
  using rTMS

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Brain stimulation for the treatment of pain is
not new
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• Although there are some encouraging results,
  neuromodulation for chronic pain is still a
  relatively unexplored field and conclusions
  regarding its clinical effects at this stage are
  not yet possible.

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Thank you
ffregni_at_bidmc.harvard.edu