Hindawi Publishing Corporation
Case Reports in Medicine
Volume 2011, Article ID 130751, 4 pages
PhantomLimb Pain:Low Frequency Repetitive Transcranial
Magnetic Stimulationin Unaffected Hemisphere
AndreaDi Rollo1,2and StefanoPallanti1,2,3
1Department of Psychiatry, University of Florence, 50134 Florence, Italy
2Institute of Neurosciences, 50137 Florence, Italy
3Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA
Correspondence should be addressed to Stefano Pallanti, email@example.com
Received 28 September 2010; Revised 9 December 2010; Accepted 1 March 2011
Academic Editor: Vincenzo Di Lazzaro
Copyright © 2011 A. Di Rollo and S. Pallanti. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Phantom limb pain is very common after limb amputation and is often difficult to treat. The motor cortex stimulation is a
valid treatment for deafferentation pain that does not respond to conventional pain treatment, with relief for 50% to 70% of
patients. This treatment is invasive as it uses implanted epidural electrodes. Cortical stimulation can be performed noninvasively
by repetitive transcranial magnetic stimulation (rTMS). The stimulation of the hemisphere that isn’t involved in phantom limb
(unaffected hemisphere), remains unexplored. We report a case of phantom limb pain treated with 1 Hz rTMS stimulation over
motorcortex inunaffected hemisphere.Thisstimulationproduces arelevantclinicalimprovementofphantomlimbpain;however,
further studies are necessary to determine the efficacy of the method and the stimulation parameters.
Phantom limb pain (PLP) is very common after limb
amputation and has a reported incidence of up to 87% of
amputees . This type of pain can be difficult to treat
and usually responds poorly to conventional pain treatments
[2–4]. Conversely, the electrical stimulation of the primary
motor cortex (M1) has proved to be an effective treatment
for intractable deafferentation pain. This treatment started
in 1990, and many patients have been treated up to now.
The patients who have been operated on were suffering
from poststroke pain (59%), trigeminal neuropathic pain,
brachial plexus injury, spinal cord injury, peripheral nerve
chronic motor cortex stimulation (MCS) through implanted
epidural electrodes. It results invasive and outcome varies
from patient to patient [6, 7]. Otherwise cortical stimulation
can be performed non-invasively by transcranial magnetic
stimulation (TMS). A number of studies have shown that a
single session of repetitive transcranial magnetic stimulation
(rTMS) can relieve pain transiently in some patients with
chronic neuropathic pain [8–10]. Other studies have shown
that the duration of pain relief can be extended by repeated
application of rTMS every day for five days in patient with
trigeminal neuralgia and poststroke pain syndrome  or
for ten days in patients with fibromyalgia . In contrast,
one study failed to see any long-term therapeutic effect of
three weeks daily parietal cortex rTMS in two patients with
phantom limb pain . The majority of studies apply
high frequencies (>1) with pulses below motor threshold on
motor cortical area corresponding to the hand of the painful
side. The reason forthisistwofold:epiduralstimulation usu-
ally employs pulses below motor threshold at ∼40Hz. and a
study shows that the applications of rTMS at high frequency
is more effective than applications of rTMS at low frequency
(≤1) in this area of stimulation . However, the effect of
stimulation inunaffectedhemisphere forphantomlimbpain
remains unexplored. In other cases, like neglect or recovery
hemisphere have shown therapeutic properties [13, 14].
We report a case of phantom pain limb treated with 1Hz
stimulation over motor cortex in unaffected hemisphere.
2 Case Reports in Medicine
rTMS-induced reduction in pain level (%)
Figure 1: The graph shows the reduction in percentage of pain in
time. The percentage of pain level modificationwas calculated from
the VAS score by the following equation (post.rTMS − pre.rTMS
pain scores) × 100/(pre.rTMS pain scores).
A 36-yr-old, right-handed man, who had had a motorbike
accident ten years ago, had total surgical amputation of
the left arm. At the time of his arrival to our institute,
he had perception of phantom limb and was experiencing
severe phantom limb pain. This perception and pain have
existed immediately after the amputation. The perception
of phantom limb was always in the same position near the
chest with the hand partially closed near the shoulder. The
patient experienced pain like paresthesia, dysaesthesia and
burning sensation especially in phantom thumb, index and
medium, and in the total phantom limb too. The pain was
present every day, always in wakefulness but not in sleep.
Such pain persisted during the day and sometime became
very intense for some seconds. In the past, the patient tried
antiepileptic drugs, tricyclic and SSRI antidepressant, anti-
inflammatory-analgesics, and opioids in order to relieve the
pain. At the time of his arrival to our institute, he was
having the best therapy that gave a partial relief to the
pain. The therapy consisted in methadone 30mg/day and
pregabalin 300mg/day. Neurological examination showed
miosis and light ptosis in left eye, like Bernard-Horner
syndrome which has existed immediately after the amputa-
tion. The examination also showed tactile hypoesthesia in
the surgical scar, while the tactile stimulation of the area
near the scar increased the pain in the phantom limb. The
tactile stimulation of the left side of the face increased the
pain in the phantom limb too. Chest MRI and CT with
contrast excluded a peripheral component of pain due to
a concomitant lesion of the inferior brachial plexus. The
patient gave the written informed consent. At the baseline,
at the end of every week, for three weeks during treatment
and at the end of every week for three weeks after treatment,
the following tests were administered: Hamilton Rating
Scale for Depression (HAM-D), Hamilton Rating scale for
Phonemic Verbal Fluency, and Visual Analogue Scale (VAS)
for pain-0 (no pain) and 10 (maximal pain). The percentage
of pain level modification was calculated from the VAS
score by the following equation (post.rTMS – pre.rTMS pain
scores) × 100/(pre.rTMS pain scores). Figure 1 below shows
the reduction in percentage of pain in time. Clinical Global
Impression-Improvement scale (CGI-I) was evaluated at the
end of the third week of treatment. rTMS sessions were
conducted in a laboratory staffed by physicians certified in
basic life support and trained in the prompt recognition
and treatment of seizures and other medical emergencies.
Repetitive TMS was administered using a MAGSTIM rapid
magnetic stimulator (Magstim Company, Ltd., Whitland,
U.K.). We used a 70-mm figure eight-shaped coil. Patient sat
in a reclining chair with a headrest for stabilization of the
head and wore protective earplugs. Resting motor threshold
(RMT) was defined as the intensity required eliciting at
least five MEPs of 50µV in peak-to-peak amplitude with
10 consecutive stimulations, when the coil was placed over
the optimal position to activate the abductor pollicis brevis
muscle in right hand based on electromyographic recording
. During treatment, the following were applied for 15
minutes, thirty 20-second trains at 1Hz at 80% of RMT
with a 10 seconds intertrain interval (a total of 600 stimuli
per session were applied over the left motor cortex), these
parameters are now widely considered safe . A full
course comprised fifteen daily sessions administered on
weekdays, beginning on Monday. At all times, the coil was
held tangentially to the scalp, with the handle pointing back
and away from the midline at 45◦. During every session of
stimulation the patient had the sensation that the phantom
limb went away from the shoulder towards mid-line in the
direction of the pelvis, and the intensity of phantom limb
pain reduced. The patient experienced no adverse event
during or after rTMS application. At the end of the third
week of treatment, the pain was reduced about 33.3% (see
Figure 1), in fact VAS changed from 6 (pretreatment) to 4
(posttreatment), with CGI-I = 2 (much improved). In three
weeks after treatment the percentage reduction of pain was
reduced to 25% in the first week after the end of treatment
and remained stable at about 16.6% in the second and in the
third week after the end of treatment (Figure 1). During the
three weeks of treatment and during the three weeks after
treatment, Ham-D, Ham-A, and MRS all remained stable at
≤6. Also, score of the CORSI TEST remained stable at 5 and
the score of the Phonemic Verbal Fluency remained stable at
17.6 and so these tests did not show cognitive impairment
or improvement. RMT of unaffected hemisphere increased
during treatment, in fact at baseline its value was 84% of
Maximum Output of the Stimulator, after the first week of
treatment, its value was 86% of Maximum Output of the
Stimulator, and at the end of the second and third week of
treatment its value was stable at 88% of Maximum Output
of the Stimulator.
Althoughthestudyhasa stronglimitation duetotheabsence
of placebo (sham) control, it nevertheless shows that the
method of stimulation in nonphantom limb hemisphere
with 1Hz stimulation ameliorates the phantom limb pain
with longlasting antalgic effects. The effects of rTMS on
pain are similar to effects obtained by Passard et al. .
Case Reports in Medicine 3
Passard in his work applied high frequency rTMS in the
left motor cortex of patients with fibromyalgia for two
weeks. He obtained the maximum result at the end of
treatment, and this result lightly decreased in followup. Also,
we obtained the maximum reduction of pain at the end
of treatment but in weeks after the end of treatment the
relief in pain reduced. In order to improve the results it
would be probably necessary to have a longer period of
stimulation or other parameters of stimulation like a higher
intensity of stimulation, respecting the safety guideline 
and considering that stimulation is applied in the motor
cortex area with high epileptic risk.
The low frequency rTMS has showed antidepressant
effects [17, 18], but in this case the relief in pain does not
depend on mood change. In fact the mood of the patient
remained stable, like the tests, Ham-D, Ham-A, and MRS
show, remaining stable at ≤6.
Instead, the low frequency rTMS is known to reduce
the excitability of the stimulated motor cortex. This can
increase the excitability of the controlateral motor cortex via
transcallosal pathways, and so it can have analgesic effects in
a way similar to the epidural motor cortex stimulation and
to the high frequency rTMS of motor cortex. In fact chronic
motor cortex stimulation using implanted electrodes is an
nism ofaction remains poorly understood. Some hypotheses
resulted from electrophysiological and PET studies [20, 21].
In these studies, cerebral blood flow was found to increase
in thalamus ipsilateral to the stimulated motor cortex, in
the orbitofrontal and anterior cingulated gyri, the anterior
insula and upper brainstem near the periacqueductal gray
matter. Cingulate/orbitofrontal activation should participate
in a modulation of affective/emotional component of pain,
while descending activation of the brainstem should inhibit
the transmission of discriminative noxious information
[20, 21]. Besides, there are lines of evidence that chronic
motor cortex stimulation using implanted electrodes might
involve endogenous opioids system in the analgesic action.
This hypothesis is supported by the demonstration that
motorcortexstimulation viaepidurallyimplanted electrodes
induces changes in endogenous opioids systems in patients
with neuropathic pain . Furthermore, it has recently
of epidural motor cortex stimulation in the rat . Besides,
a recent study shows the involvement of endogenous opioid
systems in rTMS-induced analgesia . In fact, naloxone
injectionsignificantly decreasedtheanalgesic effectsofrTMS
of motor cortex stimulation, but did not change the effects
of rTMS of the dorsolateral prefrontal cortex or sham.
The differential effects of naloxone on motor cortex and
dorsolateral prefrontal cortex stimulation suggest that the
analgesic effects induced by the stimulation of these two
cortical sites are mediated by differential mechanisms .
The physiopathology of the phantom limb pain is still
an open field between various hypotheses. The two major
research streams on the painful phantom limb are focused
on the pivotal influence of the periphery and of the spinal
cord, while the other is focused on the fundamental role
of suprasegmental structures and of the cortex. These two
research streams seem to be more complementary than in
opposition . However, the results of our paper show
that phantom limb pain could be generated by altered
interhemispheric balance. This theory and the consequent
strategy have shown effects in stroke recovery  and in
rehabilitation of visual spatial neglect . This hypothesis
is consistent with the results of R¨ oricht et al. , which
show higher excitability of the motor cortex contralateral to
the intact arm in some patients with upper arm amputation,
and higher excitability of the motor cortex controlateral
to the amputated limb in other patients. R¨ oricht says that
variability in excitability in two hemispheres could depend
on the site of amputation and on the time since amputation.
The hypothesis of interhemisferic balance is in contrast
with Schwenkreis et al.  and colleagues that found a
significant reduction of intracortical inhibition in forearm
amputees and an enhancement of intracortical facilitation
in upper arm amputees on the affected side, revealing
a hyperexcitability of phantom limb hemisphere. Others
studies, with EEG or with single-pulse and paired-pulse
TMS investigations, are necessary to evaluate excitability
of the nonphantom limb hemisphere and of phantom
limb hemisphere and its modification with treatment, to
understand the role of excitability in phantom limb pain.
ameliorates phantom limb pain with longlasting antalgic
effects. New experiments with this approach are necessary
to confirm the therapeutic results and to improve them with
better parameters of stimulation.
The authors declare no competing interest.
 C. M. Kooijman, P. U. Dijkstra, J. H. B. Geertzen, A. Elzinga,
and C. P. Van Der Schans, “Phantom pain and phantom
sensationsin upper limbamputees: anepidemiologicalstudy,”
Pain, vol. 87, no. 1, pp. 33–41, 2000.
 R. T. Kiefer, K. Wiech, S. T¨ opfner et al., “Continuous
brachial plexus analgesia and NMDA-receptor blockade in
vol. 3, no. 2, pp. 156–160, 2002.
 H. Flor and N. Birbaumer, “Phantom limb pain: cortical
plasticity and novel therapeutic approaches,” Current Opinion
in Anaesthesiology, vol. 13, no. 5, pp. 561–564, 2000.
 P. M. Arnstein, “The neuroplastic phenomenon: a physiologic
link between chronic pain and learning,” The Journal of
Neuroscience Nursing, vol. 29, no. 3, pp. 179–186, 1997.
 Y. Saitoh and T. Yoshimine, “Stimulation of primary motor
cortex for intractable deafferentation pain,” Acta Neurochirur-
gica. Supplement, vol. 97, no. 2, pp. 51–56, 2007.
 E. M. Khedr, H. Kotb, N. F. Kamel, M. A. Ahmed, R. Sadek,
and J. C. Rothwell, “Longlasting antalgic effects of daily
sessions of repetitive transcranial magnetic stimulation in
central andperipheralneuropathicpain,”Journal ofNeurology,
Neurosurgery and Psychiatry, vol. 76, no. 6, pp. 833–838, 2005.
4 Case Reports in Medicine
 B. A. Meyerson, U. Lindblom, B. Linderoth, G. Lind, and P.
Herregodts, “Motorcortex stimulationastreatmentoftrigem-
inal neuropathic pain,” Acta Neurochirurgica, Supplement, vol.
58, pp. 150–153, 1993.
 J. P. Lefaucheur, X. Drouot, Y. Keravel, and J. P. Nguyen, “Pain
relief induced by repetitive transcranial magnetic stimulation
of precentral cortex,” NeuroReport, vol. 12, no. 13, pp. 2963–
 J. P. Lefaucheur, X. Drouot, I. Menard-Lefaucheur et al.,
“Neurogenic pain relief by repetitive transcranial magnetic
cortical stimulation depends on the origin and the site of
pain,” Journal of Neurology, Neurosurgery and Psychiatry, vol.
75, no. 4, pp. 612–616, 2004.
 B. Pleger, F. Janssen, P. Schwenkreis, B. V¨ olker, C. Maier, and
M. Tegenthoff, “Repetitive transcranial magnetic stimulation
of the motor cortex attenuates pain perception in complex
regional pain syndrome type I,” Neuroscience Letters, vol. 356,
no. 2, pp. 87–90, 2004.
 A. Passard, N. Attal, R. Benadhira et al., “Effects of unilateral
repetitive transcranial magnetic stimulation of the motor
cortex onchronicwidespreadpaininfibromyalgia,”Brain, vol.
130, no. 10, pp. 2661–2670, 2007.
 R. T¨ opper, H. Foltys, I. G. Meister, R. Sparing, and B.
Boroojerdi, “Repetitive transcranial magnetic stimulation of
like syndrome,” Clinical Neurophysiology, vol. 114, no. 8, pp.
 W. Song, B. Du, Q. Xu, J. Hu, M. Wang, and Y. Luo, “Low-
frequency transcranial magnetic stimulation for visual spatial
neglect: a pilot study,” Journal of Rehabilitation Medicine, vol.
41, no. 3, pp. 162–165, 2009.
 E. M. Khedr, M. R. Abdel-Fadeil, A. Farghali, and M.
Qaid, “Role of 1 and 3 Hz repetitive transcranial magnetic
stimulation on motor function recovery after acute ischaemic
stroke,” European Journal of Neurology, vol. 16, no. 12, pp.
 P. M. Rossini, A. Berardelli, G. Deuschl et al., “Applications of
magneticcortical stimulation.TheInternationalFederation of
Clinical Neurophysiology,” Electroencephalography and Clini-
cal Neurophysiology. Supplement, vol. 52, pp. 171–185, 1999.
 S. Rossi, M. Hallett, P. M. Rossini, and A. Pascual-Leone,
“Safety, ethical considerations, and application guidelines
for the use of transcranial magnetic stimulation in clinical
practice and research,” Clinical Neurophysiology, vol. 120, no.
12, pp. 2008–2039, 2009.
 W. M. Stern, J. M. Tormos, D. Z. Press, C. Pearlman, and
A. Pascual-Leone, “Antidepressant effects of high and low
frequency repetitive transcranial magnetic stimulation to the
dorsolateral prefrontal cortex: a double-blind, randomized,
placebo-controlled trial,” Journal of Neuropsychiatry and Clin-
ical Neurosciences, vol. 19, no. 2, pp. 179–186, 2007.
 S. Pallanti, S. Bernardi, A. Di Rollo, S. Antonini, and L.
repetitive transcranial magnetic stimulation: is simpler better
for treatment of resistant depression?” Neuroscience, vol. 167,
no. 2, pp. 323–328, 2010.
 T. Tsubokawa,Y. Katayama,T. Yamamoto,T. Hirayama,andS.
Koyama, “Chronicmotorcortex stimulationforthe treatment
of central pain,” Acta Neurochirurgica, Supplement, vol. 52, pp.
 L. Garc´ ıa-Larrea, R. Peyron, P. Mertens et al., “Electrical
scan and electrophysiological study,” Pain, vol. 83, no. 2, pp.
 R. Peyron, B. Laurent, and L. Garc´ ıa-Larrea, “Functional
imaging of brain responses to pain. A review and meta-
analysis (2000),” Neurophysiologie Clinique, vol. 30, no. 5, pp.
 J. Maarrawi, R. Peyron, P. Mertens et al., “Motor cortex stim-
ulation for pain control induces changes in the endogenous
opioid system,” Neurology, vol. 69, no. 9, pp. 827–834, 2007.
 E. T. Fonoff, C. S. Dale, R. L. Pagano et al., “Antinociception
induced by epidural motor cortex stimulation in naive
conscious rats is mediated by the opioid system,” Behavioural
Brain Research, vol. 196, no. 1, pp. 63–70, 2009.
 D. C. De Andrade, A. Mhalla, F. Adam, M. J. Texeira, and D.
Bouhassira, “Neuropharmacological basis of rTMS-induced
analgesia: the role of endogenous opioids,” Pain, vol. 152, no.
2, pp. 320–326, 2011.
 R. Casale, L. Alaa, M. Mallick, and H. Ring, “Phantom limb
related phenomena and their rehabilitation after lower limb
amputation,” European Journal of Physical and Rehabilitation
Medicine, vol. 45, no. 4, pp. 559–566, 2009.
 S. R¨ oricht, B. U. Meyer, L. Niehaus, and S. A. Brandt,
“Long-term reorganization of motor cortex outputs after arm
amputation,” Neurology, vol. 53, no. 1, pp. 106–111, 1999.
 P. Schwenkreis, K. Witscher, F. Janssen et al., “Changes of
cortical excitability in patients with upper limb amputation,”
Neuroscience Letters, vol. 293, no. 2, pp. 143–146, 2000.