Bilateral vs. unilateral transcranial magnetic stimulation of the primary motor cortex to treat chronic orofacial pain: a pilot study with a randomized controlled design

In the early 1990*s, Tsubokawa and colleagues tried to provide a more effective
treatment for thalamic pain syndromes. All forms of therapy, including deep
brain stimulation (DBS) of the thalamic relay nucleus, were able to provide a
pain relief of 20-30% in patients suffering from thalamic pain syndromes.
Therefore, Tsubokawa and his group stimulated multiple brain regions in cats
after a lesion of the spinothalamic pathway was induced. Outcome measurements
of the pain control were blood flow of the thalamus and cerebral cortex,
increased skin temperature of the painful area and improved movements of the
affected limbs. They presented that chronic motor cortex stimulation (MCS) was
most effective in treating thalamic pain syndromes [2]. After their first
results, Tsubokawa*s group introduced MCS into clinical care [2-5]. Over the
years, various reports were published and more indications for MCS were
introduced and tested [5-40]. In order to test new hypothesis and investigate
the possible effects of MCS, transcranial magnetic stimulation (TMS) of the
primary motor cortex has been introduced in 1995 [41]. The main indications
for MCS today are 1)central post-stroke pain (including thalamus syndrome),
2)neuropathic orofacial pain, 3)phantom limb pain and 4)peripheral plexus
avulsion [36, 40].
The underlying mechanisms of action of MCS remain largely elusive, other than
that brain areas distant to the site of stimulation show to be involved. One of
the mechanisms that has been describes discusses the release of a variety of
neurotransmitters [42-53].
Other mechanisms concern descending volleys in the spinal cord [50, 51, 54]. In
order to explain these widespread effects of MCS, the activation of stellate
interneurons in the fourth layer of the cerebral cortex must be assumed.[55-57]
These thalamocortical afferent fibers from C-type cells do not take part in the
corticospinal tract, but connect subcortical structures and circuits to
cortical areas [58-61]. Next to these neuroanatomical substrates, corollary
discharges have been investigated as well. It has been discussed that sensory
feedback comes from the peripheral nerves, the visual input, but also from the
motor cortex itself. Therefore, a possible mechanism of action of MCS might be
these corollary discharges which counterbalances the other feedback
deficiencies[62]. Although several clinical trials showed a significant
difference in analgesic effects between sham and active stimulation of the
primary motor cortex[63-65], the placebo effect is also hypothesized to play a
role in pain relief [62, 66].

Although the aforementioned mechanisms seem to spread throughout the entire
nervous system, the thalamus that lies contralateral to the site of stimulation
seems not to be affected. However, in 2016, Henssen et al. discuss that
orofacial pain may be conducted in a bilateral fashion, inducing activation of
both thalami [1]. For this reason, bilateral stimulation of the motor cortex is
thought to induce a stronger analgesic effect compared to unilateral MCS.

Before starting to implant two electrodes into the epidural space of pain
patients, further empirical researches that investigate the effects of
bilateral stimulation of the primary motor cortex must be conducted. A
non-invasive method of brain stimulation is called transcranial magnetic
stimulation (TMS) in which electromagnetic coils held against the scalp
influence underlying cortical firing. This method of investigation is
non-invasive and safe and can help further exploration of cortical targets for
neuromodulation for the treatment of pain [67].

In 2016, Henssen et al. discuss that orofacial pain may be conducted in a
bilateral fashion, inducing activation of both thalami [1]. For this reason,
bilateral stimulation of the motor cortex is thought to induce a stronger
analgesic effect compared to unilateral motor cortex stimulation by
transcranial magnetic stimulation. This study aims to investigate the
superiority of bilateral transcranial magnetic stimulation (TMS) over
unilateral TMS of the motor cortex

For this study, we aim to include approximately 12 patients with intractable,
chronic orofacial pain of peripheral origin with a baseline NRS of at least 5
(0= no pain, 10= worst possible pain). The investigator (Dylan Henssen)
contacts the pain nurse, neurosurgeons and pain physicians to ask them to seek
contact with their patients to inform them about this research. Afterwards, if
the patients wish to learn more or wish to participate, they receive an
information package, including an information letter and an informed consent
form. When the patient agrees to be included they receive four McGill Pain
questionnaires which must be filled in weekly. After these four weeks, the
patient is invited to the outpatient clinic to meet with the investigator.
During this consultation, the patient talks about the pain he/she experiences,
submits the four filled-in questionnaires and receives further information
about the research. After the consultation, all patients are randomized in
double-blinded fashion.

At the next meeting at the Donders Institute at Nijmegen, the patient takes
place in a relaxing chair. A second, independent researcher will install the
transcranial magnetic stimulation (TMS) coils, one on each side of the patient.
The coils are positioned in such a fashion that both the coils can stimulate
the primary motor cortex. Then the independent researcher starts the
stimulation protocol. In the first session, the patient either receives
unilateral or bilateral stimulation. After this session, the patient fills in
a new McGill Pain questionnaire in order to measure the pain sensation after
the first session of TMS. Then the patient goes home for one month. At home,
another 4 McGill Pain Questionnaires are asked to fill in. After this, the
patient returns to the Donders Institute to take place in the relaxing chair in
order to be treated in the second session. Again, the patient either receives
unilateral or bilateral stimulation, depending on what was received during the
first session. Again, the patients are asked to fill in 4 new McGill Pain
questionnaires, one per week (See figure 1).

At the end of this session, the patient is invited to meet with the
investigator or independent researcher once more to talk about their
experiences and pain relief during the research. This interview takes place at
Radboudumc and is audio recorded.

All the McGill Pain questionnaires are analyzed by the researcher (Dylan
Henssen) using SPSS. Afterwards, the independent researcher discloses which
patient received uni- or bilateral in which order. The audio recorded
interviews are transcribed verbatim and analyzed using Atlas.tii.

Transcranial magnetic stimulation (TMS)

Invested time is expected to be approximately 6 hours
Adverse effects are minimal, primarily headaches.
Single provoked seizures are very rare (<1 in 10.000)