The role of active stimulation in patients that have benefited from the long-term effects of MCS in the treatment of orofacial pain

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 (Tsubokawa, Katayama,
Yamamoto, Hirayama, & Koyama, 1991). After their first results, Tsubokawa*s
group introduced MCS into clinical care (Katayama, Tsubokawa, & Yamamoto, 1994;
Tsubokawa et al., 1991; Tsubokawa, Katayama, Yamamoto, Hirayama, & Koyama,
1993; Yamamoto, Katayama, Hirayama, & Tsubokawa, 1997). Over the years,
various reports were published and more indications for MCS were introduced and
tested (Brown & Barbaro, 2003; Canavero & Bonicalzi, 1995, 2002, 2007; Carroll
et al., 2000; Ebel, Rust, Tronnier, Boker, & Kunze, 1996; Fontaine, Hamani, &
Lozano, 2009; Garcia-Larrea et al., 1999; Herregodts, Stadnik, De Ridder, &
D'Haens, 1995; Hosomi et al., 2008; Im, Ha, Kim, & Son, 2015; Katayama, Fukaya,
& Yamamoto, 1998; Katayama et al., 2001; Katayama, Yamamoto, Kobayashi, Oshima,
& Fukaya, 2003; Lazorthes, Sol, Fowo, Roux, & Verdie, 2007; Lefaucheur,
Menard-Lefaucheur, Goujon, Keravel, & Nguyen, 2011; Louppe et al., 2013;
Mertens et al., 1999; Mogilner & Rezai, 2001; Nguyen et al., 1997; Nguyen et
al., 1999; Nuti et al., 2005; Peyron et al., 1995; Pirotte et al., 2005;
Rainov, Fels, Heidecke, & Burkert, 1997; Roux, Ibarrola, Lazorthes, & Berry,
2001; Saitoh et al., 2001; Saitoh et al., 2003; Saitoh et al., 2000; Smith et
al., 2001; Sokal et al., 2015; Sol et al., 2001; Son, Kim, Moon, & Kang, 2003;
Tani, Saitoh, Hirata, Kato, & Yoshimine, 2004; Tirakotai et al., 2004; Yamamoto
et al., 1997). 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 (Fontaine et al., 2009; Sokal et
al., 2015).
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. The
opioidergic system seems of great importance, as MCS is thought to modulate the
descending volleys towards the PAG and related nuclei (de Andrade, Mhalla,
Adam, Texeira, & Bouhassira, 2011; Fonoff et al., 2009; Maarrawi et al., 2007,
2013; Pagano et al., 2012). Activation of the striatal dopaminergic system
seems to be involved as well (Strafella, Paus, Barrett, & Dagher, 2001;
Strafella, Paus, Fraraccio, & Dagher, 2003). The release of norepinephrine from
the locus coeruleus(Viisanen & Pertovaara, 2010a) and serotonin from the
rostroventromedial medulla(Franca et al., 2013; Viisanen & Pertovaara, 2010b)
has been assumed to be involved in the analgesic effects of MCS as well.
Finally, mechanisms of the descending volleys in the spinal cord have also been
described(Franca et al., 2013; Viisanen, Ansah, & Pertovaara, 2012; Viisanen &
Pertovaara, 2010b). 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.(Andre-Obadia, Mertens, Gueguen, Peyron, & Garcia-Larrea, 2008;
Lefaucheur, Holsheimer, Goujon, Keravel, & Nguyen, 2010; Nguyen, Nizard,
Keravel, & Lefaucheur, 2011) 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 (DeFelipe & Farinas, 1992; Jones,
1984; Markram et al., 2004; White, 1989). Next to these neuroanatomical
substrates, corollary discharges and the placebo effect 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(Brasil-Neto, 2016). Although
several clinical trials showed a significant difference in analgesic effects
between sham and active stimulation of the primary motor cortex(Fregni et al.,
2006; Lee, Kim, Chun, & Kim, 2012; Velasco et al., 2008), the placebo effect is
also hypothesized to play a role in pain relief (Brasil-Neto, 2016; Zubieta &
Stohler, 2009).

The release of neurotransmitters can induce a direct effect on the brain, but
they can also affect other processes. It has been suggested in animal based
studies that electrical stimulation provides a positive effect on the
regeneration of motor axons (axonotmesis)(Nix & Hopf, 1983). Another study
shows that part of the neuroplasticity is caused by the release of
neurotransmitters. The participation of NMDA (N-meyhyl-D-aspartate) receptors
has is thought to play an important role in neuroplastic changes induced by
stimulation of the motor cortex(Ambriz-Tututi, Sanchez-Gonzalez, &
Drucker-Colin, 2012; Liebetanz, Nitsche, Tergau, & Paulus, 2002).

It is known that every thalamic nucleus receives feedback from the sixth
layer of the motor cortex, suggesting that the motor cortex and the thalamus
have extensive connections with each other (Sherman, 2016). The fact that these
connections and the zona incerta are involved in the regulation of pain, via
the GABA-ergic pathways, has been shown extensively(Bestmann, Baudewig,
Siebner, Rothwell, & Frahm, 2004; Cha, Ji, & Masri, 2013; Lucas, Ji, & Masri,
2011).

Is active stimulation still necessary in patients that suffer from chronic
orofacial pain who have been successfully treated with MCS for over 4 years or
is the analgesic effect caused by permanent axonotmesis?

Randomized controlled trial

For this study, we aim to include 12 patients that have undergone MCS for
treating chronic orofacial pain. All patients have responded favourable to MCS
(at least 40% pain reduction) and had at baseline a NRS > 5 (0= no pain, 10=
worst possible pain). All patients underwent insertion of electrodes for MCS
for chronic neuropathic pain between 2005 and 2012. The investigators (Erkan
Kurt and Dylan Henssen) are all part of the medical team that treats or has
treated these patients. All patients are contacted by Erkan Kurt in order to
inform them about this research. Afterwards, if the patients want to be
contacted, they receive an information package, including an information letter
and an informed consent form.

All patients are invited to the outpatient clinic to meet with the
investigators. After a consultation, the patients meet with the pain nurse
(Inge Arnts). She randomizes the patients into two groups in order to create a
double-blinded design; blinded for the patients and the investigators. All
patients hand over their remote controls of the MCS system. Then, one group
(group A) experiences one month without MCS, whereas group B, the other half of
the patients, undergo no changes to the MCS system. After one month, all of the
patients revisit the outpatient clinic and meet with the pain nurse again. She
switches the stimulation conditions between both groups. Again, patients go
home for one month. After this month, the patients return to the outpatient
clinic where the pre-existing settings are programmed. The remote controls of
the MCS system are then returned to their owners. All the patients meet with
the investigator (Dylan Henssen) to talk about their experiences during the
last two months. These interviews are audio recorded.
During the two months of the experimental settings, the patients are asked to
keep track of their daily quality of life and intake of pain medication
(medication type and dosage) by using a personal pain notebook. During the two
months at home, patients are allowed to use prescribed pain medication if
necessary. Their daily intake must be registered in their daily reports in
their notebooks. Also, patients are asked to fill in the McGill Pain
Questionnaire once a week.
The aforementioned protocol guarantees a double-blinded, randomized, controlled
trial. If patients do experience an uncontrollable increase of pain, patients
can always contact the outpatient clinic in order to schedule an appointment
with the pain nurse to reprogram their MCS device. After this, the patient
will continue the clinical trial. This means that if this request for
reprogramming occurs during the first month, the patient will continue the
clinical trial in his/her own group (Figure 1).
At the end of the research, the McGill Pain Questionnaires are analyzed using
SPSS by the investigator (Dylan Henssen). The audio recorded interviews are
transcribed verbatim and analyzed using Atlas.tii. Then, the pain nurse (Inge
Arnts) discloses which patient was part of which group.

The investigators believe that the pain will not increase during the month in
which the electrodes were switched off. We do not believe that patients will
experience the pain that they experienced before they were treated. When the
pain reoccurs, patients are always invited to the outpatient pain clinic at
Dekkerwald-Radboudumc. As always,we take the pain of the patients very serious.

If the pain reoccurs in an unbearable fashion, patients are requested to
contact the outpatient pain clinic immediatey. It is always possible to
reprogram the settings of the MCS system.