Summary of Our Long-Term Observations and Comparison with Published Human Studies Addressed to Different MCS Waveforms for Post-Stroke Pain
We first determined the long-term effects of burstMCS for refractory CPP adjunctive to cMCS and pharmacological therapy. Meaningful pain suppression was achieved after combined cMCS/burstMCS without stimulation-related side effects (e.g., seizure).
Our findings confirmed those of a small-scale MCS study reporting similar results despite a shorter observation period . In addition, adjunctive pain medication (pregabalin) was removed after 7 months; this medication is usually prescribed as adjunctive pharmacological seizure treatment. The results during the observation period (60 months) should be interpreted with caution, because the effects of MCS are well known to deteriorate over longer time frames. In general, the lack of a sham treatment period (MCS “off”) limits our findings, because our patient was not blinded to the activation of the device. Furthermore, a trial period was not performed, because MCS responsiveness in general appears to occur over relatively long time periods of weeks rather than days. To date, no evidence exists either in favor of or against the true value of MCS trials, particularly in view of the long-term responsiveness to MCS. The lead location may explain the clinical observations and support an enhanced response in the upper limb.
The concept of applying electrical stimulation targeting the motor cortex dates to the early 1970s, and was an incidental consequence of observations made by Penfield and colleagues in epilepsy surgery resecting the postcentral gyrus. In later years, extension of the resection area toward the precentral strip was found to promote sufficient pain suppression . Although cMCS has been applied in a broad variety of chronic pain disorders, trigeminal facial pain and post-stroke pain exhibit the highest degree of responsiveness and are classified as the two major indications for cMCS [14, 15].
Since the pioneering work of Yamamoto and colleagues, several uncontrolled cohort studies have confirmed that cMCS is safe and efficient for the treatment of post-stroke pain and trigeminal facial pain. Notably, among hardware-related failures or dysfunction, seizure, implant infection, and rarely post-implant hematomas have been observed after MCS surgery. Despite several recommendations, MCS therapy has been performed with heterogeneous implantation techniques, because some physicians prefer to perform MCS surgery according to intraoperative neurophysiologic recordings, whereas others use neuroimaging (functional sequences). In addition, some surgeons approach the central cortex area via a burrhole rather than performing more invasive craniotomy, and assess trial test stimulations before permanent MCS implantation; however, consensus is lacking regarding the usefulness and predictive value of a trial period for MCS treatment [6, 7, 9,10,11, 13, 16,17,18,19,20,21,22,23,24,25,26,27,28,29]. Velasco et al. performed the only existing randomized sham-controlled study in a heterogeneous, small cohort of patients with chronic neuropathic pain, with an observation period of 12 months . Most enrolled patients with pain had postherpetic neuralgia, and one patient had post-stroke pain (thalamic infarct). However, after 1 year, the participants with post-stroke pain perceived a significant reduction in pain (69%) with respect to allodynia and hyperalgesia, whereas pre-MCS hypesthesia remained unchanged, with the following MCS parameters: 40 Hz, 90 µsec, and 2.0–6.5 V .
In general, in view of the invasiveness of cMCS, efforts have been made to provide potential predictive measures for cMCS responsiveness [5, 29]. Yamamoto and co-workers have determined the predictive potential of pre-implantation pharmacological drugs such as morphine, thiamylal, and ketamine, and have demonstrated that patients with neuropathic pain who are sensitive to thiamylal and ketamine, and insensitive to morphine, display pronounced long-lasting cMCS responsiveness, thus indicating the potential utility of analgesic drugs in predicting cMCS outcome. However, these remarkable findings have not been further re-examined on a systemic evidence-based level .
TMS is a non-invasive first-line neuromodulation treatment in different drug-resistant chronic pain disorders; its response rate depends on parameters such as TMS frequency and the location of the lesion. In contrast to MCS treatment, previously performed TMS did not elicit a response in our patient; however, the available published literature indicates controversial findings regarding the predictive value of TMS before MCS implantation [1, 3]. MCS parameters for central post-stroke pain (CPSP) have usually been kept at frequencies between 1 and 20 Hz, and resulted in a broad response rate of 30–50% in CPSP [1, 6].
According to several human studies, non-invasive TMS targeting the motor cortex has used different frequencies (1 Hz–20 Hz), and better outcomes have been reported for 20 Hz-driven TMS. Notably, in some cases, 1 Hz TMS has been reported to increase pain intension/perception, whereas treatment with 20 Hz TMS elicits a sufficient response; more interestingly, cMCS implantation later in the course of pain treatment has achieved sustained cMCS outcomes [3, 5].
Mechanistic Insights into the Effects of Tonic and BurstMCS on Brain Pain Circuits Originating from Central Stroke
Along with observational cohort studies supporting the use of cMCS for chronic pain—in which trigeminal facial pain and post-stroke pain are classified as the most suitable disorders—neuroimaging studies (PET) and electrophysiological measures have shown that several brain areas are relevant to the mechanism of action of cMCS, including the thalamus, cingulate cortex, brainstem, orbitofrontal cortex, and, via descending pain-inhibiting pathways, the corticospinal tract .
Electrophysiological studies have shown that irregular burst discharges are often encountered in the posterolateral thalamus in patients with central thalamic pain after stroke. The more often irregular burst discharges are encountered, the greater the decrease in sensory response in the posterolateral thalamus. Decreased activity with abnormal burst discharge in the posterolateral sensory thalamus has been suggested to be associated with changes in cortical activity adjacent to the central sulcus, which might contribute to the generation of central thalamic pain . The ischemic lesion in our case report occurred between the ventral posterolateral nucleus and the pulvinar of the thalamus. In addition, because of thalamic stroke affecting the sensory nuclei–pulvinar zone of the thalamus, MCS appears likely to modulate parts of the medial thalamic pain pathway, which was not affected after stroke in our case. In addition, the cingulate cortex, brainstem, and corticospinal tracts have been suspected to play a key role in neural pain transmission and processing .
Although the precise mechanism of action of MCS remains to be established, experimental studies have provided valuable insights. Through behavioral tasks, immunohistochemistry (c-fos and serotonin expression), micro-PET, and electrophysiological recording, MCS has been found to alter c-fos/serotonin expression and activity in the thalamus, the periaqueductal grey, and the cerebellum. In addition, neuronal activity in the thalamic nuclei, which are responsible for sensory processing (nucleus ventralis posterolateralis), was induced by mechanical stimulation but was reversed by MCS treatment. These interesting experimental findings may partly explain the effects of MCS observed in humans, involving ascending and descending central circuits relevant to neural pain transmission . MCS using a burst stimulation pattern may interact with thalamo-cingulate plasticity, particularly with the intra-laminar nuclei of the thalamus, a key relay structure associated with pain attention [4, 34]. A burst-firing pattern of the thalamus (burst hyperactivity) may evoke short- and/or long-term plasticity in connected circuits such as the nociceptive thalamic-anterior cingulate pathway. The medial thalamic complex, for instance, is believed to potentiate anterior cingulate cortex neuronal activity through its burst-firing pattern. Such neuronal transmission enables temporal response and processing of peripheral persisting noxious stimuli (e.g., pain). The transition from acute to chronic pain may be a result of the dysrhythmicity of the thalamic-cingulate network responsible for pain attention and pain-induced fear/anxiety behavior [34, 35]. Of note, previously applied cMCS may have evoked a priming effect for further pain reduction, as observed under secondarily applied burstMCS in our report. Therefore, both MCS patterns (conventional and burst) may interact and induce changes in the neural transmission from the thalamus to the anterior cingulate cortex and back . Beyond its effects on the sensory brain and spinal cord pathways, MCS has been suggested to modulate pain attention by affecting orbitofrontal areas .
Pros and Cons of Minimally Invasive and Invasive Central Neurostimulation Therapies for Chronic Pain through MCS And DBS
Although consensus is lacking regarding standardized implantation techniques, stimulation parameters and outcome assessment, minimally invasive MCS and invasive DBS have been widely used to treat chronic pain conditions of different origins, leading to limited evidence, acceptance, comparability, recommendation, and interpretation of positive and negative outcomes of MCS and DBS. Various DBS targets have been explored, such as the thalamic sensory nuclei (ventralis posterolateralis), thalamic affective nuclei (centrum medianum parafascicularis), anterior cingulate cortex, periaqueductal grey, and most recently the posterior limb of the internal capsule [37,38,39]. Preliminary data from a study assessing thalamic DBS and MCS in neuropathic patients found similar effectiveness for brain stimulation modalities in a small cohort . However, the results have led to several concerns and promoted an ongoing debate regarding simultaneous combined MCS–DBS approaches instead of performing less invasive MCS before DBS [40, 41].
Proposal for Future Targeted MCS Clinical Trial Protocol
In the past, the main criticism in neurostimulation trials has been the lack of control groups (sham stimulation) to exclude and/or characterize the placebo effect, which is known to promote pain suppression in a substantial portion of treated people [42, 43]. Although, for various reasons, some difficulties have arisen with the inclusion of sham-surgery/-stimulation, currently available MCS systems allow for easily performed sham stimulation and should be considered in further MCS trials comparing different waveforms (e.g., tonic versus burst). Hence, future targeted MCS clinical research should seek to classify and include potentially valuable predictive methodologies, such as TMS, to further investigate the effects of analgesic drugs, and to explore placebo control groups. All the described strategies would contribute to and extend current knowledge of relevant MCS induced changes in chronic pain pathways [3, 5, 29, 42, 43].