ABSTRACT
BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) at high frequency (HF) is an effective treatment of neuropathic pain. The classical HF-rTMS protocol (CHF-rTMS) includes a daily session for one week as an induction phase of treatment followed by more spaced sessions. Another type of protocol without an induction phase and based solely on spaced sessions of HF-rTMS (SHF-rTMS) has also been shown to produce neuropathic pain relief. However, CHF-rTMS and SHF-rTMS of M1 have never been compared regarding their analgesic potential. Another type of rTMS paradigm, called accelerated intermittent theta burst stimulation (ACC-iTBS), has recently been proposed for the treatment of depression, the other clinical condition for which HF-rTMS is proposed as an effective therapeutic strategy. ACC-iTBS combines a high number of pulses delivered in short sessions grouped into a few days of stimulation. This type of protocol has never been applied to M1 for the treatment of pain. METHODS/DESIGN: The objective of this single-centre randomized study is to compare the efficacy of three different rTMS protocols for the treatment of chronic neuropathic pain: CHF-rTMS, SHF-rTMS, and ACC-iTBS. The CHF-rTMS will consists of 10 stimulation sessions, including 5 daily sessions of 10Hz-rTMS (3,000 pulses per session) over one week, then one session per week for 5 weeks, for a total of 30,000 pulses delivered in 10 stimulation days. The SHF-rTMS protocol will only include 4 sessions of 20Hz-rTMS (1,600 pulses per session), one every 15 days, for a total of 6,400 pulses delivered in 4 stimulation days. The ACC-iTBS protocol will comprise 5 sessions of iTBS (600 pulses per session) completed in half a day for 2 consecutive days, repeated 5 weeks later, for a total of 30,000 pulses delivered in 4 stimulation days. Thus, CHF-rTMS and ACC-iTBS protocols will share a higher total number of TMS pulses (30,000 pulses) compared to SHF-rTMS protocol (6,400 pulses), while CHF-rTMS protocol will include a higher number of stimulation days (10 days) compared to ACC-iTBS and SHF-rTMS protocols (4 days). In all protocols, the M1 target will be defined in the same way and stimulated at the same intensity using a navigated rTMS (nTMS) procedure. The evaluation will be based on clinical outcomes with various scales and questionnaires assessed every week, from two weeks before the 7-week period of therapeutic stimulation until 4 weeks after. Additionally, three sets of neurophysiological outcomes (resting-state electroencephalography (EEG), nTMS-EEG recordings, and short intracortical inhibition measurement with threshold tracking method) will be assessed the week before and after the 7-week period of therapeutic stimulation. DISCUSSION: This study will make it possible to compare the analgesic efficacy of the CHF-rTMS and SHF-rTMS protocols and to appraise that of the ACC-iTBS protocol for the first time. This study will also make it possible to determine the respective influence of the total number of pulses and days of stimulation delivered to M1 on the extent of pain relief. Thus, if their analgesic efficacy is not inferior to that of CHF-rTMS, SHF-rTMS and especially the new ACC-iTBS protocol could be an optimal compromise of a more easy-to-perform rTMS protocol for the treatment of patients with chronic neuropathic pain.
ABSTRACT
Diagnosis and management of chronic neuropathic pain are challenging, leading to current efforts to characterize 'objective' biomarkers of pain using imaging or neurophysiological techniques, such as electroencephalography (EEG). A systematic literature review was conducted in PubMed-Medline and Web-of-Science until October 2021 to identify EEG biomarkers of chronic neuropathic pain in humans. The risk of bias was assessed by the Newcastle-Ottawa-Scale. Experimental, provoked, or chronic non-neuropathic pain studies were excluded. We identified 14 studies, in which resting-state EEG spectral analysis was compared between patients with pain related to a neurological disease and patients with the same disease but without pain or healthy controls. From these heterogeneous exploratory studies, some conclusions can be drawn, even if they must be weighted by the fact that confounding factors, such as medication and association with anxio-depressive disorders, are generally not taken into account. Overall, EEG signal power was increased in the θ band (4-7Hz) and possibly in the high-ß band (20-30Hz), but decreased in the high-α-low-ß band (10-20Hz) in the presence of ongoing neuropathic pain, while increased γ band oscillations were not evidenced, unlike in experimental pain. Consequently, the dominant peak frequency was decreased in the θ-α band and increased in the whole-ß band in neuropathic pain patients. Disappointingly, pain intensity correlated with various EEG changes across studies, with no consistent trend. This review also discusses the location of regional pain-related EEG changes in the pain connectome, as the perspectives offered by advanced techniques of EEG signal analysis (source location, connectivity, or classification methods based on artificial intelligence). The biomarkers provided by resting-state EEG are of particular interest for optimizing the treatment of chronic neuropathic pain by neuromodulation techniques, such as transcranial alternating current stimulation or neurofeedback procedures.