Protocol Assessment of Motor Cortex rTMS for Treating Neuropathic Pain

Description of the research proceedings and study design This is a 3-parallel-group monocentric randomized study, in which 36 patients, aged between 18 and 80 years, suffering from painful peripheral neuropathy (DN4 and NRS pain scores ≥4/10), will be randomly assigned to one of three rTMS protocols: CHF-rTMS, SHF-rTMS, and ACC-iTBS. The group allocation of the patients will be performed by one investigator not involved in the experimental task or clinical assessment. Patients will be recruited in the Clinical Neurophysiology department of the Henri Mondor University Hospital, Créteil, France, where the research will take place

Screening and inclusion visits During a routine medical visit, the study will be explained and proposed to the eligible patients and a letter of information about the protocol will be given to them. The list of the patients receiving the letter of information will be collected to determine the ratio between the number of patients definitively included and the number of patients screened. After a delay of reflection of at least a week, patients who agree to perform this research will be convened for an inclusion visit. After checking the inclusion/exclusion criteria, the informed consent form will be completed and signed by the participant and duly countersigned by the investigator.

During this inclusion visit, performed two weeks after the rTMS intervention, information regarding demographic data (age, gender), medical history and the list of drug treatments will be collected. A pain diary of 13 pages will be given to the patient with one page per week presenting a 0-10 numeric pain intensity rating scale (NRS) per day and a box to indicate the number of pain attacks and analgesic pills taken in addition to the usual treatment for each day of the week (cf. Appendix). Finally a code will be assigned to the patient (first 3 letters of the surname and the inclusion number) and this code will be sent to the person responsible for the randomization between the three types of stimulation protocol (CHF-rTMS / SHF-rTMS / ACC-iTBS).

First assessment visit One week after the inclusion visit (i.e. one week before the rTMS intervention), the first complete assessment visit will be managed to record all the clinical and neurophysiological outcome measures assessed in this study.

Clinical outcome measures: Scales and questionnaires

In addition to the report of all the daily NRS scores from the patient's pain diary, the following questionnaires (annexes) will be filled by the patients, based on the overall assessment of the preceding week:

* 7-item Interference Scale of the Brief Pain Inventory (BPI) \[48\] to assess the impact of pain on the patient's daily functioning; this scale rates from 0 (does not interfere) to 10 (complete interference) the degree to which pain interfered with general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life (max score 70) * 0-5 pain Verbal Rating Scale (VRS) to assess the global painful feeling with adjectives reflecting pain intensity * Neuropathic Pain Symptom Inventory (NPSI) \[49\] based on 10 questions to quantitatively assess pain intensity according to various sensory descriptors (max total score 100), five subscores (burning (superficial) and pressing (deep) spontaneous pain, paroxysmal pain, evoked pain, paresthesia/dysesthesia), and 2 questions to assess the duration of spontaneous pain and the number of pain paroxysms on categorical scales * Pain Catastrophizing Scale (PCS) \[50\] based on 13 questions to quantitatively assess various types of negative feelings and emotions that can be associated with the tendency to catastrophizing (irrational thinking by the patient with the belief that her/his health condition is or will be worse than it actually is) and rated from 0 (not present) to 4 (permanent) (max score 52) * Hospital Anxiety and Depression scale (HAD) \[51\] based on 14 questions to quantitatively assess symptoms of anxiety or depression rated from 0 (not present) to 3 (maximal impairment) (max score 21 for each anxiety and depression dimension subscores) * Fatigue Severity Scale (FSS) \[52\] based on 9 questions to quantitatively assess the physical aspect of fatigue and its influence on daily functioning, especially related to medical illness (max score 63) * Leeds Sleep Evaluation Questionnaire (LSEQ) \[53\] based on 10 questions to quantitatively assess various aspects of sleep quality and early morning behavior, leading to four subscores: getting to sleep (items 1-3), quality of sleep (items 4-5), awakening following sleep (items 6-7), and behavior following awakening (items 8-10) (max score 100).

Neurophysiological outcome measures (1): Resting-state Electroencephalography (rsEEG)

* One period of 5 min of EEG will be recorded in the patients remaining calm and relaxed (resting state) without any particular task to perform and with eyes closed. The rsEEG will be recorded using a cap with 60 scalp electrodes and a 60-channel EEG machine (eXimia, Nexstim, Helsinki, Finland). Electrode impedance will be maintained below 5 kΩ. * EEG signal will be analyzed offline using MATLAB software (The MathWorks, Inc., Natick, MA, USA) and EEGLab Toolbox. Following an initial sampling frequency of 1,450 Hz, the EEG signal will be down-sampled to 256 Hz and bandpass filtered (1-97Hz, with a zero-phase 3rd-order Butterworth filter and the application of a 50 Hz (± 2 Hz) notch filter) using EEGLAB plugin Cleanline. Once the data reconstructed, continuous data will be segmented into 4 second, non-overlapping epochs. Independent Component Analysis (ICA) decomposition will be used to identify and reject blink artifacts. Amplitude-based automatic rejection ± 80 μV will be applied to reject epochs with eye movement activities. After visual inspection, channels with a rejection rate superior to 20% across trials will be rejected and will be interpolated with non-artifacted neighboring channels. * Analysis of the power spectral density (PSD) will be carried out using a Welch's method, with a 2-s window size, 50% overlapping Hamming window. PSD analysis will be performed by dividing the EEG signal into three frequency bands, according to what is known about how chronic pain affects the EEG signal \[54\]: the θ band (theta: 4-7 Hz), the α-β1 band (alpha: 8-12 Hz; beta1: 13-20 Hz), and the β2 band (beta2: 21-35 Hz). EEG signal power is thought to be increased in the θ band and possibly in the β2 band, but decreased in the α-β1 band in the presence of ongoing neuropathic pain. For each of these three frequency bands, the absolute (aPSD, μV2) and relative (rPSD, %) PSD values will be calculated, rPSD being defined as the ratio of the aPSD in a given frequency band to the overall aPSD value in the entire 4-35 Hz frequency band. * Also according to what is known about how chronic pain affects the EEG signal \[54\], the dominant peak frequency (DPF, Hz) will be determined for two different frequency bands of interest: the θ-α band (4-13 Hz) and the β1-β2 band (13-35 Hz). The DPF is thought be decreased in the θ-α band and increased in the whole β1-β2 band in neuropathic pain patients. * PSD and DPF will be computed on each of the 60 scalp recordings and a grand-averaging will be performed for 11 brain regions defined as follows according to EEG electrode sites: right Frontal (FP2, AF2, F2, F4, F6), left Frontal (FP1, AF1, F1, F3, F5), right Central (FC2, FC4, FC6, C2, C4, C6), left Central (FC1, FC3, FC5, C1, C3, C5), right Parietal (CP2, CP4, CP6, P2, P4, P6, P8), left Parietal (CP1, CP3, CP5, P1, P3, P5, P7), right Occipital (PO4, O2), left Occipital (PO3, O1), right Temporal (FT8, FT10, T8, TP8, TP10), left Temporal (FT7, FT9, T7, TP7, TP9), and midline (FPZ, AFZ, FZ, FCZ, CZ, CPZ, PZ, POZ, OZ). * Four metrics of EEG Functional Connectivity (FC) will be analyzed: magnitude square coherence (MSC), lagged coherence (LC), phase locking value (PLV), and phase lag index (PLI) \[55-58\]. The MSC is a function of the PSD of two electrodes x (Pxx) and y (Pyy), and the cross PSD (Pxy) of electrodes x and y in frequency f. The MSC is calculated as follows: MSCxy(f)=∣Pxy(f )∣²/(Pxx(f )Pyy(f)). The LC allowed to avoid the impact of volume conduction of the EEG signal and takes into account the imaginary part of the cross-spectrum coherence. LC is calculated as follows: LC(f)=imag(C(f))/square(1-real(C(f))²), where imag(C(f)) and real(C(f)) are the imaginary part and the real part of the cross-spectrum in a frequency f. The PLV characterizes the phase synchronization between two narrow-band signals for two time-series. The PLV is calculated as follows: PLV(t) ≜ \|E\[ejΔφ(t)\]\|, where Δφ(t) is the phase difference of two signal (using Hilbert transform). PLV range from 0 for a random phase relationship to 1 for a fixed phase relationship. However, when computing synchrony between pairs of electrodes or cortical locations, nonzero PLVs can arise from a single source contributing to both signals because of volume conduction or limited spatial resolution (linear mixing) and not corresponding to a "true" phase locking between two distinct signals. To distinguish between these two conditions, the PLI will be measured, which is equal to zero in the case of linear mixing (completely symmetric phase distribution) and nonzero when there is a consistent phase difference (phase lag) between two time-series (maximum 1 for completely asymmetric phase distribution). The PLI is calculated as follows: PLI(t) ≜ \|E(sign(Δφ(t)\|. * The FC metrics (MSC, LC, PLV, PLI) will be assessed between all pairs of scalp electrodes (pairwise measures, resulting in a 60x60 FC matrix) for each frequency band (θ, α, β1, β2). Averaged values of the FC metrics will also be computed between the 10 right and left brain regions (as defined above), resulting in a 10x10 FC matrix to assess intrahemispheric and interhemispheric FC. * Finally, we will perform a graph analysis of the FC metrics to extract the following variables: clustering coefficient (CC), modularity (MOD), characteristic path length (CPL), and global efficiency (GE) \[59,60\]. The CC and MOD are thought to reflect the functional segregation properties of a complex network. On the other hand, CPL and GE are thought to reflect functional integration of a complex network. An increase vs. decrease in CC and CPL defines a 'regular' vs. 'random' organization typology, respectively. Finally, the Eigenvector centrality (EC), or nodal centrality, will be determined to quantify the importance of a single node within the entire network \|61\]. All FC graph variables will be calculated on the weighted connectivity matrices for each band and for each FC metric.

Neurophysiological outcome measures (2): TMS-EEG evoked potentials (TEPs)

* Following the 5 minutes of rsEEG recording, using the same EEG electrode montage, TMS-EEG evoked potentials (TEPs) will be recorded to TMS pulses delivered with a focal figure-of-eight coil (mean/outer winding diameter 50/70 mm, biphasic pulse shape, pulse length 280 ms, focal area of the stimulation 0.68 cm² ) connected to an eXimia TMS Stimulator (Nexstim). All participants will be seated in an armchair in a relaxed position with eyes open, visually fixating on a cross 1 m in front of them to reduce eye movement. The primary motor cortex contralateral to pain (or of the left hemisphere) will be stimulated with the coil centered over the hand knob (hand motor cortical representation). At this stimulation site, the resting motor threshold (RMT) will be measured (as the minimum intensity of stimulation producing at least 5 motor evoked potentials (MEPs) of more than 50 µV amplitude in a series of 10 stimuli). Then, 60 pulses will be delivered at an intensity of 120% of RMT with a random interstimulus interval around 2 seconds (total examination time: less than 5 minutes). The precision and reproducibility of the TMS pulse location will be

• Average intensity of daily ongoing pain on a 0-10 numeric rating scale (NRS) [Срок оценки: From enrollment to 5 weeks after the last TMS session]
• Average intensity of daily ongoing pain on a 0-5 verbal rating scale (VRS) [Срок оценки: From enrollment to 5 weeks after the last TMS session]
• Patient global impression of change (PGIC) [Срок оценки: From enrollment to 5 weeks after the last TMS session]
• Symptomatic profile of neuropathic pain on the Neuropathic Pain Symptom Inventory (NPSI) [Срок оценки: From enrollment to 1 weeks after the last TMS session]
• Tendency to catastrophizing on the Pain Catastrophizing Scale (PCS) [Срок оценки: From enrollment to 1 weeks after the last TMS session]
• Anxiety and depression on the Hospital Anxiety and Depression scale (HAD) [Срок оценки: From enrollment to 1 weeks after the last TMS session]
• Fatigue on the Fatigue Severity Scale (FSS) [Срок оценки: From enrollment to 1 weeks after the last TMS session]
• Quality of sleep on the Leeds Sleep Evaluation Questionnaire (LSEQ). [Срок оценки: From enrollment to 1 weeks after the last TMS session]
• Absolute PSD from EEG recording [Срок оценки: From enrollment to 1 weeks after the last TMS session]
• Relative PSD from EEG recording [Срок оценки: From enrollment to 1 weeks after the last TMS session]
• TMS-EEG evoked potentials [Срок оценки: From enrollment to 1 weeks after the last TMS session]
• Global mean field power [Срок оценки: From enrollment to 1 weeks after the last TMS session]