Sessions of Prolonged Continuous Theta Burst Stimulation or High-frequency 10 Hz Stimulation to Left Dorsolateral Prefrontal Cortex for 3 Days Decreased Pain Sensitivity by Modulation of the Efficacy of Conditioned Pain Modulation

Abstract

10Hz repetitive transcranial magnetic stimulation (10Hz-rTMS) to the left dorsolateral prefrontal cortex (L-DLPFC) produces analgesia, probably by activating the pain modulation system. A newer rTMS paradigm, called theta burst stimulation (TBS), has been developed. Unlike 10Hz-rTMS, prolonged continuous TBS (pcTBS) mimics endogenous theta rhythms, which can improve induction of synaptic long-term potentiation. Therefore, this study investigated whether pcTBS to the L-DLPFC reduced pain sensitivity more efficiently compared with 10Hz-rTMS, the analgesic effects lasted beyond the stimulation period, and the reduced pain sensitivity was associated with increased efficacy of conditioned pain modulation (CPM) and/or intra-cortical excitability. Sixteen subjects participated in a randomized cross-over study with pcTBS and 10Hz-rTMS. Pain thresholds to heat (HPT), cold (CPT), pressure (PPT), intra-cortical excitability assessment, and CPM with mechanical and heat supra-pain threshold test stimuli and the cold pressor test as conditioning were collected before (Baseline), 3 (Day3) and 4 days (Day4) after 3-day session of rTMS. HPTs and PPTs increased with 10Hz-rTMS and pcTBS at Day3 and Day4 compared with Baseline (P=0.007).Based on pooled data from pcTBS and 10Hz-rTMS, the increased PPTs correlated with increased efficacy of CPM at Day3 (P=0.008), while no correlations were found at Day4 or with the intracortical excitability.Perspective: Preliminary results of this comparative study did not show stronger pain sensitivity reduction by pcTBS compared with 10Hz-rTMS to the L-DPFC. Both protocols maintained increased pain thresholds up to 24-hours after the last session, which were partially associated with modulation of CPM efficacy but not with the intra-cortical excitability changes.

Prolonged Continuous Theta Burst Stimulation of the Motor Cortex Modulates Cortical Excitability But not Pain Perception

“…Therefore, our results do not allow us to establish a relationship between the change of CE and analgesia induced by intracortical modulation with pTBS in healthy subjects. Nevertheless, different techniques used to measure pain threshold should be mentioned as a possible explanation for dissimilar findings compared to previous pain-related pTBS studies (Moisset et al, 2015;De Martino et al, 2019). Also, we cannot exclude type II error risk if true differences in thermal thresholds are moderate-sized.…”

“…The main limitation of our study is that, unlike other pTBS studies (Moisset et al, 2015 ; De Martino et al, 2019 ), we did not include non-pcTBS or conventional HF-rTMS as a positive control to verify the analgesic effect previously demonstrated by HF-rTMS/cTBS studies (Summers et al, 2004 ; Yoo et al, 2006 ; Nahmias et al, 2009 ; Borckardt et al, 2011 ). However, for testing stimulation-induced changes of CE, HF-rTMS would not be appropriate as a positive control since previous studies showed that the after-effects of rTMS-induced change in CE were highly variable and inhomogeneous among individuals (Maeda et al, 2000 ; Pell et al, 2011 ).…”

“…It is supposed that various rTMS paradigms affect A-delta-fiber and C-fiber-mediated induced pain in different ways (Leo and Latif, 2007 ). Also, stimulation-induced changes in pain perception in some rTMS (Summers et al, 2004 ; Lefaucheur et al, 2010 ; de Andrade et al, 2011 ) and TBS (Csifcsak et al, 2009 ; Torta et al, 2013 ; Moisset et al, 2015 ; De Martino et al, 2019 ) studies may be explained by the various measurement methods used. Laser and cold stimulation are standard methods in measuring pain perception.…”

“…Regarding pTBS, only two studies with healthy subjects using pcTBS examined the analgesic effect, with both yielding positive results (Moisset et al, 2015 ; De Martino et al, 2019 ) despite different cortical areas were targeted (M1 and prefrontal cortex, respectively).…”

“…These opposite results may be explained by the difference in the processing of acute provoked pain in healthy subjects and chronic pain symptoms, which are associated with maladaptive neuroplastic processes (Antal and Paulus, 2010 ). Interestingly, pcTBS studies have also shown that facilitatory pcTBS results in analgesic effects in healthy subjects (Moisset et al, 2015 ; De Martino et al, 2019 ). Overall, the exact mechanisms of action of rTMS-induced analgesic effects remain unclear and depend on many stimulation parameters.…”