Shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients

Abstract

Background: Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the alleviation of acute and chronic pain by altering the activity of cortical areas involved in pain sensation. However, current single-coil rTMS technology only allows for effects in surface cortical structures. The ability to affect activity in certain deep brain structures may however, allow for a better efficacy, safety, and tolerability. This study used PET imaging to determine whether a novel multi-coil rTMS would allow for preferential targeting of the dorsal anterior cingulate cortex (dACC), an area always activated with pain, and to provide preliminary evidence as to whether this targeted approach would allow for efficacious, safe, and tolerable analgesia both in a volunteer/acute pain model as well as in fibromyalgia chronic pain patients.

Methods: Part 1: Different coil configurations were tested in a placebo-controlled crossover design in volunteers (N = 16). Tonic pain was induced using a capsaicin/thermal pain model and functional brain imaging was performed by means of H2(15)O positron emission tomography - computed tomography (PET/CT) scans. Differences in NRS pain ratings between TMS and sham treatment (NRS(TMS)-NRS(placebo)) which were recorded each minute during the 10 minute PET scans. Part 2: 16 fibromyalgia patients were subjected to 20 multi-coil rTMS treatments over 4 weeks and effects on standard pain scales (Brief Pain Inventory, item 5, i.e. average pain NRS over the last 24 hours) were recorded.

Results: A single 30 minute session using one of 3 tested rTMS coil configurations operated at 1 Hz consistently produced robust reduction (mean 70% on NRS scale) in evoked pain in volunteers. In fibromyalgia patients, the 20 rTMS sessions also produced a significant pain inhibition (43% reduction in NRS pain over last 24 hours), but only when operated at 10 Hz. This degree of pain control was maintained for at least 4 weeks after the final session.

Conclusion: Multi-coil rTMS may be a safe and effective treatment option for acute as well as for chronic pain, such as that accompanying fibromyalgia. Further studies are necessary to optimize configurations and settings as well as to elucidate the mechanisms that lead to the long-lasting pain control produced by these treatments.

Figure 1

Time course of numerical pain ratings (rTMS-sham) for each configuration. The inset shows the averaged area under the curve (AUC ± SEM). *, ^#: p < 0.05 for configuration B vs. configuration A and configuration C, respectively (one-way ANOVA).

Figure 2

Ratio of deep vs. superficial PET ROI activity changes (real treatment – sham treatment). Configurations A and B lead to a marked decrease, whereas configuration C lead to a small increase in activity ratio. *: indicated p < 0.05 (one way ANOVA).

Figure 3

Time course of BPI item 5 ratings (average pain in the last 24 hours) in fibromyalgia patients for the investigated configurations. T1, T10, T20: day of 1st, 10th, and 20th treatment session, respectively. PT1 and PT4: 72 hours and 4 weeks after the last treatment.*: p < 0.05 vs. 4coil 1 Hz real (2-way ANOVA with post hoc Bonferroni analysis).

Figure 4

Three coil configurations used in the PET imaging study are displayed over standard EEG10-20 coil positions. Large circles represent the coils, and the arrows within represent the direction of the primary electrical current within that coil at the point of contact with the scalp. Note that all configurations have the same four geometric centers for each coil, but the coils are variously rotated so as to shape the magnitude and direction of the resulting magnetic field. The diagram is a planar representation of the curved head surface such that F3, F4 (lateral) and Fpz (anterior) positions are actually approximately vertical and at 90 degrees from the most posterior (“top” coil).

Figure 5

Representative PET scan images of one subject during noxious heat pain stimulation after sham (left side of the panel) and real (ride side of the panel) multi-coil rTMS treatment. The red arrow indicates the ACC region. After sham treatment activity in the ACC region seems to be increased by the noxious heat pain stimulus. After real multi-coil rTMS this activation was not observed.