Effects of Combined and Alone Transcranial Motor Cortex Stimulation and Mirror Therapy in Phantom Limb Pain: A Randomized Factorial Trial

Abstract

Phantom limb pain (PLP) is a frequent complication in amputees, which is often refractory to treatments. We aim to assess in a factorial trial the effects of transcranial direct current stimulation (tDCS) and mirror therapy (MT) in patients with traumatic lower limb amputation; and whether the motor cortex plasticity changes drive these results. In this large randomized, blinded, 2-site, sham-controlled, 2 × 2 factorial trial, 112 participants with traumatic lower limb amputation were randomized into treatment groups. The interventions were active or covered MT for 4 weeks (20 sessions, 15 minutes each) combined with 2 weeks of either active or sham tDCS (10 sessions, 20 minutes each) applied to the contralateral primary motor cortex. The primary outcome was PLP changes on the visual analogue scale at the end of interventions (4 weeks). Motor cortex excitability and cortical mapping were assessed by transcranial magnetic stimulation (TMS). We found no interaction between tDCS and MT groups (F = 1.90, P = .13). In the adjusted models, there was a main effect of active tDCS compared to sham tDCS (beta coefficient = -0.99, P = .04) on phantom pain. The overall effect size was 1.19 (95% confidence interval: 0.90, 1.47). No changes in depression and anxiety were found. TDCS intervention was associated with increased intracortical inhibition (coefficient = 0.96, P = .02) and facilitation (coefficient = 2.03, P = .03) as well as a posterolateral shift of the center of gravity in the affected hemisphere. MT induced no motor cortex plasticity changes assessed by TMS. These findings indicate that transcranial motor cortex stimulation might be an affordable and beneficial PLP treatment modality.

Keywords: mirror therapy; motor cortex; phantom limb pain; transcranial direct current stimulation; transcranial magnetic stimulation.

Figure 1.

Study Flowchart.

Figure 2.

(A and B) PLP longitudinal changes (VAS) per group. We reported raw mean ± standard errors. The main time point was at the end of intervention. Sample sizes at follow-up were the following: 1-month follow-up = 91, 2-month follow-up = 86. (C and D) Effect sizes within (panel C) and between groups (panel D) of different therapies on PLP (ΔVAS). Measures calculated using Cohen’s d effect sizes formula and reported with 95% confidence interval. Note = bars represent standard errors.

Figure 3.

Baseline and after treatment values of PLP, RLP, and PLS intensities per group.

Figure 4.

Cortical mapping changes after tDCS in the hand area of the affected hemisphere. At baseline (panels A and B) the cortical representation was disorganized and heterogeneous (panel A) with an anterior and medial center of gravity (COG) (panel B). After tDCS (panels C and D) the cortical representation reorganized, and the COG becomes less anterior (difference = −0.63 cm) and lateral (difference = 1.05 cm).

Figure 5.

TMS variables changes from baseline per group.