Improvement of tactile discrimination performance and enlargement of cortical somatosensory maps after 5 Hz rTMS

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to investigate mechanisms of brain functions and plasticity, but also as a promising new therapeutic tool. The effects of rTMS depend on the intensity and frequency of stimulation and consist of changes of cortical excitability, which often persists several minutes after termination of rTMS. While these findings imply that cortical processing can be altered by applying current pulses from outside the brain, little is known about how rTMS persistently affects learning and perception. Here we demonstrate in humans, through a combination of psychophysical assessment of two-point discrimination thresholds and functional magnetic resonance imaging (fMRI), that brief periods of 5 Hz rTMS evoke lasting perceptual and cortical changes. rTMS was applied over the cortical representation of the right index finger of primary somatosensory cortex, resulting in a lowering of discrimination thresholds of the right index finger. fMRI revealed an enlargement of the right index finger representation in primary somatosensory cortex that was linearly correlated with the individual rTMS-induced perceptual improvement indicative of a close link between cortical and perceptual changes. The results demonstrate that repetitive, unattended stimulation from outside the brain, combined with a lack of behavioral information, are effective in driving persistent improvement of the perception of touch. The underlying properties and processes that allow cortical networks, after being modified through TMS pulses, to reach new organized stable states that mediate better performance remain to be clarified.

Figure 1. Experimental Design

S1–S5 served to create a stable discrimination performance for the right D2. D4 and the left index finger (D2), serving as controls to assess spatial specificity of the effects, were tested at session S5 (pre-rTMS), because task familiarization has been shown to generalize across fingers. After S5, pre-fMRI measurements were performed, then two rTMS sessions separated by 45 min were applied over the left cortical index finger representation in SI. After the termination of rTMS, in session S6 the post-rTMS condition was measured for both index fingers and the ring finger. Then post-fMRI measurements were repeated. S7–S10 served to assess the recovery of the rTMS-induced effects on thresholds. Recovery of BOLD signals was assessed 3 h after termination of rTMS.

Figure 2. Effects of rTMS on Discrimination Thresholds

(A) Effects of rTMS on discrimination thresholds on the right index finger. Data represent average from all participants (n = 33). Dots represent mean thresholds, boxes show the standard errors, and whiskers correspond to the standard deviation. rTMS period over of the right index finger representation in left SI is indicated by an arrow. Shown are the baseline measurements from 5 consecutive sessions before rTMS. After session S5 (pre-rTMS condition), rTMS was applied. After rTMS (post-rTMS), discrimination thresholds were significantly reduced. (B) Comparison of the rTMS-induced threshold changes of D2 and D4, and of the time course of recovery (mean ± SEM). For D4, threshold changes were smaller, and persistence of threshold changes was shorter, compared to D2, suggesting that rTMS efficacy drops over a cortical distance spanning the representations between D2 and D4.

Figure 3. Perceptual Effects Evoked by 5 Hz TMS

Mean percent changes (± SEM) in discrimination thresholds after rTMS application expressed as post-rTMS relative to pre-rTMS (pre = 100 %). At the bottom, the site of assessment of tactile acuity is given in black, and the site of TMS application is given in blue. Threshold changes are shown for the right index finger after sham rTMS (red); right index finger after rTMS over left representation of right lower leg (yellow); right index finger after rTMS over left representation of right index finger (dark blue); right ring finger after rTMS over left representation of index finger (light blue); and left index finger after rTMS over left representation of right index finger (green).

Figure 4. Effects of rTMS on BOLD Signals

(A) rTMS effect on BOLD signals of a single participant detected pre-rTMS, post-rTMS, and 3 h after rTMS in the left SI ipsilateral to the rTMS site in the postcentral gyrus, and in the contralateral SII in the parietal operculum above the Sylvian fissure. Activations are projected on a rendered T1-weighted MRI dataset. Comparing pre- with post-rTMS fMRI sessions revealed enlarged activation and increased BOLD signal intensity in left SI ipsilateral to the rTMS site. These changes of BOLD signal characteristics recovered 3 h after termination of rTMS. (B) Psychometric functions illustrating the rTMS-induced improvement of discrimination threshold for the individual shown in (A). Correct responses in percent (red squares) are plotted as a function of separation distance together with the results of a logistic regression line (blue with blue diamonds). 50% levels of correct responses are shown as well as thresholds. Top graph, pre-rTMS; middle graph, post-rTMS condition, immediately after rTMS; bottom graph, recovery after 3 h. After rTMS there is a distinct shift in the psychometric functions towards lower separation distances by 0.20 mm, which recovers to pre-rTMS conditions 3 h later (pre-rTMS, 1.75 mm; recovered, 1.72 mm). (C) Random-effect analysis (paired t-test pre-post, right D2 stimulation) revealed significant changes of activated patterns localized in SI ipsilateral to the rTMS stimulated D2 representation (n = 12, pre- versus post-rTMS; threshold, p = 0.001, uncorrected for multiple comparisons; S1-parameters, 32 voxels; T-score = 4.15; x,y,z (mm), −54, −14, 50; Talairach position, postcentral gyrus, Brodmann area 3). (D) No changes of BOLD activity were found in the right hemisphere contralateral to the rTMS site (paired t-test pre- versus post-rTMS, left index finger stimulation; threshold, p = 0.001, uncorrected for multiple comparisons) and in SII. (E) Changes in activation pattern as obtained from random effects analysis (paired t-test pre- versus post-rTMS, right index finger stimulation; compare with [C]), superimposed on a glass brain for visualization. Views are from top (left grid), back (middle grid), and right (right grid).

Figure 5. Cortical Effects Evoked by 5 Hz TMS

Mean percent changes (± SEM) of the number of activated voxels after rTMS application expressed as post-rTMS relative to pre-rTMS (pre = 100 %). At the bottom, the site of cortical measurement (cortical representation of the index finger D2 in SI) is given in black, and the site of TMS application is given in blue. Shown are cortical changes in activation of the representation of the right index finger in left SI after sham rTMS (red); right index finger in left SI after rTMS over the lower leg representation in left SI (yellow); right index finger in left SI after rTMS over the index finger representation in left SI (blue); and left index finger in right SI after rTMS over the index finger representation in left SI (green).

Figure 6. Relation between Perceptual and Cortical rTMS-Evoked Changes

Linear correlation analysis (Pearson, r = 0.603, p = 0.037) between individual rTMS induced changes in BOLD signals in SI (difference in activated voxels post-pre) and associated changes of two-point discrimination thresholds post-pre.