Correlation between MEP latency at T0 and the after-effect of cTBS delivered using an AP-PA or PA-AP current direction on the magnitude of MEPs, TEPs (N100), and SEPs (at 103.5ms) recorded from the ipsilateral or contralateral hemisphere relative to the hemisphere onto which cTBS was applied.

<p>* p<0.05</p><p>** p<0.01</p><p>Correlation between MEP latency at T0 and the after-effect of cTBS delivered using an AP-PA or PA-AP current direction on the magnitude of MEPs, TEPs (N100), and SEPs (at 103.5ms) recorded from the ipsilateral or contralateral hemisphere relative to the hemisphere onto which cTBS was applied.</p

TEPs elicited by TMS delivered over M1 at T0.

<p>(A) Group-level average waveforms of the TEPs recorded before applying cTBS, and elicited by TMS pulses delivered in the AP-PA and PA-AP current direction. The grey areas represent the standard-deviation across individuals. Five peaks were consistently identified: P30, N40, P60, N100 and P190. (B) Group-level average magnitude (±standard deviation) and scalp topography of the P30, N40, P60, N100 and P190 elicited by TMS pulses delivered in the AP-PA and PA-AP directions.</p

Experimental design.

<p>The experiment included three recording time points: before cTBS (T0), immediately after cTBS (T1) and 20 minutes after cTBS (T2). Each recording was completed within 20 minutes and included four blocks of stimulation. In two of the four blocks, TMS was delivered to the hand area of the left or right M1 in order to record (1) MEPs from the first dorsal interosseous muscle (FDI) of the contralateral hand and (2) TEPs. In the other two blocks, transcutaneous electrical stimuli were delivered to the left or right median nerve at the level of the wrist in order to record (3) early-latency SEPs. The order of the blocks was identical in T0, T1 and T2 for each experiment.</p

MEP Latencies Predict the Neuromodulatory Effect of cTBS Delivered to the Ipsilateral and Contralateral Sensorimotor Cortex

<div><p>Background</p><p>Recently, it was shown that the highly variable after-effect of continuous theta-burst stimulation (cTBS) of the primary motor cortex (M1) can be predicted by the latency of motor-evoked potentials (MEPs) recorded before cTBS. This suggests that at least part of this inter-individual variability is driven by differences in the neuronal populations preferentially activated by transcranial magnetic stimulation (TMS).</p><p>Methods</p><p>Here, we recorded MEPs, TMS-evoked brain potentials (TEPs) and somatosensory-evoked potentials (SEPs) to investigate the effects of cTBS delivered over the primary sensorimotor cortex on both the ipsilateral and contralateral M1, and the ipsilateral and contralateral primary somatosensory cortex (S1).</p><p>Results</p><p>We confirm that the after-effects of cTBS can be predicted by the latency of MEPs recorded before cTBS. Over the hemisphere onto which cTBS was delivered, short-latency MEPs at baseline were associated with an increase of MEP magnitude (i.e. an excitatory effect of cTBS) whereas late-latency MEPs were associated with reduced MEPs (i.e. an inhibitory effect of cTBS). This relationship was reversed over the contralateral hemisphere, indicating opposite effects of cTBS on the responsiveness of the ipsilateral and contralateral M1. Baseline MEP latencies also predicted changes in the magnitude of the N100 wave of TEPs elicited by stimulation of the ipsilateral and contralateral hemisphere, indicating that this TEP component is specifically dependent on the state of M1. Finally, there was a reverse relationship between MEP latency and the effects of cTBS on the SEP waveforms (50–130 ms), indicating that after-effects of cTBS on S1 are opposite to those on M1.</p><p>Conclusion</p><p>Taken together, our results confirm that the variable after-effects of cTBS can be explained by differences in the neuronal populations activated by TMS. Furthermore, our results show that this variability also determines remote effects of cTBS in S1 and the contralateral hemisphere, compatible with inter-hemispheric and sensorimotor interactions.</p></div

Relationship between MEP latency at T0 and the after-effect of cTBS on the magnitude of MEPs, TEPs and SEPs ipsilateral and contralateral hemisphere relative to the hemisphere onto which cTBS was applied.

<p>(TMS delivered using an AP-PA current direction). (A) At the ipsilateral hemisphere, there was a significant negative correlation between MEP latency at T0 and change in MEP amplitude. Also note, at the contralateral hemisphere, the significant positive correlation between MEP latency and MEP amplitude, as well as (B) TEP N100 amplitude. (C) Finally, note the inverse correlation between MEP latency and the magnitude of the SEP waveform recorded from the ipsilateral and contralateral hemisphere, extending between approximately 50–130 ms, both at T1 and at T2. The grey areas mark the time intervals during which the correlation coefficients obtained at the ipsilateral and contralateral hemisphere were significantly different (p<0.05). (D) At 103.5 ms, the negative correlation between MEP latency at T0 and change in SEP amplitude arrives maximum.</p

Group-level average TEP waveforms recorded before (T0) and after (T1, T2) cTBS.

<p>On average, the magnitude of the N100 wave was decreased at both T1 and T2, regardless of the TMS current direction (AP-PA vs. PA-AP) and regardless of whether cTBS was delivered over the ipsilateral or contralateral hemisphere. A point-by-point repeated measures ANOVA with the factors ‘time’ (T0, T1, T2), ‘hemisphere’ (cTBS delibered to the ipsilateral or contralateral hemisphere) and ‘current direction’ was used to assess the effect of cTBS on the entire TEP waveform. The scalp maps show the topographical distribution of the N100 at the different times points and in the different conditions. The bar graphs show the change in N100 magnitude after cTBS (group-level average ± standard deviation). Significant changes are marked by an asterisk (p < .05; t-test against zero).</p

Group-level average SEP waveforms recorded before (T0) and after (T1, T2) cTBS.

<p>SEPs recorded from the ipsilateral/contralateral hemisphere were elicited by stimulation of the contralateral/ipsilateral hand, relative to the hemisphere onto which cTBS was applied. A point-by-point repeated measures ANOVA with the factors ‘time’ (T0, T1, T2), ‘hemisphere’ (cTBS delibered to the ipsilateral or contralateral hemisphere) and ‘current direction’ was used to assess the effect of cTBS on the entire SEP waveform. The time intervals showing a significant 3-way interaction between the three factors are shown in green. This included the N20 wave, as well as a longer-lasting period encompassing the late P100 wave. The bar graphs represent the change in magnitude of the N20 wave as well as the late P100 (99.5 ms) (group-level average ± standard deviation). Significant changes are marked by an asterisk (p < .05; t-test against zero). The scalp maps show the topographical distribution of the N20 and later P100 at the different times points and in the different conditions.</p

Group-level effects of cTBS on the magnitude of MEPs.

<p>(A) cTBS was delivered over M1, using biphasic pulses with an AP-PA or PA-AP current direction. The resting motor threshold (RMT) was significantly lower for TMS pulses delivered in the AP-PA as compared to the PA-AP direction (p<10⁻⁵; paired-sample t- test). The latency and amplitude of the MEPs elicited at baseline by AP-PA vs. PA-AP pulses delivered using an intensity of 120% the RMT were not significantly different. (B) Following cTBS delivered in the AP-PA current direction, the magnitude of MEPs elicited by stimulation of the ipsilateral and contralateral M1 tended to increase at both time points (T1 and T2). However, this effect was highly variable across individuals. (C) Similarly, following cTBS delivered in the PA-AP direction, the magnitude of MEPs elicited by stimulation of the ipsilateral and contralateral hemisphere tended to decrease in most participants. However, this effect was also highly variable across individuals. On average, there was no significant group-level effect of cTBS on MEP magnitude.</p

Exendin-4 prevents apoptosis induced by t-BHP.

<p>A, FACS analysis of apoptosis. Min6 cells were divided into four groups: control, t-BHP (200 µM for 24 hours), Exendin-4 (100 µM for 24 hours) and Exendin-4 (100 µM for 48 hours). Before being treated with t-BHP, the cells were treated with Exendin-4 for 24 or 48 hours). The cells were collected and stained with Annexin V and PI and analyzed by FACS. Figure B presents a summary of the results and includes a comparison of the apoptosis percentages of early-stage and late-stage. The data are expressed as the means±S.D. (<i>n</i> = 6). a, b, c and d indicate the blank control, t-BHP (200 µM for 24 hours), Exendin-4 (100 µM for 24 hours) and group comparisons with the Exendin-4 (100 µM for 48 hours) group (<i>p</i><0.05).</p

Image_1_Magnitude and Temporal Variability of Inter-stimulus EEG Modulate the Linear Relationship Between Laser-Evoked Potentials and Fast-Pain Perception.TIF

<p>The level of pain perception is correlated with the magnitude of pain-evoked brain responses, such as laser-evoked potentials (LEP), across trials. The positive LEP-pain relationship lays the foundation for pain prediction based on single-trial LEP, but cross-individual pain prediction does not have a good performance because the LEP-pain relationship exhibits substantial cross-individual difference. In this study, we aim to explain the cross-individual difference in the LEP-pain relationship using inter-stimulus EEG (isEEG) features. The isEEG features (root mean square as magnitude and mean square successive difference as temporal variability) were estimated from isEEG data (at full band and five frequency bands) recorded between painful stimuli. A linear model was fitted to investigate the relationship between pain ratings and LEP response for fast-pain trials on a trial-by-trial basis. Then the correlation between isEEG features and the parameters of LEP-pain model (slope and intercept) was evaluated. We found that the magnitude and temporal variability of isEEG could modulate the parameters of an individual's linear LEP-pain model for fast-pain trials. Based on this, we further developed a new individualized fast-pain prediction scheme, which only used training individuals with similar isEEG features as the test individual to train the fast-pain prediction model, and obtained improved accuracy in cross-individual fast-pain prediction. The findings could help elucidate the neural mechanism of cross-individual difference in pain experience and the proposed fast-pain prediction scheme could be potentially used as a practical and feasible pain prediction method in clinical practice.</p