Short-latency afferent-induced facilitation and inhibition as predictors of thermally induced variations in corticomotor excitability.

Recently (Ansari et al., PeerJ 6:e6163, 2018a; Somatosens Mot Res 35:69-79, 2018b), we showed using transcranial magnetic stimulation (TMS) that focal application of innocuous thermal stimuli to the distal hand produced variable responses in terms of motor-evoked potential (MEP) suppression or enhancement. Here, we sought to investigate possible causes of this variability by examining circuits mediating sensorimotor integration and intra-cortical inhibition. Participants (n = 21) first underwent TMS to assess baseline corticomotor excitability by measuring MEPs at rest with the index finger wrapped in a gel pack at room temperature (24 °C). Then, conditioned protocols were applied to assess short-latency afferent inhibition (SAI), short-latency afferent facilitation (SAF) and short-interval intra-cortical inhibition (SICI). Following baseline measures, MEP modulation in response to distal cooling was recorded with the index finger wrapped in a gel pack at ~ 10 °C. At baseline, participants exhibited variable levels of SAI, SAF and SICI. Participant also exhibited variable responses to cooling with about half of them (11/21) showing suppressed excitability and one-third showing enhanced excitability (7/21). A linear regression analysis revealed that SAI and SAF proved to be good predictors of cooling-induced variations in corticomotor excitability but not SICI. These results provide novel evidence linking variations in SAI and SAF with those in corticomotor excitability elicited in response to focal thermal stimulation, suggesting that these markers could be used to predict responses to sensory stimulation protocols.

Variations in corticomotor excitability in response to distal focal thermal stimulation.

PURPOSE: This study investigated the effects of thermal stimulation on corticomotor excitability with transcranial magnetic stimulation (TMS). MATERIAL AND METHODS: Participants consisted of healthy young adults (n = 20) and seniors (n = 15). Each experimental session consisted of a baseline (BL) assessment, followed by a warming and a cooling protocol. At BL, recordings of motor evoked potentials (MEPs) and skin temperature were performed with the index finger covered with a 'neutral' gel pack (24 °C). For warming, the same measurements were performed, but with the index covered with a warmed gel pack (45 °C). The gel pack was kept for 5 min, and the measurements were performed at 1 min during warming and 5 and 10 min post. After a break, participants were tested with the cooling protocol (gel pack 10 °C) by repeating the same sequence as in the warming. RESULTS: The two thermal protocols induced the desired range of skin temperatures (warming = 35-45°; cooling = 13-24°). For MEP modulation, the primary analysis revealed no main effects or interactions, owing to the variability of responses to either warming or cooling stimulation. Further analysis of individual responses revealed that modulation, when present, was short-lasting and was characterized by a depression in about half of the participants. Facilitation was also observed, but only in smaller clusters, especially with cooling (13/35). Modulation in MEP amplitude did not correlate with changes in skin temperature. CONCLUSION: These results are consistent with previous reports regarding variability in response to sensory stimulation protocols. In the case of thermal stimulation, such variability likely reflects individual differences in the influences exerted by thermal afferents centrally.

Neurophysiological outcomes following mesenchymal stem cell therapy in multiple sclerosis.

OBJECTIVE: To report on neurophysiological outcomes derived from transcranial magnetic stimulation (TMS) following autologous mesenchymal stem cells (aMSCs) therapy in patients with multiple sclerosis (MS). METHODS: 20 adults with confirmed MS were recruited to participate in a phase II randomized control trial to assess the safety and potential benefits of aMSCs infusion. At Week 0, patients were randomly assigned to receive either aMSCs (n = 9) or a placebo infusion (n = 11). At Week 24, the placebo group received the aMSCs infusion. Blind assessments were performed at Weeks 0, 24 and 48. Outcomes consisted of TMS measures of corticomotor excitability and motor conduction along with measures of motor impairments and disability. RESULTS: Post-infusion, no change was detected in measures of corticomotor excitability or measures of intra- or interhemispheric inhibition. The latency of motor evoked potentials and central motor conduction time were significantly prolonged. These changes in motor conduction were associated with declines in hand dexterity post-infusion. CONCLUSION: Clinical and neurophysiological measures showed no improvement following aMSCs therapy in this cohort of MS patients. SIGNIFICANCE: Although promising, stem cell therapy remains elusive regarding its benefits in influencing disease activity in MS patients.

Effect of a tailored upper extremity strength training intervention combined with direct current stimulation in chronic stroke survivors: A Randomized Controlled Trial.

Strengthening exercises are recommended for managing persisting upper limb (UL) weakness following a stroke. Yet, strengthening exercises often lead to variable gains because of their generic nature. For this randomized controlled trial (RCT), we aimed to determine whether tailoring strengthening exercises using a biomarker of corticospinal integrity, as reflected in the amplitude of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS), could optimize training effects in the affected UL. A secondary aim was to determine whether applying anodal transcranial direct current stimulation (tDCS) could enhance exercise-induced training effects. For this multisite RCT, 90 adults at the chronic stage after stroke (>6 months) were recruited. Before training, participants underwent TMS to detect the presence of MEPs in the affected hand. The MEP amplitude was used to stratify participants into three training groups: (1) low-intensity, MEP <50 µV, (2) moderate-intensity, 50 µV < MEP < 120 µV, and (3) high-intensity, MEP>120 µV. Each group trained at a specific intensity based on the one-repetition maximum (1 RM): low-intensity, 35-50% 1RM; moderate-intensity, 50-65% 1RM; high-intensity, 70-85% 1RM. The strength training targeted the affected UL and was delivered 3X/week for four consecutive weeks. In each training group, participants were randomly assigned to receive either real or sham anodal tDCS (2 mA, 20 min) over the primary motor area of the affected hemisphere. Pre-/post-intervention, participants underwent a clinical evaluation of their UL to evaluate motor impairments (Fugl-Meyer Assessment), manual dexterity (Box and Blocks test) and grip strength. Post-intervention, all groups exhibited similar gains in terms of reduced impairments, improved dexterity, and grip strength, which was confirmed by multivariate and univariate analyses. However, no effect of interaction was found for tDCS or training group, indicating that tDCS had no significant impact on outcomes post-intervention. Collectively, these results indicate that adjusting training intensity based on the size of MEPs in the affected extremity provides a useful approach to optimize responses to strengthening exercises in chronic stroke survivors. Also, the lack of add-on effects of tDCS applied to the lesioned hemisphere on exercise-induced improvements in the affected UL raises questions about the relevance of combining such interventions in stroke. Clinical trial registry number: NCT02915185. https://www.clinicaltrials.gov/ct2/show/NCT02915185.

Modulation of corticomotor excitability in response to distal focal cooling.

BACKGROUND: Thermal stimulation has been proposed as a modality to facilitate motor recovery in neurological populations, such as stroke. Recently (Ansari, Remaud & Tremblay, 2018), we showed that application of cold or warm stimuli distally to a single digit produced a variable and short lasting modulation in corticomotor excitability. Here, our goal was to extend these observations to determine whether an increase in stimulation area could elicit more consistent modulation. METHODS: Participants (n = 22) consisted of a subset who participated in our initial study. Participants were asked to come for a second testing session where the thermal protocol was repeated but with extending the stimulation area from single-digit (SD) to multi-digits (MD, four fingers, no thumb). As in the first session, skin temperature and motor evoked potentials (MEPs) elicited with transcranial magnetic stimulation were measured at baseline (BL, neutral gel pack at 22 °C), at 1 min during the cooling application (pre-cooled 10 °C gel pack) and 5 and 10 min post-cooling (PC5 and PC10). The analysis combined the data obtained previously with single-SD cooling (Ansari, Remaud & Tremblay, 2018) with those obtained here for MD cooling. RESULTS: At BL, participants exhibited comparable measures of resting corticomotor excitability between testing sessions. MD cooling induced similar reductions in skin temperature as those recorded with SD cooling with a peak decline at C1 of respectively, -11.0 and -10.3 °C. For MEPs, the primary analysis revealed no main effect attributable to the stimulation area. A secondary analysis of individual responses to MD cooling revealed that half of the participants exhibited delayed MEP facilitation (11/22), while the other half showed delayed inhibition (10/22); which was sustained in the post-cooling phase. More importantly, a correlation between variations in MEP amplitude recorded during the SD cooling session with those recorded in the second session with MD cooling, revealed a very good degree of correspondence between the two at the individual level. CONCLUSION: These results indicate that increasing the cooling area in the distal hand, while still eliciting variable responses, did produce more sustained modulation in MEP amplitude in the post-cooling phase. Our results also highlight that responses to cooling in terms of either depression or facilitation of corticomotor excitability tend to be fairly consistent in a given individual with repeated applications.