Association Between Responsiveness to Transcranial Magnetic Stimulation and Interhemispheric Functional Connectivity of Sensorimotor Cortex in Older Adults

Abstract

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is a promising therapeutic technique, and is believed to accomplish its effect by influencing the stimulated and remotely connected areas. However, responsiveness to rTMS shows high interindividual variability, and this intersubject variability is particularly high in older adults. It remains unclear whether baseline resting-state functional connectivity (rsFC) contributes to this variability in older adults. The aims of this study are to (1) examine rTMS effects over the primary motor cortex (M1) in older adults, and (2) identify baseline network properties that may contribute to the interindividual variability. Methods: We tested response to intermittent theta burst stimulation (iTBS), an effective rTMS protocol, over M1 by using both electromyography and resting-state functional magnetic resonance imaging in older adults. Outcome measures included motor-evoked potential (MEP) elicited by single-pulse transcranial magnetic stimulation and rsFC before and after an iTBS session. Results: iTBS significantly increased MEP amplitudes and rsFC between the stimulation site, sensorimotor cortex, and supplementary motor area (SMA) in older adults. iTBS-induced changes in MEP amplitude were positively correlated with increases in interhemispheric rsFC after iTBS. Furthermore, older adults with lower baseline interhemispheric rsFC between sensorimotor cortex and SMA exhibited stronger MEP response after iTBS. Discussion: Findings of the study suggest that different levels of interhemispheric communication during resting state might contribute to the response heterogeneity to iTBS in older adults. Interhemispheric rsFC may have great potential serving as a useful marker for predicting iTBS responsiveness in older adults. ClinicalTrials.gov ID: 1707654427 Impact statement Factors contributing to interindividual variability of the responsive to repetitive transcranial magnetic stimulation (rTMS) in older adults remain poorly understood. In this study, we examined the effects of rTMS over the primary motor cortex in older adults, and found that response to rTMS is associated with prestimulation interhemispheric connectivity in the sensorimotor and premotor areas. Findings of the study have great potential to be translated into a connectivity-based strategy for identification of responders for rTMS in older adults.

Keywords: functional connectivity; interindividual variability; older adults; theta burst stimulation; transcranial magnetic stimulation (TMS).

FIG. 1.

Experimental procedures. Each participant took part in two sessions to complete this study. During the first session, participants underwent the UDS Neuropsychological Battery. During the second session, outcome measures including cortical excitability and resting-state functional connectivity were acquired immediately before and after the iTBS. Single-pulse TMS was applied over the left primary motor cortex to assess aMT and other cortical excitability measures. aMT, active motor threshold; iTBS, intermittent theta burst stimulation; MRI, magnetic resonance imaging; TMS, transcranial magnetic stimulation; UDS, Uniform Data Set.

FIG. 2.

Parameters derived from aIO curve fitted by the Boltzmann equation. a = Change in amplitude of MEP across TMS intensities, b = the spread of the curve, s₀ = sensitivity index (i.e., midpoint of the curve = TMS intensity at which 0.5a + ɛ₀ was elicited). aIO, active input–output; MEP, motor-evoked potential.

FIG. 3.

The aIO curve was used to model the MEP amplitudes as a function of TMS intensity (% motor threshold) by fitting the data to a Boltzmann equation. Red line denotes the pre-iTBS cortical excitability profile, and blue line denotes the post-iTBS cortical excitability profile. The inset represents the Boltzmann curve fit to the aIO curve of each participant within the green zone for both pre-iTBS and post-iTBS conditions.

FIG. 4.

Brain regions that exhibited increased resting-state functional connectivity with the stimulation site (i.e., left primary motor cortex or M1) after iTBS. Results are cluster-size, FDR corrected for multiple comparisons (Z > 2.92; p < 0.005) and are overlaid on the MNI template. FDR, false discovery rate.

FIG. 5.

(A) Partial correlations between changes in IHFC (ΔIHFC) and λ₁ΔMEPs. Resting-state functional connectivity between the left primary motor cortex (M1) and right somatosensory cortex (S1), between left M1 and right M1, and between left S1 and right S1 was positively correlated with changes in MEPs (i.e., λ₁ΔMEPs). The Pearson correlation coefficients (r) and p-values are displayed. The Pearson partial correlations are computed controlling for cognitive performance measured by the UDS Neuropsychological Battery. (B) Partial correlations between baseline IHFC and λ₁ΔMEPs in response to iTBS. Resting-state functional connectivity between the left M1 and right M1, between left M1 and right S1, and between left S1 and right SMA was negatively correlated with λ₁ΔMEPs. The shaded error bands indicate 95% confidence intervals. IHFC, interhemispheric functional connectivity; SMA, supplementary motor area.

FIG. 6.

(A) Partial correlations between changes in IHFC (ΔIHFC) and aMT. Functional connectivity within the sensory motor cortex was negatively correlated with aMT. (B) Partial correlations between baseline IHFC and aMT are provided. Functional connectivity within the sensory motor cortex was positively correlated with aMT. The Pearson correlation coefficients (r) and p-values are displayed. The Pearson partial correlations are computed controlling for cognitive performance measured by the UDS Neuropsychological Battery. The shaded error bands indicate 95% confidence intervals.