Modulating cortical connectivity in stroke patients by rTMS assessed with fMRI and dynamic causal modeling

Abstract

Data derived from transcranial magnetic stimulation (TMS) studies suggest that transcallosal inhibition mechanisms between the primary motor cortex of both hemispheres may contribute to the reduced motor performance of stroke patients. We here investigated the potential of modulating pathological interactions between cortical motor areas by means of repetitive TMS using functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM). Eleven subacute stroke patients were scanned 1-3 months after symptom onset while performing whole hand fist closure movements. After a baseline scan, patients were stimulated with inhibitory 1-Hz rTMS applied over two different locations: (i) vertex (control stimulation) and (ii) primary motor cortex (M1) of the unaffected (contralesional) hemisphere. Changes in the endogenous and task-dependent effective connectivity were assessed by DCM of a bilateral network comprising M1, lateral premotor cortex, and the supplementary motor area (SMA). The results showed that rTMS applied over contralesional M1 significantly improved the motor performance of the paretic hand. The connectivity analysis revealed that the behavioral improvements were significantly correlated with a reduction of the negative influences originating from contralesional M1 during paretic hand movements. Concurrently, endogenous coupling between ipsilesional SMA and M1 was significantly enhanced only after rTMS applied over contralesional M1. Therefore, rTMS applied over contralesional M1 may be used to transiently remodel the disturbed functional network architecture of the motor system. The connectivity analyses suggest that both a reduction of pathological transcallosal influences (originating from contralesional M1) and a restitution of ipsilesional effective connectivity between SMA and M1 underlie improved motor performance.

Fig. 1.

Regions of interest (ROI) and connectivity model used for estimating interregional coupling. Scans from patients with right-sided lesions were flipped at the midsagittal plane. Moving the left or right hand yielded significant activations in primary sensorimotor cortex (with local maxima in M1), lateral PMC, SMA and visual cortex. (A) Connectivity model for endogenous neural coupling (connections between V5 and contralateral premotor areas not shown). (B) Task-dependent modulations of connectivity for movements of the affected, unaffected and bilateral hands.

Fig. 2.

Interregional connectivity at baseline. Coupling parameters (rate constants in 1/s) indicate connection strength (changes in activation per second), which is also coded in the size and color of the arrows representing effective connectivity. Positive (green) values represent facilitatory, negative (red) values inhibitory influences on neuronal activity. The greater the absolute value (reflecting the rate constant of the observed influence in 1/s), the more predominant the effect one area has over another. (A) Endogenous coupling of motor areas irrespective of hand movements. (B) Hand-specific modulation of connections. Note the additional inhibitory coupling between contralesional (CL) M1 and ipsilesional (IL) M1 for movements of the affected hand.

Fig. 3.

Significant changes in endogenous coupling after stimulation of contralesional M1. (A) Significant increase in ipsilesional SMA–M1 coupling compared to both baseline and vertex stimulation. Significant trend (P= .09) of reduced endogenous inhibition exerted from M1-CL over M1-IL between vertex and M1 stimulation. (B) The reduction in inhibitory influences from M1-C1 upon M1-IL (red arrow in A) after rTMS over M1-CL significantly correlated with improvements in task performance (Pearson correlation).

Fig. 4.

Significant differences in modulatory influences during movements of the affected hand. (A) Pathological inhibition exerted from M1-CL over M1-IL at baseline that persisted after vertex stimulation. This influence was not significant after rTMS over M1-CL compared to both baseline (P= .02) and vertex stimulation (P= .02). (B) The degree of reduction in pathological coupling (disinhibition) significantly correlated with improvements in task performance of the paretic hand (Pearson correlation).