The role of ipsilateral premotor cortex in hand movement after stroke

Abstract

Movement of an affected hand after stroke is associated with increased activation of ipsilateral motor cortical areas, suggesting that these motor areas in the undamaged hemisphere may adaptively compensate for damaged or disconnected regions. However, this adaptive compensation has not yet been demonstrated directly. Here we used transcranial magnetic stimulation (TMS) to interfere transiently with processing in the ipsilateral primary motor or dorsal premotor cortex (PMd) during finger movements. TMS had a greater effect on patients than controls in a manner that depended on the site, hemisphere, and time of stimulation. In patients with right hemiparesis (but not in healthy controls), TMS applied to PMd early (100 ms) after the cue to move slowed simple reaction-time finger movements by 12% compared with controls. The relative slowing of movements with ipsilateral PMd stimulation in patients correlated with the degree of motor impairment, suggesting that functional recruitment of ipsilateral motor areas was greatest in the more impaired patients. We also used functional magnetic resonance imaging to monitor brain activity in these subjects as they performed the same movements. Slowing of reaction time after premotor cortex TMS in the patients correlated inversely with the relative hemispheric lateralization of functional magnetic resonance imaging activation in PMd. This inverse correlation suggests that the increased activation in ipsilateral cortical motor areas during movements of a paretic hand, shown in this and previous functional imaging studies, represents a functionally relevant, adaptive response to the associated brain injury.

Fig 1.

In controls, choice RT tasks (Right) produced more overall, and more bilateral fMRI activation than simple RT tasks (Left). Activation from left- and right-hand groups have been combined by rotating the data for left-hand movement about the midline. The left hemisphere is on the right-hand side of the images. Images are thresholded at Z > 3.1; cluster extent threshold of P < 0.01. Arrows indicate position of the central sulcus.

Fig 2.

Mean values for fMRI signal change within VOIs for healthy controls. More activity occurred during choice (white bars) than during simple (black bars) RT tasks (F = 69.562, P < 0.001) for all VOIs (CM1: t = 6.2, P < 0.001; IM1: t = 5.2, P < 0.001; cPMd: t = −7.0, P < 0.001; iPMd: t = −5.6, P < 0.001). More activity occurred contralateral than ipsilateral to the hand moved (F = 10.519, P = 0.006). This laterality difference was significant for M1 (simple: t = 3.10, P = 0.007; choice: t = 4.64, P < 0.001) but not PMd (simple: NS; choice: t = 1.83, P = 0.088). Error bars represent standard errors.

Fig 3.

Behavioral effects of TMS for the healthy control group. (A) During choice RT task an early time period exists during which ipsilateral TMS has an effect when applied over premotor (dotted line) but not primary motor (solid line) cortex. (B) Early involvement of iPMd is specific to choice (dotted line) rather than simple (solid line) RT tasks. (C) Early involvement of iPMd in choice RT was greater for left (dotted) than right (solid) hemisphere stimulation. Error bars represent standard errors.

Fig 4.

Variability occurred in the relative lateralization of fMRI activation in patients. (A and B) Representative activation maps for a simple RT task versus rest for two individual patients. Bilateral motor cortex activation was most common in more impaired patients (e.g., A, illustrating results from a patient with impairment score of 17.9). Predominantly contralateral activation (i.e., similar to the control pattern) was most common in less impaired patients (e.g., B, from a patient with impairment score of −6.2). We found a correlation between impairment and lateralization of fMRI activity (C) fMRI data are thresholded at Z >3.1, and a cluster extent threshold of P < 0.01.

Fig 5.

(A) TMS over iPMd during a simple RT task had distinct effects in patients (dotted line) and controls (solid line). Pulses at 100 ms slowed patients but not controls. This early slowing effect of iPMd TMS was only seen in controls during a choice RT task (see Fig. 3). (B) No clear differences between patients and controls were seen with TMS over iMC. Error bars represent standard errors.

Fig 6.

In patients significant correlation occurred between TMS and fMRI measures. Patients with a low PMd fMRI laterality index (i.e., relatively bilateral) during a simple RT task also showed a large slowing effect of 100-ms iPMd TMS during the same task. The upper confidence limit (one-tailed, P < 0.05) for percent change in RT with TMS for age-matched controls was −0.006%. Seven of 10 patients fall outside this limit.

Fig 7.

MRI guided confirmation of sites of TMS for patients (blue) and controls (yellow) in standard space. TMS targets for all subjects overlaid on the control fMRI maps (Z > 3.1, P < 0.01). (Left) PMd site; (Right) M1 site. Sagittal slices are at the mean × coordinate for each site (PMd, x = 24; M1, x = 40).