Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study

Abstract

The pattern and role of brain plasticity in stroke recovery has been incompletely characterized. Both ipsilesional and contralesional changes have been described, but it remains unclear how these relate to functional recovery. Our goal was to correlate brain activation patterns with tissue damage, hemodynamics, and neurologic status after temporary stroke, using functional magnetic resonance imaging (fMRI). Transverse relaxation time (T2)-weighted, diffusion-weighted, and perfusion MRI were performed at days 1 (n = 7), 3 (n = 7), and 14 (n = 7) after 2 hr unilateral middle cerebral artery occlusion in rats. Functional activation and cerebrovascular reactivity maps were generated from contrast-enhanced fMRI during forelimb stimulation and hypercapnia, respectively. Before MRI, rats were examined neurologically. We detected loss of activation responses in the ipsilesional sensorimotor cortex, which was related to T2 lesion size (r = -0.858 on day 3, r = -0.979 on day 14; p < 0.05). Significant activation responses in the contralesional hemisphere were detected at days 1 and 3. The degree of shift in balance of activation between the ipsilesional and contralesional hemispheres, characterized by the laterality index, was linked to the T2 and apparent diffusion coefficient in the ipsilesional contralesional forelimb region of the primary somatosensory cortex and primary motor cortex at day 1 (r = -0.807 and 0.782, respectively; p < 0.05) and day 14 (r = -0.898 and -0.970, respectively; p < 0.05). There was no correlation between activation parameters and perfusion status or cerebrovascular reactivity. Finally, we found that the laterality index and neurologic status changed in parallel over time after stroke, so that when all time points were grouped together, neurologic status was inversely correlated with the laterality index (r = -0.571; p = 0.016). This study suggests that the degree of shift of activation balance toward the contralesional hemisphere early after stroke increases with the extent of tissue injury and that functional recovery is associated mainly with preservation or restoration of activation in the ipsilesional hemisphere.

Fig. 1.

Multislice ADC and T₂ maps (3 adjacent slices are shown) and single-slice CBF_i maps (same slice position as the left image of the ADC and T₂maps) at 1 d (top panel), 3 d (middle panel), and 14 d (bottom panel) after 2 hr middle cerebral artery occlusion. Each panel represents data from a single animal. Below the CBF_imaps is an outline of a coronal rat brain section centered 0.7 mm from bregma [reproduced from Paxinos and Watson (1997), with permission from Academic Press]. S1fl, Forelimb region of the primary somatosensory cortex; M1, primary motor cortex (Paxinos and Watson, 1997).

Fig. 2.

Plateau CBV change (ΔCBV_max[CO₂]) in the ipsilesional (gray bars) and contralesional (white bars) parietal cortex (A) and M1/S1fl (B) during 5% CO₂ inhalation at 1, 3, and 14 d after 2 hr middle cerebral artery occlusion (mean + SD; n = 7). *p < 0.05 versus contralesional. Insets show averaged ΔCBV_max[CO₂] maps of a coronal rat brain slice at the specific time points after stroke (data are averaged across animals). Gray arrowheads point to ROI locations in the parietal cortex (A) and M1/S1fl (B).

Fig. 3.

Averaged T₂-weighted images of coronal rat brain slices overlaid by statistical activation maps, calculated from the averaged activation-induced cerebral CBV changes (n = 7) (data are averaged across animals). The map of p values has been color-coded corresponding to the degree of significance (see bars below images). Thegraphs show the mean of the averaged time course of CBV changes (averaged across six on–off periods for each forelimb) in an ROI (5 voxels) in ipsilesional (right) and contralesional (left) M1/S1fl (mean ± SD;n = 7). Top row, 24 hr after stroke;middle row, 3 d after stroke; bottom row, 14 d after stroke. Right, Unimpaired forelimb stimulation (represented by the green bars in the graphs) induced significant activation responses in the contralateral (right) M1/S1fl at all time points. Stimulation of the left, impaired forelimb (represented by theblue bars in the graphs) resulted in diminished responsiveness in the right, ipsilesional M1/S1fl at 24 hr and 3 d after stroke. However, clear responses were found in the contralesional hemisphere. After 14 d, activation responses were predominantly in ipsilesional M1/S1fl. Infarction areas are characterized by increased T₂-weighted signal intensity.

Fig. 4.

Laterality indices during stimulation of the left, impaired (gray bars) and right, unimpaired forelimb (white bars) at 1, 3, and 14 d after 2 hr middle cerebral artery occlusion (mean ± SD;n = 7). The negative laterality indices during impaired forelimb stimulation at days 1 and 3 represent the enhanced relative activity in the contralesional hemisphere (i.e., ipsilateral to the stimulated forelimb) as compared with the ipsilesional hemisphere. At 14 d after stroke, the laterality index was near baseline, indicating that bulk activation was in the ipsilesional hemisphere (i.e., contralateral to the stimulated forelimb). *p < 0.05; ^#p = 0.052.

Fig. 5.

Relationship between lesion volume and plateau CBV change (ΔCBV_max[act.]) in ipsilesional M1/S1fl (A) and laterality index (B) during impaired forelimb stimulation at 1 d (×), 3 d (○), and 14 d (▪) after 2 hr middle cerebral artery occlusion (n = 7 for each time point). *p < 0.05.