Longitudinal changes in resting-state brain activity in a capsular infarct model

Abstract

Strokes attributable to subcortical infarcts have been increasing recently in elderly patients. To gain insight how this lesion influences the motor outcome and responds to rehabilitative training, we used circumscribed photothrombotic capsular infarct models on 36 Sprague-Dawley rats (24 experimental and 12 sham-operated). We used 2-deoxy-2-[(18)F]-fluoro-D-glucose-micro positron emission tomography (FDG-microPET) to assess longitudinal changes in resting-state brain activity (rs-BA) and daily single-pellet reaching task (SPRT) trainings to evaluate motor recovery. Longitudinal FDG-microPET results showed that capsular infarct resulted in a persistent decrease in rs-BA in bilateral sensory and auditory cortices, and ipsilesional motor cortex, thalamus, and inferior colliculus (P<0.0025, false discovery rate (FDR) q<0.05). The decreased rs-BA is compatible with diaschisis and contributes to manifest the malfunctions of lesion-specific functional connectivity. In contrast, capsular infarct resulted in increase of rs-BA in the ipsilesional internal capsule, and contralesional red nucleus and ventral hippocampus in recovery group (P<0.0025, FDR q<0.05), implying that remaining subcortical structures have an important role in conducting the recovery process in capsular infarct. The SPRT training facilitated motor recovery only in rats with an incomplete destruction of the posterior limb of the internal capsule (PLIC) (Pearson's correlation, P<0.05). Alternative therapeutic interventions are required to enhance the potential for recovery in capsular infarct with complete destruction of PLIC.

Figure 1

Experimental set-up: grouping of experimental animals (top right), time line of longitudinal microPET scan (middle bar) and behavioral training (low bar) in the capsular stroke model. For the time line of longitudinal microPET scan, each rat was scanned five times: Baseline scanning before infarct lesioning, postlesion days 4, 7, 14, and 21 (PL 4, PL 7, PL 14, and PL 21) to longitudinally follow-up on changes in regional glucose metabolism from stroke onset to behavioral recovery. For the behavior training, initial single-pellet reaching task (SPRT) was performed 7 to 10 days before the surgery. Additional training was resumed 2 days after operation and continued until 21 days after the surgery. PET, positron emission tomography.

Figure 2

Histologic findings of the capsular infarct lesion using H&E (A), glial fibrillary acidic protein (GFAP) (B), and Luxol fast blue–PAS staining (C). Note the destruction of the internal capsule with minimal encroachment of the neighboring thalamus (arrow).

Figure 3

Motor recovery patterns in single-pellet reaching task (SPRT) performances for the three different groups after capsular infarct over time. Statistical significance was determined using Student's t-test (P<0.05). ^†SOG versus MRG; ^‡SOG versus PRG; *MRG versus PRG. SOG, sham-operated group; MRG, moderately recovered group; PRG, poorly recovered group.

Figure 4

Longitudinal change in resting-state brain activity (rs-BA) in the capsular infarct model over time at PL4, PL7, PL14, and PL21 in MRG, PRG, and SOG. Brain metabolic differences between baseline (PL0) and longitudinal scans were used to determine decrease or increase in rs-BA. Images were thresholded at a significant level of P<0.0025 after false discovery rate correction (q<0.05). The cortical network and ipsilesional inferior colliculus are impaired (colored in cyan to blue), and motor-related subcortical structures (internal capsule and red nucleus) and contralesional ventral hippocampus show increased activity (colored in yellow to red). The y coordinates indicate the distance from anterior commissure. MRG, moderately recovered group; PRG, poorly recovered group; SOG, sham-operated group; M, motor cortex; S, sensory cortex; Aud, auditory cortext; IC, internal capsule; RN, red nucleus; HT, hypothalamus; VH, ventral hippocampus; CC, corpus callosum; I.Coll, inferior colliculus; S.Coll, superior colliculus; RSG, retrosplenial cortex; LSN, lateral septal nucleus; PL, postlesion.

Figure 5

Schematic drawing showing the changes of resting-state brain activities (corrected, *P<0.05) during poststroke recovery period. Asterisk (*) indicates the significant brain activities compared with the basal brain activities (baseline scan). I, ipsilesional; C, contralesional; Sup. Coll., superior colliculus; Inf. coll, inferior colliculus; RSG, retrosplenial gyrus; IC, internal capsule; Red Nu., red nucleus; Vent. Hippo., ventral hippocampus; Lat. Sep. Nu., lateral septal nucleus; MRG, moderately recovered group; PRG, poorly recovered group; SOG, sham-operated group.

Figure 6

Correlation analyses of activity changes after single-pellet reaching task (SPRT) performances in the moderately recovered group (N=11). (A) Example plots of positive correlation between metabolic activity and SPRT in ipsilesional motor and sensory cortices (B) Example plots of negative correlation in the contralesional red nucleus and ventral hippocampus. Pearson's correlation analysis (P<0.04, false discovery rate (FDR) q<0.05). I, ipsilesional; C, contralesional; Nu., nucleus; Vent. Hippo., ventral hippocampus.