Interhemispheric neuroplasticity following limb deafferentation detected by resting-state functional connectivity magnetic resonance imaging (fcMRI) and functional magnetic resonance imaging (fMRI)

Abstract

Functional connectivity magnetic resonance imaging (fcMRI) studies in rat brain show brain reorganization following peripheral nerve injury. Subacute neuroplasticity was observed 2 weeks following transection of the four major nerves of the brachial plexus. Direct stimulation of the intact radial nerve reveals a functional magnetic resonance imaging (fMRI) activation pattern in the forelimb regions of the sensory and motor cortices that is significantly different from that observed in normal rats. Results of this fMRI experiment were used to determine seed voxel regions for fcMRI analysis. Intrahemispheric connectivities in the sensorimotor forelimb representations in both hemispheres are largely unaffected by deafferentation, whereas substantial disruption of interhemispheric sensorimotor cortical connectivity occurs. In addition, significant intra- and interhemispheric changes in connectivities of thalamic nuclei were found. These are the central findings of the study. They could not have been obtained from fMRI studies alone-both fMRI and fcMRI are needed. The combination provides a general marker for brain plasticity. The rat visual system was studied in the same animals as a control. No neuroplastic changes in connectivities were found in the primary visual cortex upon forelimb deafferentation. Differences were noted in regions responsible for processing multisensory visual-motor information. This incidental discovery is considered to be significant. It may provide insight into phantom limb epiphenomena.

Fig. 1

Functional averaged activation map resulting from electrical forepaw stimulation. (A) Left-paw stimulation in six healthy rats. (B) Right-paw stimulation in six healthy rats. (C) Left-paw stimulation in six right-paw-deafferented rats. (D) Right-paw stimulation in six right-paw-deafferented rats. Stimulation parameters were 2 mA, 3 ms, and 10 Hz. A p-value of 0.005 was the threshold used for plotting. The color bar displays task correlation from −1.0 to 1.0.

Fig. 2

Functional activation map in response to direct radial nerve stimulation. (A, B) Direct radial nerve stimulation to left limb in six healthy rats. (C, D) Direct radial nerve stimulation to left limb in six right-side-deafferented rats. (A, C) Slice centered 0.64 mm from bregma. (B, D) Slice centered −1.36 mm from bregma. Stimulation parameters were 1 mA, 1 ms, and 5 Hz. A p-value of 0.005 was the threshold used for plotting. An asterisk (*) indicates the hemisphere contralateral to simulation. The color bar displays task correlation from −1.0 to 1.0. See Material and Methods for abbreviations.

Fig. 3

Percent signal change in response to direct radial nerve stimulation. Time-courses averaged across both deafferented (black) and healthy control (red) rats. Activated voxels originated in three different regions of the sensorimotor system. Stimulation parameters were 1 mA, 1 ms, and 5 Hz. A p-value of 0.005 was the threshold considered for activation. Error bars indicate standard error of the mean.

Fig. 4

Resting-state fcMRI seed voxel correlation maps. (A) Map generated from a normal healthy rat. (B) Map generated from a deafferented rat. Seed region located in the right S1FL region (ipsilateral to the right denervated forelimb in the experimental animals). The seed region has the highest correlation and is shown in yellow. Presented slice located −0.64 mm from bregma. The color bar displays correlation coefficient strength from 0.35 to 1.0.

Fig. 5

Power spectra from regional resting-state time-courses. Power vs. frequency in hertz is plotted. The blue spectrum was created by using a region located outside the brain. The red spectrum was created using a representative region used in the PCA analysis.

Fig. 6

Simplified connection flowcharts of the rodent brain networks determined by prior studies. (A) Rodent sensorimotor system. (B) Rodent visual system. System hierarchy moves from top to bottom. Arrows indicate primary information flow in the low to high hierarchy, although reciprocal connections are usually present.

Fig. 7

RPCC matrices of average resting-state BOLD time-courses in the rat motor/sensory system. (A) RPCC matrix from average of 20 healthy rats. (B) RPCC matrix from average of six animals that received a surgical procedure to denervate the right forepaw. Both the left and right sides of each region were tabulated. The superior colliculus (SC) from the visual system was included as a control. The lower triangular part of the graph displays the coefficient values according to the color bar located between Figs. 7B and 7C, and the upper triangular part (mirror image) of the graph tabulates the corresponding correlation coefficient values. (C) Difference matrix resulting from subtraction of Fig. 7B from Fig. 7A. The lower triangular part of the difference matrix displays the coefficient values according to the color bar on the far right, and the upper triangular part (mirror image) of the graph tabulates the corresponding correlation coefficient differences between Figs. 7A and 7B. A difference of > 0.2 corresponds to a p-value of approximately 0.001 (unpaired t-test). See Material and Methods for abbreviations.

Fig. 8

RPCC matrices of average resting-state BOLD time-courses in the rat visual system. (A) RPCC matrix from average of 15 healthy rats. (B) RPCC matrix from average of six animals that received a surgical procedure to denervate the right forepaw. Both the left and right sides of each region were tabulated. The hippocampus (HIP) was included as a control. The lower triangular part of the graph displays the coefficient values according to the color bar located between Figs. 8B and 8C, and the upper triangular part (mirror image) of the graph tabulates the corresponding correlation coefficient values. (C) Difference matrix resulting from subtraction of Fig. 8B from Fig. 8A. The lower triangular part of the difference matrix displays the coefficient values according to the color bar on the far right, and the upper triangular part (mirror image) of the graph tabulates the corresponding correlation coefficient differences between Figs. 8A and 8B. A difference of > 0.2 corresponds to a p-value of approximately 0.001 (unpaired t-test). See Materials and Methods for abbreviations.

Fig. 9

Interhemispheric resting-state BOLD fcMRI correlation coefficients between cortical brain regions. Cross-hemispheric connections for both healthy and right-limb-deafferented rats are listed. All differences between matched connections between experimental groups are statistically significant when tested with an unpaired t-test with a 95% confidence interval.