The Effect of Lesion Size on the Organization of the Ipsilesional and Contralesional Motor Cortex

Abstract

Recovery of hand function following lesions in the primary motor cortex (M1) is associated with a reorganization of premotor areas in the ipsilesional hemisphere, and this reorganization depends on the size of the lesion. It is not clear how lesion size affects motor representations in the contralesional hemisphere and how the effects in the 2 hemispheres compare. Our goal was to study how lesion size affects motor representations in the ipsilesional and contralesional hemispheres. In rats, we induced lesions of different sizes in the caudal forelimb area (CFA), the equivalent of M1. The effective lesion volume in each animal was quantified histologically. Behavioral recovery was evaluated with the Montoya Staircase task for 28 days after the lesion. Then, the organization of the CFA and the rostral forelimb area (RFA)--the putative premotor area in rats--in the 2 cerebral hemispheres was studied with intracortical microstimulation mapping techniques. The distal forelimb representation in the RFA of both the ipsilesional and contralesional hemispheres was positively correlated with the size of the lesion. In contrast, lesion size had no effect on the contralesional CFA, and there was no relationship between movement representations in the 2 hemispheres. Finally, only the contralesional RFA was negatively correlated with chronic motor deficits of the paretic forelimb. Our data show that lesion size has comparable effects on motor representations in premotor areas of both hemispheres and suggest that the contralesional premotor cortex may play a greater role in the recovery of the paretic forelimb following large lesions.

Keywords: contralesional; cortex; hand; intact hemisphere; ipsilesional; lesion size; motor representations; plasticity; recovery; stroke.

Figure 1.

Experimental design: A. Side view of a rat performing the behavioral task in the Montoya staircase box. For a trial, a single food pellet is placed on each step, and the rat has 3 minutes to retrieve the pellets. Its performance score is based on the number of pellets left at the end of the 3-minute period. B. Cartoon showing the location of the different motor representations in the 2 hemispheres and the nonparetic and paretic forelimbs in relation to the lesion (gray shadow). The ischemic lesion was induced in the cortex contralateral to the arm with the best performance score. C. Timeline of experimental procedures for animals with cortical lesions. Baseline behavioral performance data were collected prior to the lesion and averaged to create a baseline score. After the lesion, recovery was monitored for 4 weeks. Intracortical microstimulation techniques (ICMS) were used to study the organization of motor areas in a terminal experiment on the 35th day after the lesion. D. To create a range of cortical lesion sizes, we used 2 lesion protocols. Each panel shows ICMS data from a control animal where CFA and RFA are outlined. Small dots on the panels show sites of electrode penetration and ICMS stimulation. The color of the dots indicates the category of the movements evoked at the site. Based on stereotaxic coordinates (numbers and white lines on top and right of each panel), the locations of the 6 (left panel) and 12 (right panel) ET-1 injections used in the 2 lesion protocols are overlaid onto the ICMS data. The protocols were designed so that they both spare the RFA, but lesions induced with 12 ET-1 injections should destroy a greater portion of the CFA. Scale bar = 1 mm. Note: Color version of the figure is present with the online March 2016 issue at www.nnr.sagepub.com. Abbreviations: ET-1, endothelin-1; iRFA, ipsilesional RFA; iCFA, ipsilesional CFA; cRFA, contralesional RFA; cCFA, contralesional CFA; L, lateral; R, rostral.

Figure 2.

Effective lesion size and behavioral recovery: A. Example of a Nissl stained section of the ipsilesional hemisphere in an animal that recovered from a small (left panel) and a large lesion (right panel). The box shows the location of the high-resolution photograph of the lesion in the inset. Lesions were essentially limited to the cortex and affected all layers of the cortical gray matter. For each animal, we made a histological reconstruction of the brain to quantify the lesion size. The 3D reconstruction of the tissue bloc is shown below the inset. The bloc is viewed from above. The location and extent of the lesion is outlined in black, and the arrow indicates the location of the Nissl-stained section in the reconstructed bloc. The red X shows the location of Bregma. Scale bars = 1 mm. B. Values of effective lesion size for each animal included in the study (n = 18). Lesion sizes are reported as a percentage of the reconstructed contralesional hemisphere. Our lesion protocols resulted in a wide range of cortical lesion sizes. Filled black symbols show animals from 2A. C. Relationship between the size of the lesion and the recovery score of the paretic (left panel) and nonparetic (right panel) forelimbs for individual animals. Only the recovery score of the paretic forelimb was significantly related to the lesion size (*). Filled black symbols show animals from 2A. Note: Color version of the figure is present with the online March 2016 issue at www.nnr.sagepub.com. Abbreviation: R, rostral.

Figure 3.

Impact of the lesions on the ipsilesional CFA (iCFA): A. Examples of ICMS data in 2 control rats. Each dot shows a stimulation site and the evoked movement (color coded). The CFA and RFA are outlined. B. Examples of ipsilesional ICMS data in 2 rats that recovered from a small (left panel) and large lesion (right panel). In all animals from which we collected ipsilesional data, we found sites that evoked trunk, neck, or face movements between the lesion and RFA, supporting that iRFA was spared by the lesion. The lesion scar is shown with an asterisk. Scale bar = 1 mm. C. Correlation between the size of the lesion and the cortical surface area of DFL (left panel) and PFL (right panel) in the iCFA. The mean surface area value of the control group for each representation is shown with a solid line, and the 95% confidence interval with dashed gray lines. There was a significant negative correlation between the size of the lesion and the PFL in the iCFA (*). Filled black symbols show the 2 animals from 3B. Note: Color version of the figure is present with the online March 2016 issue at www.nnr.sagepub.com. Abbreviations: ICMS, intracortical microstimulation techniques; L, lateral; R, rostral.

Figure 4.

Examples of analyzed motor maps: A. Examples of motor maps generated from the ICMS data of 2 control animals. Each small black dot shows the location of an electrode penetration and cortical stimulation. Evoked movements at threshold current intensity are color coded, and CFA and RFA are outlined. Contralesional (B) and ipsilesional (C) motor maps of 3 animals that recovered from cortical lesions of various sizes (5.0%, 12.6%, and 14.6%, from left to right). The approximate location of the lesion scar is shown, but lesion size was determined with histological reconstructions (see Figure 2). The red X shows the location of bregma. Scale bars = 1 mm. Note: Color version of the figure is present with the online March 2016 issue at www.nnr.sagepub.com. Abbreviations: ICMS, intracortical microstimulation techniques; CFA, caudal forelimb area; RFA, rostral forelimb area; M, medial; R, rostral.

Figure 5.

The effect of lesion size on motor representations. Plots of motor representations in relation to the size of lesion for individual animals. For each row, a cartoon on the right shows the location of the motor representation in the brain. The area of the distal forelimb representation (DFL) and the proximal forelimb representation (PFL) are plotted in the left and right columns, respectively. A. In the ipsilesional RFA (iRFA), there was a significant correlation between the size of the lesion and the DFL. Lesion size did not affect the PFL in the iRFA. B. Similarly, in the contralesional RFA, animals with larger lesions had bigger DFL, but there was no relationship between lesion size and the PFL. C, In the contralesional CFA, DFL and PFL were not affected by the size of the lesion.

Figure 6.

Relation between the distal forelimb representation (DFL) in the ipsilesional and contralesional rostral forelimb areas (iRFA and cRFA) and the final recovery. A. Plot showing the relationship between the size of DFL in the iRFA and the recovery score of the nonparetic forelimb (left panel) and the paretic forelimb (right panel) for each rat (n = 14). There was no relationship between the size of the DFL area in the iRFA and the functional recovery of the 2 forelimbs. B. Plot showing the relationship between the DFL area in the cRFA and the recovery score of the 2 forelimbs (n = 18). No relationship was found between the cRFA and the recovery of the nonparetic forelimb (left panel). However, there was a significant relationship between the DFL area in the cRFA and the recovery score of the paretic forelimb (right panel). Rats with greater chronic deficits with the paretic forelimb (lower recovery scores) had bigger DFL in the cRFA.