Nogo-A inhibition induces recovery from neglect in rats

Abstract

Neglect is a complex human cognitive spatial disorder typically induced by damage to prefrontal or posterior parietal association cortices. Behavioral treatments for neglect rarely generalize outside of the therapeutic context or across tasks within the same therapeutic context. Recovery, when it occurs, is spontaneous over the course of weeks to months, but often it is incomplete. A number of studies have indicated that anti-Nogo-A antibodies can be used to enhance plasticity and behavioral recovery following damage to motor cortex, and spinal cord. In the present studies the anti-Nogo-A antibodies IN-1, 7B12, or 11C7 were applied intraventricularly to adult rats demonstrating severe neglect produced by unilateral medial agranular cortex lesions in rats. The three separate anti-Nogo-A antibody groups were treated immediately following the medial agranular cortex lesions. Each of the three antibodies induced dramatic significant behavioral recovery from neglect relative to controls. Severing the corpus callosum to destroy inputs from the contralesional hemisphere resulted in reinstatement of severe neglect, pointing to a possible role of interhemispheric mechanisms in behavioral recovery from neglect.

Figure 1

Maximum and minimum (black) lesion extents of individual subjects in each group. There were no differences in lesion sizes among the six groups.

Figure 2

Mean number of days to recovery from neglect in the 7B12, 11C7, IN-1 experimental groups and the IgG, HRP and Cyclosporin control groups. (*) indicates a significant difference between groups in the number of days it takes to reach recovery (p < .01). Recovery was defined as a Mean Total Neglect Ratio of 0.6 or higher for two consecutive test days. Error bars represent standard error of the mean.

Figure 3

Cumulative percentage of subjects demonstrating recovery over the 10 week (70 day) testing period. Subjects in the 7B12, 11C7, and IN-1 groups recovered faster than subjects in the control groups.

Figure 4

Comparison of total neglect ratios among the three treatment groups (IN-1, 7B12, 11C7) and the control groups (HRP, Cyclosporine A, IgG) for the first two neglect tests and last two neglect tests. Results indicated no differences among groups for the first two tests (p>.05), but a significant difference between all treatment groups (IN-1, 7B12, 11C7) and all control groups (HRP, Cyclosporine A, IgG) on the last two tests (p=.000). There was a significant decrease in severity of neglect in the three experimental groups (all p’s <.01) and a significant increase in severity of neglect in the IgG group (p<.01).

Figure 5

(A) Responding in the ipsilesional direction decreased at the end of testing compared to the beginning (p = .00). (B) Responding in the contralesional direction showed no difference between groups at the beginning of testing (p = .66), but a significant increase in responding for the 7B12, 11C7 and IN-1 groups at the end of testing (p = .00). The IgG group showed a significant difference in responding at the end of testing in the opposite direction.

Figure 6

(A) In the visual modality all experimental groups differed significantly from control groups (all p’s < .05), except the IN-1 group, which did not differ from the HRP group (p = .177), but differed from the IgG and Cyclosporin control groups (p’s < .05). (B) The only difference observed in the tactile modality was between the 11C7 and IgG groups (p = .025). (C) In the auditory modality there was a main effect of test (p = .00) showing a general increase in responding at the end of testing.

Figure 6

(A) In the visual modality all experimental groups differed significantly from control groups (all p’s < .05), except the IN-1 group, which did not differ from the HRP group (p = .177), but differed from the IgG and Cyclosporin control groups (p’s < .05). (B) The only difference observed in the tactile modality was between the 11C7 and IgG groups (p = .025). (C) In the auditory modality there was a main effect of test (p = .00) showing a general increase in responding at the end of testing.

Figure 7

Maximum and minimum lesion extents of individual subjects in each group. There were no differences in lesion sizes between the two knife-cut groups and the cuts were in the intended target area.