Stages of motor output reorganization after hemispheric stroke suggested by longitudinal studies of cortical physiology

Abstract

Reorganization of motor circuits in the cerebral cortex is thought to contribute to recovery following stroke. These can be examined with transcranial magnetic stimulation (TMS) using measures of corticospinal tract integrity and intracortical excitability. However, little is known about how these changes develop during the important early period post-stroke and their influence on recovery. We used TMS to obtain multiple measures bilaterally in a group of 10 patients during the early days and weeks and up to 6 months post-stroke, in order to examine correlations with tests of hand function. Ten age-matched healthy subjects were also studied. After stroke, day-to-day variation in performance was unrelated to physiological measures in the first 3 weeks. Measures of corticospinal integrity averaged over the same period correlated well with hand function, but this relationship became weaker at 3 months. In contrast, most intracortical excitability measures did not correlate acutely but did so strongly at 3 months. Thus in the acute stage, patients' performance is limited by damage to corticospinal output. Improved performance at 3 months may depend on reorganization in alternative cortical networks to maximize the efficiency of remaining corticospinal pathways--intracortical disinhibition may aid recovery by promoting access to these networks.

Figures

Figure 1.

Clinical scores describing upper limb function. Scores in the ARAT and NHPT are shown as performance in the affected limb as a percentage of that in the intact limb. (A) Individual scores in the ARAT (A1) and NHPT (A2) are shown for every assessment performed in the first (ca.) 3 months. (B) Scores are displayed for each patient at the principal time points, along with group means. Both ARAT (B1) and NHPT (B2) were significantly improved by 1 month (paired t-tests P < 0.05 vs. initial assessment) and changes beyond this point were not significant. A number of patients had NHPT scores of 0 (or near 0) at the first assessment, whereas many had a maximum ARAT score by 3 months—thus, the ARAT is more informative of the 2 tests in the early period, whereas the NHPT becomes more sensitive later on.

Figure 2.

Corticospinal excitability. (A) Group means values for resting (A1) and active (A2) motor thresholds in the UH and AH are shown at the principal time points. Thresholds are shown here as the logarithm of percentage of maximum stimulator output. The value described as acute has been determined in each patient as the mean of all values within the first 3 weeks. Time has differing effects on rMT in the 2 hemispheres—thresholds are initially raised in the AH and subsequently reduce but do not significantly change in the UH. For aMTs, there is a trend reduction in the AH from the acute period to 3 months but no time × hemisphere interaction and no Time effect across all 4 time points (see text for ANOVA details). Both rMT and aMT are significantly higher in the AH than the UH during the acute period (paired t-tests: * P < 0.05), but this difference is not significant later. rMT values in the AH are raised compared with the healthy group only during the acute period, whereas aMT values are also raised at 3 months (unpaired t-tests: † P < 0.05, corrected for multiple comparisons). (B) Group means for the first 3 measurements of aMT in each patient are shown—these were taken 10.1 (±1.3), 13.3 (±1.4), and 17.3 (±1.9) days after the stroke (mean ± standard error). There is a significant time × hemisphere interaction across these 3 time points, explained by a significant increase in aMT in the AH between the first and third measurements (paired t-test: * P = 0.009—see text for ANOVA details). Thus, an increase in aMT in this early period is followed by a reduction in thresholds between months 1 and 3 (Fig. 2A). (C) Group means are shown for RC gradients in either hemisphere at the principal time points. There is a significant time × hemisphere interaction across the 4 time points, but no effect of Time on either hemisphere alone (significant effect of Hemisphere). From the acute period to 6 months, there is also a significant equivalent interaction, explained by a significant decrease in excitability in the UH (paired t-test: * P < 0.05) and a trend increase in the AH (P = 0.059). Excitability in the AH is significantly reduced with respect to the UH at the first 2 time points (paired t-tests: * P < 0.05, ** P < 0.01), but this difference is not significant at later time points. Compared with the healthy control group, RC gradients are significantly reduced in the AH at all time points (unpaired t-tests: †† P < 0.01, † P < 0.05, corrected for multiple comparisons), whereas those in the UH are not significantly different from normal.

Figure 3.

Intracortical Excitability. Mean values at the principal time points are shown for 3 measures of intracortical excitability: (A) SICI, (B) ICF, and (C) LICI. The value shown in each case represents the percentage change of the response to a TS in the presence of a CS: thus 100% would denote no inhibition or facilitation (shown as a dotted line). None of these values were significantly different from the healthy control group at individual time points (unpaired t-tests, values corrected for multiple comparisons). No parameter showed a significant time × hemisphere interaction. A mean value across all time points was thus calculated in each patient (and each parameter and hemisphere). This mean value is significantly raised compared with the normal group in the AH for SICI and LICI (unpaired t-tests: * P < 0.05). This suggests that these forms of intracortical inhibition are weak in the AH (i.e., increased excitability to paired pulse stimuli). The values for SICI and LICI also appear raised in the UH but are not significantly different from the healthy control group.

Figure 4.

Correlations with clinical status—2 examples. The relationships between measures of clinical performance and 2 physiological parameters are shown, each point representing a patient. (A) There is a significant positive correlation between AH RC gradients in the acute period and ARAT scores at initial assessment (r = 0.754, P = 0.006). (B) SICI in the UH is negatively correlated with NHPT scores when the patients are assessed at 3 months, such that weaker inhibition (i.e., increased excitability to paired pulse TMS) is associated with poor clinical status at this stage (r = −0.686, P = 0.021).

Figure 5.

Correlations with clinical status—changes with time. Correlation coefficients between the physiological parameters measured and clinical outcome scores are presented for the 3 phases of stroke recovery studied. Significant correlations are denoted by filled symbols (P < 0.05). Because of the respective floor and ceiling effects seen in NHPT and ARAT scores in the early and late stages, the correlations in the acute period are with ARAT scores and those at later time points are with NHPT scores. The complete correlation coefficients are given in Table 3, and the plots can be seen in Supplementary Figures 4–8. (A) Physiological parameters reflecting integrity of the corticospinal tract are shown. rMTs and aMTs show negative clinical correlations, whereas RC gradients show positive correlations. Thus, poor clinical performance is associated with depressed RC gradients and raised motor thresholds. These correlations are significant for both resting and active thresholds in the acute period and for rMT at 3 months and aMT at 6 months. RC gradients show significant correlations in the acute period. (B) Measures of intracortical excitability are shown, as assessed by paired pulse TMS in each hemisphere . No significant/trend clinical correlations were seen with ICF in the AH, which is not shown. In the acute period, LICI in the AH showed a negative clinical correlation—weaker inhibition associated with worse clinical status—but no other measures showed significant correlations. At 3 months, however, all these measures showed significant negative clinical correlations except for SICI in the AH (which showed a trend correlation, P = 0.063)—weaker SICI/LICI or stronger ICF at this stage was associated with poorer motor function. By 6 months, none of the intracortical excitability measures showed significant or trend clinical correlations. Thus, although clinical status relates closely to corticospinal excitability in the acute period (but less so beyond), intracortical excitability measures become important by 3 months—this relationship is lost by 6 months.

Figure 6.

A) Proposed model for the relationship of physiological changes to recovery from the acute to the chronic stage, compatible with the present results. (B) A scheme depicting the possible roles in hand movement of primary and secondary motor areas of 1 hemisphere. The stroke scenarios are represented in the reorganized (chronic) state. Darker shading denotes greater involvement in movement of the affected hand. A stepwise recruitment of motor areas is depicted with increasing disruption of the corticospinal tract. Minor disruption (small stroke) results in the recruitment of perilesional M1, whereas more extensive disruption (large stroke) requires the use of secondary motor areas and even transcallosal inputs from the intact hemisphere. We propose that during the subacute stage after stroke a smaller or larger degree of intracortical disinhibition is necessary to maintain access to these additional networks, depending on the extent of disruption of the original corticospinal projection.