The relationship between corticospinal tract and the affected lower limb function and walking ability in subacute stroke patients: a preliminary study

Abstract

[Purpose] The relationship between corticospinal tract (CST) integrity and upper limb motor function after stroke is well studied, but its association with lower limb motor function remains unclear. In addition, the analysis by type of stroke are remains insufficient. This study examined the relationship between CST integrity, lower limb motor function, and walking ability in subacute stroke patients, considering type of stroke. [Participants and Methods] In this study, 27 patients with cerebral infarction and 13 patients with intracerebral hemorrhage were included. Diffusion tensor imaging (DTI) assessed CST integrity using the fractional anisotropy ratio (rFA) at the cerebral peduncle. Motor function was evaluated with the Fugl–Meyer Assessment of Lower Extremity (FMA-LE), the affected-side muscle strength with a handheld dynamometer, and walking ability with Functional Ambulation Categories (FAC). Group differences between types of stroke and correlations between rFA and motor function were analyzed. [Results] Patients with intracerebral hemorrhage had significantly lower rFA. rFA correlated with FMA-LE and lower limb muscle strength, except for hip extensors. Walking ability was also associated with rFA and FAC. [Conclusion] CST integrity as assessed by DTI was associated with motor function of the affected-side lower limb and walking ability in subacute stroke patients and warrant further study.

INTRODUCTION

Stroke patients frequently present with motor paralysis¹⁾, which can affect both gait^{2, 3)} and activities of daily living⁴⁾. The corticospinal tract (CST) originates in the cerebral cortex, crosses in the medulla oblongata, and projects to the ventral horn of spinal cord. Damage to the CST is known to cause motor paralysis⁵⁾. Diffusion tensor imaging (DTI) is an imaging method using magnetic resonance imaging (MRI) that allows visualization of white matter fiber tracts⁶⁾. Unlike clinical scores, electrophysiologic methods, and functional neuroimaging, DTI has been shown to be useful in visualizing the CST⁷⁾. In addition, suggesting that combining clinical scores with neurological biomarkers such as brain imaging information including DTI may facilitate the prediction of prognosis for motor function⁸⁾.

Evaluation of white matter fibers in DTI includes region of interest (ROI) analysis, tract-specific analysis⁹⁾, and whole brain analysis¹⁰⁾, in addition to quantitative evaluations such as fractional anisotropy (FA). Setting the ROI in ROI analysis is subject to arbitrariness by the researcher, but conversion of images to an anatomical standard brain allows analysis without arbitrariness¹¹⁾. Studies in stroke patients have shown an association between CST integrity as assessed using an anatomical standard brain conversion method and severity of upper and lower limb motor paralysis and independence in activities of daily living^{12, 13)}. In addition, setting the ROI distal to the lesion allows for proper evaluation of Wallerian degeneration without being affected by the lesion¹²⁾. Damage to the CST is known to adversely impact axonal integrity, leading to Wallerian degeneration and reduced FA within a few weeks¹⁴⁾. In stroke patients with supratentorial lesions, setting a ROI in the cerebral peduncle is common practice to assess CST integrity. The association between CST integrity and motor function of the affected-side upper limb has been identified in multiple reports^{15,16,17,18,19,20,21,22,23)}, and CST integrity has been associated with the Brunnstrom Recovery Stage in the lower extremity¹³⁾. On the other hand, CST integrity is reportedly not associated with prognosis²⁴⁾ or degree of improvement²⁵⁾ in motor function of the affected-side lower limb. As a result, this issue remains contentious. In addition, most reports of lower limb muscle strength have used an ordinal scale^{26, 27)}, with limited reports using a ratio scale^{28, 29)} such as from a hand-held dynamometer. Further, no study has examined which specific muscle strengths of the affected-side lower limb are associated with integrity of the CST. Clarification of the relationship between CST integrity and motor function of the affected-side lower limb in stroke patients is important because motor function of the affected-side lower limb affects walking ability^30,31,32,33).

In stroke patients, the association between CST integrity as assessed from DTI and motor function has been reported in studies that included patients with either cerebral infarction, intracerebral hemorrhage, or a mixed population. However, only one study³⁴⁾ has directly compared this association between different types of stroke, and this issue therefore has not been sufficiently investigated. Clarifying the relationship between CST integrity as assessed by DTI and motor function separately by type of stroke may provide greater clinical utility for DTI in stroke rehabilitation.

The purpose of this preliminary study was thus to examine the relationship between CST integrity and motor function of the affected-side lower limb and walking ability using DTI in a cross-sectional study by type of stroke.

PARTICIPANTS AND METHODS

This cross-sectional study was conducted at a single institution. The sample comprised patients with ischemic or hemorrhagic stroke who were admitted to the recovery rehabilitation unit of Geriatrics Research Institute and Hospital (Maebashi, Gunma, Japan) between March 2022 and October 2023. Inclusion criteria were as follows: patients with a modified Rankin Scale³⁵⁾ of 0 before stroke onset, with supratentorial lesions, who had undergone MRI (including DTI) of the head at the time of admission to the recovery rehabilitation unit. Exclusion criteria were as follows: patients with a history of psychiatric or neurological disorders before stroke onset; patients who were not independent in activities of daily living before stroke; patients with a subarachnoid hemorrhage; patients who were unable to understand the tests and measurements performed in the study; patients with an absolute contraindication to MRI; patients with serious disorders that would interfere with rehabilitation; and patients who did not consent to participate in this study. The institutional review boards at the Geriatrics Research Institute and Hospital approved this study (approval no. 84) and all participants provided written informed consent to participate. The Fugl–Meyer Assessment of Lower Extremity (FMA-LE)³⁶⁾, muscle strength of the affected-side lower limb using a hand-held dynamometer (HHD), Functional Ambulation Categories (FAC)³⁷⁾ were assessed within 1 week of admission to the recovery rehabilitation unit.

FMA-LE was used to evaluate the severity of lower limb motor paralysis. Muscle strength was measured using a HHD (Sakai Medical, Tokyo, Japan; Mobie MT-100) and raw force data (in Newtons) were normalized to body weight (Newtons per kilogram). Muscle strength was measured as hip flexion and extension, knee extension, and ankle dorsiflexion in the affected-side lower limb. Each patient was required to perform three maximal isometric contractions of 5 seconds each. Measurement posture and HHD position were measured as described in previous studies^38,39,40,41). Knee extensor strength was measured in the sitting position, while the strengths of all other muscles were measured in the supine position. This method has been reported to offer high test-retest reliability⁴²⁾ and intra-rater reliability⁴³⁾ for affected-side lower limb measurements. FAC assess walking ability based on the amount of assistance. FAC were determined without restricting the use of walking aids or lower limb orthoses. DTI was performed on admission to the recovery rehabilitation unit. MRI data were acquired using a 1.5-T scanner (Siemens Co., Ltd., Erlangen, Germany; Magnetom Avanto). The DTI protocol acquired 12 images with non-collinear diffusion gradients (b=1,000 s/mm²) and 1 non-diffusion-weighted image (b=0 s/mm²) and using a single-shot echo-planer imaging sequence. Image parameters were as follows: repetition time=7,000 ms; echo time=102 ms; field of view=230 mm × 230 mm; voxel size=1.8 mm × 1.8 mm × 4 mm; slice thickness=4.0 mm; and matrix=128 × 128. Image processing was performed as described in previous studies¹²⁾. Functional Magnetic Resonance Imaging of the Brain Software Library (FSL version 6.0.4) was used for image processing. To align all images in volumetric relation to the first image (b=0 s/mm²), DTI data were corrected for motion and eddy current distortion using FDT. The extracerebral matter was excluded from images using BET. To calculate each patient’s FA by using FDT. These FA values were mapped to a standard stereotaxic space (International Consortium of Brain Mapping DTI-81 Atlas) using FNIRT. Regional brain FA values were calculated to yield an FA brain map for each patient. FA values were calculated for the ROI covering bilateral cerebral peduncles. The rFA was calculated as the FA value of the affected hemisphere divided by that of the unaffected hemisphere. Patients were divided into cerebral infarction and intracerebral hemorrhage groups according to the type of stroke. The Mann–Whitney U test was used to test for differences in patient information and clinical characteristics between the two groups. Spearman’s rank correlation was calculated between rFA and FMA-LE, muscle strength of the affected-side lower limb, and FAC in all participants, as well as separately in the two groups.

All statistical analyses were analyzed using SPSS for Mac version 28.0 (IBM, Armonk, NY, USA), with values of p<0.05 considered significant.

RESULTS

A flow diagram of participation is shown in Fig. 1. Of the 286 patients admitted to the recovery rehabilitation unit, 245 patients were ruled out based on the exclusion criteria. Another patient was excluded due to image distortion. Finally, 40 patients with a mean age of 72.0 ± 12.7 years were included in the present study. Table 1 shows participant characteristics and results obtained from comparisons of patient information and clinical characteristics between the cerebral infarction and intracerebral hemorrhage groups. Participants with a mean rFA exceeding 0.9, indicating relatively preserved CST integrity, were included in this study. While rFA was significantly lower in patients with intracerebral hemorrhage than in patients with cerebral infarction, no other significant differences were observed.

Fig. 1.

Flow diagram of participation in the present study.

286 patients were hospitalized and 40 patients were included in the study.

Table 1. Patient characteristics and results.

	All (n=40)	Cerebral infarction (n=27)	Intracerebral hemorrhage (n=13)	p
Age, years	72.0 ± 12.7	74.4 ± 11.8	67.0 ± 13.5
Sex (female/male), n	17/23	18/9	5/8
Affected hemisphere (right/left), n	23/17	15/12	8/5
Lesion location (P/Th/PLIC/CR/FL/PL), n	8/5/12/8/4/3	1/2/12/8/3/1	7/3/0/0/1/2
Types of cerebral infarction (lacunar/atherosclerosis/cardio embolism), n	-	4/21/2	-
Time from stroke onset to recovery rehabilitation unit, days	21.6 ± 9.2	19.9 ± 7.7	25.2 ± 11.1
Time from stroke onset to DTI, days	32.0 ± 9.0	30.3 ± 7.8	35.4 ± 10.5
FA in affected side	0.49 ± 0.06	0.49 ± 0.06	0.47 ± 0.06
FA in unaffected side	0.53 ± 0.03	0.53 ± 0.03	0.53 ± 0.02
rFA	0.92 ± 0.09	0.93 ± 0.08	0.88 ± 0.09	*
FMA-LE	24.9 ± 9.5	26.4 ± 9.3	21.6 ± 9.3
Muscle strength of hip flexion, N/kg	1.6 ± 0.8	1.7 ± 0.7	1.3 ± 0.9
Muscle strength of hip extension, N/kg	3.6 ± 1.6	3.6 ± 1.7	3.3 ± 1.5
Muscle strength of knee extension, N/kg	2.0 ± 1.1	1.9 ± 1.0	2.0 ± 1.4
Muscle strength of ankle dorsiflexion, N/kg	1.3 ± 1.2	1.5 ± 1.2	0.9 ± 1.3
FAC (0/1/2/3/4/5), n	12/4/6/7/10/1	6/2/4/6/9/0	6/2/2/1/1/1

*p<0.05.

The Mann–Whitney U test was used to test for differences in background and clinical characteristics of patients in cerebral infarction and intracerebral hemorrhage. Muscle strength is for the lower limb on the affected side. P: putamen; Th: thalamus; PLIC: posterior limb of the internal capsule; CR: corona radiata; FL: frontal lobe; PL: parietal lobe; FA: fractional anisotropy; rFA: ratio of fractional anisotropy; FMA-LE: Fugl–Meyer assessment of lower extremity; FAC: functional ambulation categories.

The results of correlation analysis are shown in Table 2. A positive correlation was observed between rFA and FMA-LE in all patients. A positive correlation was also observed between rFA and muscle strengths of hip flexion, knee extension, and ankle dorsiflexion. However, no correlation was detected between rFA and muscle strength of hip extension. In terms of walking ability, FAC showed a significant positive association with all types of strokes.

Table 2. Results for correlation coefficients between rFA and motor function.

	All (n=40)	Cerebral Infarction (n=27)	Intracerebral hemorrhage (n=13)
FMA-LE	0.64**	0.61**	0.57*
Muscle strength of hip flexion	0.49**	0.51**	0.31
Muscle strength of hip extension	0.13	0.21	0.04
Muscle strength of knee extension	0.42**	0.50**	0.40
Muscle strength of ankle dorsiflexion	0.59**	0.65**	0.35
FAC	0.64**	0.64**	0.56*

*p<0.05, **p<0.01.

rFA: fractional anisotropy ratio; FMA-LE: Fugl–Meyer Assessment of Lower Extremity; FAC: Functional Ambulation Categories. Correlation analysis in cerebral infarction and intracerebral hemorrhage. Spearman’s rank correlations were calculated to evaluate relationships between rFA and motor function.

Both cerebral infarction and intracerebral hemorrhage groups showed generally similar correlation coefficients. In patients with cerebral infarction, the correlation was significant, as were results for all patients. Conversely, patients with intracerebral hemorrhage showed no significant correlations except for FMA-LE, but as in patients with cerebral infarction, weak to moderate correlation coefficients were found except for muscle strength of hip extension.

DISCUSSION

This study examined the relationship between CST integrity and motor function of the affected-side lower limb and walking ability in stroke patients approximately 1 month after onset. A total of 40 participants with a mean age of 72 years were included in this study, with more than half of the participants having cerebral infarction. The mean rFA among all participants exceeded 0.9, indicating that CST integrity was relatively well preserved overall. However, because more than half of the participants were unable to ambulate independently, the study included individuals with a wide range of stroke severity. The timing of DTI in this study was considered appropriate because Wallerian degeneration progresses rapidly during the first month after onset⁴⁴⁾, and CST integrity at 1 month from onset has shown the strongest association with motor function in the chronic phase⁴⁵⁾. Further, since all patients in this study had supratentorial lesions and the ROI was set to cover the cerebral peduncles, measurements were unaffected by the lesion, allowing for an appropriate evaluation of nerve fiber integrity based on Wallerian degeneration.

Few studies have examined the relationship between CST integrity using DTI and motor function of the affected-side lower limb and walking ability, and the present study is one of the few to examine the relationship with motor function of the affected-side lower limb. This is also the first study to investigate which specific motor functions of the affected-side lower limb are associated with CST integrity as assessed by DTI.

This study identified an association between motor function of the affected-side lower limb, excluding muscle strength of hip extension, and CST integrity in recovering stroke patients. As shown in previous studies²⁸⁾, an association was identified between severity of lower limb motor paralysis and CST integrity. Regarding muscle strength of the affected-side lower limb, significant positive correlations were found for both hip flexor strength as a proximal muscle and ankle dorsiflexor strength as a distal muscle. Studies in monkeys have shown that the CST exerts a strong influence on distal muscles of the lower limb^{46, 47)}. Similarly, studies in humans have shown that the CST provides stronger, more extensive innervation for distal muscles than for proximal muscles^48,49,50). In the present study, correlations were found for both proximal and distal muscles, indicating that the CST is related to overall lower limb muscle strength. However, the correlation coefficient of ankle dorsiflexion muscle strength was the highest among the lower limb muscle strengths evaluated.

On the other hand, no significant correlation with hip extensor strength was identified. The reason for this may be the measurement posture adopted. Normally, hip extensors are measured with the patient in the prone position, but since the posture is assumed to be difficult to change to the prone in patients with subacute stroke, we used the supine position based on previous studies^38,39,40,41). In the supine position, the HHD was placed on the posterior aspect of the thigh with 90° flexion at both the hip and knee joints. Unlike the other strength assessments, which required isolated movement, the measurement posture used for hip extensor strength likely elicited an extension pattern within a synergistic movement pattern. Therefore, even in cases of severe motor impairment, strong hip extensor force may have been generated if an extension synergy movement was present. This might help explain why the interpretation of hip extensor strength could differ from that of the other muscle strength measures. If hip extensor strength had been assessed in the prone position, which is the conventional method, it would likely have reflected isolated hip extension strength. Although the results might have differed if this method had been used, whether such posture-specific measurement is associated with CST integrity remains unclear. Therefore, this issue should be addressed in future studies.

For walking ability, a significant association with FAC was found. Previous studies⁵¹⁾ have reported that CST integrity is associated with recovery of walking ability. Previous review³³⁾ has demonstrated an association between CST integrity and independent walking at approximately three months after stroke onset. Preserved CST integrity has been shown to support good leg strength and contribute to good sitting and independence in activities of daily living. Accordingly, CST integrity has been reported as the only stroke-related factor independently linked to walking independence. Similarly, the present study found an association with FAC. In the assessment of walking ability using the FAC, all participants were classified based on the amount of assistance, allowing the evaluation of walking ability across a wide range of stroke severities.

In the analysis by type of stroke, rFA was significantly lower in patients with intracerebral hemorrhage than in those with cerebral infarction. This finding is consistent with previous studies³⁴⁾ that reported lower rFA in patients with intracerebral hemorrhage than in patients with cerebral infarction, but comparable correlation coefficients in FMA-LE, which reflects the severity of lower limb motor paralysis. In general, intracerebral hemorrhage is associated with a higher mortality rate and is more severe than cerebral infarction. This is due to hematoma expansion, edema formation, and increased intracranial pressure, all of which increase mortality. The larger maximum diameter of the lesion compared to cerebral infarction is also thought to contribute to disease severity⁵²⁾. However, the significantly lower rFA observed in intracerebral hemorrhage in this study is likely attributable to the characteristics of the included sample. Many patients presented with hemorrhagic lesions located near the CST, such as in the putamen and thalamus, where substantial damage to CST fibers is plausible. Previous studies^{53, 54)} have reported that functional outcomes are influenced not by lesion size itself but rather by the integrity of the CST. Thus, the importance of CST integrity has been highlighted regardless of the type of stroke.

This study showed several limitations. First, this study was a cross-sectional study of stroke patients about 1 month after onset, and we were unable to examine data longitudinally. The first month after onset corresponds to the early subacute phase of the timeline of stroke recovery in previous studies⁵⁵⁾, when rapid functional recovery is occurring. Since most of the functional recovery occurs in the first few weeks to months after onset, it is necessary to observe changes longitudinally. Additionally, the study included only 13 patients with cerebral hemorrhage, representing a very small sample size, which is another limitation of this research. Second, this study was only able to investigate white matter fibers in the CST. Previous studies have also suggested the involvement of cortical reticular tracts in proximal muscle strength^56,57,58). Target white matter fibers should thus not be limited to the CST, and other white matter fibers should be considered in future work. Furthermore, although the region of interest was placed in the cerebral peduncles, it should be noted that the cerebral peduncles contain fibers other than the CST, and therefore this assessment does not exclusively reflect CST integrity. Third, the DTI protocol used in this study may not have yielded a valid FA value. A previous study reported no significant correlation with FMA-LE under imaging conditions using a 3.0-T scanner and 45 non-collinear diffusion gradients⁵⁹⁾. It should be noted that this study’s results were obtained under imaging conditions with lower validity, using a 1.5-T scanner and 12 non-collinear diffusion gradients. Fourth, the measurement posture for muscle strength should be reconsidered. Hip extensor strength should be interpreted with careful attention to the testing position. It is important to consider whether the posture elicits isolated movement or permits synergistic movement patterns when determining how such measurements are obtained.

The results of this study indicate that the integrity of the CST in subacute stroke patients plays an important role in motor function of the affected-side lower limb and walking ability. These findings suggest that evaluating CST integrity using DTI may allow for more appropriate assessment of walking ability and its impacts on activities of daily living. Future longitudinal studies are expected to enable the evaluation of long-term changes in motor function and walking ability associated with CST integrity. As this was a preliminary study, further research with a larger sample size is warranted to validate and further explore these findings.

In conclusion, CST integrity as assessed by DTI was associated with motor function of the affected-side lower limb and walking ability in subacute stroke patients, and further studies with an appropriate sample size are warranted to confirm and expand these findings.

Funding

This work received no funding.

Conflict of interest

The authors declare no conflicts of interest.