Corticospinal tract changes in acute brainstem ischemic stroke patients: A diffusion kurtosis imaging study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.232281
Source of Support: None, Conflict of Interest: None
Keywords: Brainstem, corticospinal tract, diffusion kurtosis imaging, ischemic stroke, MRI
Acute brainstem ischemic stroke accounts for approximately 10% of all acute ischemic strokes., Posterior circulation stroke has been traditionally associated with a high morbidity and mortality, with the mortality often reaching upto 30–70%., Many stroke survivors experience difficulties in carrying out activites of daily living. The initial stroke severity appears to be having a dominant influence on the overall stroke outcome. After focal cerebral ischemia, pathological changes in neural structures occur in the area that has undergone cerebral infarction; the proper flow of neuronal information critically depends on the structural integrity of fiber tracts. The integrity of the corticospinal tract (CST) is critical for the recovery of motor function in stroke. A long-term observational study focusing on the outcome of the patients who have suffered from a posterior circulation stroke suggested that the prognosis in many of the patients could still be improved after 3 months post-stroke. Therefore, identification of the CST microstructural changes early in patients with acute stroke would assist in predicting the motor recovery of these patients. The early microstructural changes occurring in the CST in brainstem ischemic stroke have, however, not yet been fully elucidated.
The conventional diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) techniques assume that water molecule diffusion appears to be in a free and non-restricted environment with a Gaussian distribution. The complex structure of the brain tissues can often cause a deviation in the diffusion of the water molecules and may result in a distortion of the Gaussian form of the curve obtained., These models cannot detect the true diffusion of water molecules. Diffusional kurtosis imaging (DKI) has been proven to be a new type of diffusion-weighted sequence that reflects the non-Gaussian nature of the curve of water diffusion. DKI uses the kurtosis values to estimate this non-Gaussian distribution, which can reveal a more complex microstructure of the brain tissue. The traditional MRI parameters based on DTI technique, such as fractional anisotropy (FA) and mean diffusivity (MD) may also be obtained using the same sequences., Previous studies have demonstrated that the mean kurtosis (MK) value is sensitive to the subtle structural alterations that are seen following the occurrence of an acute ischemic stroke. Thus, a recent DKI study identified that the diffusion metrics derived from DKI could be used to detect the early CST microstructural changes after acute ischemic stroke; and that a correlation existed between the DKI-derived metrics of the CST and the motor outcome after 3 months. Moreover, DKI may reveal a complex ischemic tissue injury and provide information for individualized stroke management.
Given the crucial role that DKI appears to play in detecting the CST microstructural changes in acute ischemic stroke, the present study aimed at providing a novel avenue for clinical treatment by using DKI to measure the CST microstructural changes of brainstem ischemic stroke patients at an early stage. This specific radiological imaging technology, therefore, significantly individualizes the treatment protocol and the treatment protocol and the specific rehabilitation strategies required for patients with stroke.
This study was conducted from August 2016 to May 2017. All the patients satisfied the following criteria: (1) they had developed their first ever stroke; (2) they had obtained an MRI scan within 72 h of the symptom-onset (since the published studies on stroke have usually defined those patients who are treated within 72 hours of their symptom onset as being in an acute phase; (3) the lesion was limited to a unilateral side within the brainstem, which was confirmed on the DWI and the conventional MR sequences. The exclusion criteria were as follows: (1) the coexistence of any current history or a past history of neurological or neuropsychiatric disorders; (2) the presence of any clinically significant or unstable medical disorders; (3) the simultaneous presence of severe white matter hyperintensity, manifesting as Fazekas scale score >1; (4) the presence of any contraindication for the performance of an MRI. A total of 21 patients who had developed a brainstem stroke were enrolled in the study. The study included 11 male and 10 female patients, with their mean age and standard deviation being 67.6 ± 12.4 years (range, 46–91 years). Eleven patients had a predominantly left-sided brainstem ischemia and 10 had a predominantly right-sided brainstem ischemia. In addition, 21 healthy controls were recruited through community health screening and newspaper advertisements. The age of the control group ranged from 53 to 76 years (the mean age with standard deviation being 65.9 ± 11.6 years). The patients with brainstem stroke and the healthy subjects were group-matched in terms of age, sex, and education. All the participants provided written informed consent before their participation in the study protocol, which was approved by The Research Ethics Committee of the Nanjing Medical University.
Magnetic resonance imaging acquisition
MRI data were acquired using a 3.0 Tesla MRI scanner (Ingenia, Philips Medical Systems, Netherlands) with an 8-channel receiver array head coil. All patients underwent a conventional MRI (including axial T1 and T2 weighted images, fluid-attenuated inversion recovery [FLAIR], diffusion weighted imaging [DWI], and apparent diffusion coefficient [ADC] maps) and the DKI scan. DKI images were obtained by an echo sequence with 15 gradient encoding directions with three b values (0, 1,000, 2,000 s/mm 2). The acquisition parameters were as follows: repetition time (TR) = 6,441 ms; echo time (TE) = 109 ms; slices = 48; thickness = 3 mm; gap = 0 mm; field of view (FOV) =256 mm × 256 mm; and flip angle = 90°. The DKI sequence took 9 min and 54 s.
Diffusion-weighted images were processed using the Diffusional Kurtosis Estimator (DKE) software. Parametric maps for fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) were subsequently obtained.
Regions of interest analysis
Regions of interest (ROIs) were manually drawn in transverse slices using ImageJ software (http://rsb.info.nih.gov/ij/). ROIs were placed at four levels: the pons, posterior limb of the internal capsule (PLIC), corona radiata, and the precentral gyrus of both sides on the FA, MD, and MK maps of the two groups. The ROI size was set as 15 mm 2 and the shape of the region of interest (ROI) was set as a circle manually on ImageJ software. At the pons slice, we set the ROI at both the lesion and the contralateral sides. For all regions, the FA, MD, and MK values were measured. Diagnosis of the infarction lesions and the ROI analyses were conducted by two radiologists (HC and LJ). A third radiologist (XY) was consulted when there were differences in opinion between the two radiologists.
The statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software (version 19.0; SPSS, Inc., Chicago, IL). All values were presented as mean ± standard deviation. P < 0.05 were considered to be statistically significant. For the within-group analysis, paired t-tests were performed, whereas for the between-group analysis, two-sample t-tests were performed.
Comparison of diffusion kurtosis imaging (DKI)-derived variables between both sides of the CST in patients with brainstem ischemic stroke
[Figure 1] shows the parametric maps of DKI, including FA (a–d), MD (e–h), MK (i–l) maps, and DWI (m–p) from the four anatomical slices: pons, PLIC, corona radiata, and precentral gyrus. Signal on MK in the right pons demonstrated an irregularly high signal but showed a relatively low signal on MD and FA. [Table 1] presents the DKI metrics including the FA, MD, and MK values at four levels of the brainstem in ischemic stroke patients. Compared to the contralateral side, the ipsilateral side of the ischemic lesion showed a decrease in FA and MD values and an increase in the MK values with statistically significant difference at all the four selected levels (P < 0.05).
Comparison of DKI-derived variables between both sides of the CST in healthy controls
[Figure 2] exhibits the parametric maps of a health control including the FA, MD, MK metrics. DKI metrics including FA, MD, and MK at the four levels of the healthy controls are listed in [Table 2]. At all the four selected levels, there are no differences between both the left and right sides (P > 0.05).
Comparison of DKI-derived variables between the contralateral side of the patients and the corresponding side of the healthy controls
As the FA, MD, and MK values did not have any differences between the left and right sides at the four selected levels in healthy controls, we just chose one side of health controls to compare with the contralateral side of the patients. [Table 3] shows the DKI metrics including the FA, MD, and MK values at the four selected levels of the contralateral side of patients and the corresponding side of healthy controls. The MD values of the contralateral side of patients at the four selected levels were significant higher than those in the healthy controls (P < 0.05). Compared to the healthy controls, there was a decrease at the PLIC in FA values of the contralateral side of the ischemic lesion in stroke patients (P < 0.05). However, on assessment of MK values, there were no significant differences between them (P > 0.05).
Motor impairment has been the most common deficit after acute stroke. Clinical assessment of motor impairment in the acute phase is a significant predictor of chronic motor outcome. The CST is regarded as the most critical motor pathway in human brain. Thus, estimating the motor impairment accurately could assist in predicting the motor outcome. If clinicians can have access to an early marker of motor pathway injury, the patient will definitely benefit from the intervention. Zhang et al., demonstrated that DKI could detect subtle changes in the CST of the patients with middle cerebral artery territory infarction in the acute phase. Similarly, our current study found that in the acute brainstem ischemic stroke patients, the DKI metrics had large differences between the hemisphere on the ipsilateral side of the CST lesion and that of the contralateral side of the lesion.
DKI is a new type diffusion-weighted sequence that measures the non-Gaussian nature of water diffusion. Duchene et al., performed a comparison of the sensitivity of diffusion parameters obtained from DTI and DKI metrics in hyperacute stroke patients and found that diffusion kurtosis imaging showed an enhanced sensitivity. Previous DKI studies on stroke have shown that compared with the normal-appearing region, MD and FA values decreased but MK values increased significantly in the ischemic lesions of every brain region., Consistently, in the ischemic lesions, the MD, FA values decreased and the MK values increased in acute brainstem stroke patients in our study.
Many studies have demonstrated that Wallerian degeneration More Details (WD) occurs after nerve damage; this degeneration exists for days to weeks in the central nervous system. Several studies have shown that through WD, diffusion changes occur first in the infarcted region and extend to the distal parts of nerve fibers later., Guo et al., demonstrated that after the onset of infarction for 3 days, DTI could detect signals of early post-infarction WD of the pyramidal tract. The PLIC has been confirmed as a critical region that is related to the motor outcomes after stroke. A study utilizing DTI observed that the local diffusion homogeneity of ipsi-lesional CST was a predictor of motor improvement in patients with a subcortical infraction 1, 4, and 12 weeks after its onset. Similarly, Moulton et al., found that the axial diffusivity of the corona radiata at 24 h post-stroke is the most appropriate diffusion metric for quantifying stroke damage to predict outcome by using DTI. The CST is known to originate from the primary motor cortex. Moreover, DTI has addressed this structure–function relationship to the CST fibers originating from the subcortical white matter of the precentral gyrus. In our study, compared with the contralateral side, the hemisphere on the side of the lesion showed a decrease in FA and MD values and an increase in the MK values at the four selected levels of the CST. Nevertheless, the DKI metrics did not reveal any differences between the left and right sides of CST in healthy controls. Interestingly, we found that the MD values of the contralateral side of the patients at four selected levels of the CST were significantly higher than those in the healthy controls. High MD values usually indicate pathological conditions such as demyelination or edema. The result suggested that the damage to the CST was not limited to the ipsilateral side of the ischemic lesion. As we know, based on anatomical tracing and electrophysiological assays, CST has an early bilateral organization. Via CST projections to the spinal cord and cortical projections to the brainstem, circuit-level interactions between the two hemispheres can be abundant. Hence, the contralateral side of the CST could be injured by this way. On assessment of FA values, compared to the healthy controls, only the PLIC of the contralateral side of the patients had a decreased value. As we know, MD is a measure of the average magnitude of water diffusion in three dimensions. However, as FA measures the percent of diffusion tensor associated with anisotropic movement, the reduced FA value in this region might be related to disintegration of the fibers. FA metrics is usually acquired days after the occurrence of a stroke to predict the motor outcome. Nevertheless, Park et al., have pointed out that FA values of the PLIC are reasonably robust to alterations in the early phase. Previous study suggested that the FA reduction reflected deterioration of axonal integrity, which could lead to WD. Puig et al., found that acute CST damage at the level of the PLIC was a significant predictor of an unfavorable motor outcome. The change of the PLIC on the contralateral side of the patients may be one of the causes that may lead to a worsened prognosis in patients with a brainstem infarction.
Several constraints must be acknowledged in the current study. First, this study only detected the CST changes in the acute phase of the patients with brainstem stroke. A dynamic measurement of the CST changes is required to be observed in the future study. Second, the correlation between the CST changes and the outcomes also needs to be determined in another study. Moreover, the current study was cross-sectional with a relatively small sample size. Further longitudinal investigations with larger patient samples would be beneficial to evaluate the early microstructural changes occurring in the CST by using the DKI metrics.
In this study, the DKI metrics of bilateral CSTs were found to have been changed in patients who had developed acute brainstem infarction. We suggest that DKI is capable of distinguishing early microstructural changes of the motor pathway in patients who have developed an acute brainstem infarction and that these changes were not limited to the ipsilateral side of the ischemic lesion but were also evident on the contralateral side, especially within the PLIC. Thus, these findings may lead to a better understanding of the MRI changes in brainstem stroke, which may help in providing an improved clinical treatment.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This work was funded by Jiangsu Provincial Special Program of Medical Science (BE2017614), Youth Medical Talents of Jiangsu Province (No. QNRC2016062), China Postdoctoral Science Foundation (No. 2017M610337), Jiangsu Postdoctoral Science Foundation (No. 1701007A), and 14th “Six Talent Peaks” Project of Jiangsu Province (No. YY-079).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]