Beyond the well-known concept of lesion-symptom mapping, some lesions in a single location in the brain could disrupt brain functions routed to widespread neural networks [1,30]. Our analysis confirmed that local destruction of certain anatomic regions could affect remote areas in the brain.
White matter degeneration in the CST pathway of stroke patients
The degree of anisotropy depends on the level of organization, the integrity of the white matter tract, and the degree of freedom of water diffusion movement caused by the oriented axonal membranes and myelin sheaths . Reduced anisotropy along the CST far from the original lesions has been interpreted as Wallerian degeneration (WD) . DTI can quantify the FA values to evaluate the pathology change of the white matter, such as WD. Using the good classification ability of MVPA, we reported that apart from the basal ganglia region which has direct infarcts, brain areas with significantly decreased FA values were also located in the brainstem of the lesioned hemisphere, and a few in the bilateral frontal lobes, which might be indicative of degenerative lesions caused by WD.
The acute and chronic phases of stroke probably differ in the white matter changes since neural changes can contain anterograde and retrograde degeneration, or refactoring. However, no matter what kind of alteration is present, it should generate specific structural changes and affect corresponding functions. Therefore we performed the pattern recognition classification using the whole brain FA map and explored the key brain regions important for distinguishing the stroke patients from the controls.
Our study verified degenerative changes in the white matter of stroke patients. The infarcted lesions were mainly located in the basal ganglia region, but the FA reduction of some remote areas has reached the point where they can be differentiated from the controls. In conclusion, the damaged structual anatomy of the subcortical areas may induce the deterioration of the key white matter areas in the brain.
Decreased WM connections were widely distributed across brain regions of stroke patients
Many patients were left with motor dysfunctions after the occurrence of cerebral infarction. Usually, it is related to the injury of the corticospinal tract. The CST originates from multiple motor and somatosensory cortices including premotor cortex, supplementary motor cortex (SMA), primary motor cortex, as well as primary and secondary somatosensory cortices. The CST is crucial for proper execution of a volitional movement [33,34]. Apart from the CST and the motor areas of the cortex, the proper execution of movements involving balance and coordination also requires the extrapyramidal tract and other brain regions such as the nucleus in basal ganglia and the cerebellum . The NBS analysis showed that the structural subnetwork connection of the stroke group was weaker than that of the control group, which indicate that the nerve fibers involved in the subnetwork were affected. When the integrity and order of the brain structure were destroyed, it can be reflected in the white matter. Not only the brain regions directly related to the motor commands (e.g. precentral and SMA) but also other regions that might participate in the regulation of motor control were involved in the subnetwork.
In addition, since the MVPA analysis is multivariate, all voxels in the white matter mask contribute to the decision function in the processing stage. We observed that the area where the left CST passes is reddish, and there is a light green distribution in the corpus callosum and some other areas (Fig. 3). Combined with the NBS results, the affected brain tissues were distributed across a wide range of brain regions (Fig. 5). In short, the local abnormalities spread among the whole network as time elapses after the acute stage of the stroke onset. There is implicational information contained in the patterns of white matter degeneration.
Next, we briefly discuss the brain regions involved in the subnetwork (Table 4).
The bilateral frontal lobe
Similar to previous studies results showing infarct-related focal thinning of the motor area in remote cortex via degeneration of inter-hemispheric connection fiber of the corpus callosum [36,37], we found changes in the connection between the frontal hemispheres, as well as reduced FA values in a small area located in the contralesional frontal cortex. It has been reported that secondary degeneration occurred in the ipsilesional precentral gyrus after subcortical stroke involving the CST at the 6-month follow-up in stroke patients by calculating the mean kurtosis (MK) value of manually drawing ROI from diffusion kurtosis imaging (DKI) imaging study . We speculated that the degeneration in remote parts of the CST occurred in subacute phases of stroke.
In addition to motor-related brain areas, the affected brain areas in the frontal lobe may generate mild or long-term cognitive changes in patients. Recently, a research reported that the Reading the Mind in the Eyes Test (RMET) was associated with damages to the white-matter tracts connecting the frontal and the temporo-parietal components of the RMET functional network . Cognitive impairment still requires sensitive detection of subtle changes by complex experimental design or long-term observations .
The basal ganglia region
The patients were infarcted mainly in the basal ganglia region. The CST section passing through the posterior limb of the internal capsule may receive regulatory information from the nucleus of basal ganglia or constitute loops within them. Due to the cortico-basal ganglia-thalamocortical ‘motor’ loop, any impact on the circuit constituent can lead to a shift in the balance between neural interactions in the direct and indirect pathways and subsequently lead to variations in the brain functions [41,42]. In the early stage of rehabilitation, stroke patients with hemiplegia often have synergistic movements, which are thought to be related to this loop.
The occipital lobe
In our study, changes in white matter connections involving the occipital (cuneus and precuneus) region were most likely related to visual effects. Voluntary actions modulate perception that follows the anatomical-functional bias of the motor system. Therefore stroke patients with dysfunction of normal voluntary movements may develop corresponding abnormal sensory modulations that gradually affect brain structure . A study indicated a reduction in functional connectivity (FC) between the motor and executive control and the visuospatial networks in patients with motor deficits vs. healthy controls . This demonstrated the existence of FC between the visual cortex, the ipsilateral/ contralateral motor cortex and the cerebellum. We conformed that this decline in FC is probably accompanied by a decrease in white matter structural connectivity.
The cerebellum is often related to balance adjustment and patients with hemiplegia after stroke usually have problems of stability and coordination. The connections between the cerebrum and the cerebellum pass through the cerebral peduncle in the brainstem. So we assume that the weakening of those connections is partially consistent with the decrease in FA in the brainstem. Previous DTI studies also found decreased FA in midbrain of the stroke patients by manually plotting ROI . A recent study indicated that the cerebellum plays a role on residual motor output by facilitating cortical excitability in chronic stroke . Changes in cortico-cerebellar structural connectivity are probably caused by brain injuries related to the neural fibers connecting the cerebellum. The inability to perform normal movements might gradually lead to abnormal balance that is reflected in the decrease of cortico-cerebellar connectivity.
Limitations and Expectations
Despite our significant findings, this research is not free of limitations. First, the sample size is small. Second, the interval of DTI acquirement from stroke onset ranging from 2-24 weeks. Recovery of FA in penumbra regions occurs most rapidly during the first two weeks following stroke, with continued slow increases in FA for many weeks thereafter [46-47]. The phases of stroke rehabilitation may influence white matter organization considering that we only discussed stroke patients with motor impairments in a cross-sectional insight. Future work can be further explored by expanding the sample size and dynamically observing imaging changes from the acute phase to the recovery phase. Additionally, emphasis should be placed on the classification and refinement of clinical behaviors of stroke patients, with specific brain feature changes that correspond to the functional outcome.
A study on 132 stroke patients using rest-fMRI has revealed that although structural damage from stroke is focal, remote dysfunction can occur in regions of the brain distant from the lesions. These results link key organizational features of the brain networks to behavior in stroke . To date, there is no large-scale post-stroke structural network analysis similar in quantity and method to the above functional analysis. In this study, only stroke patients with motor dysfunction were recruited for analysis using DTI data. By MVPA and NBS, we detected the reduced FA values and abnormal white matter connections in the brain of those patients from a global level.
We need to further investigate the structure changes of the brain or the functional network in the natural process of different types of brain injuries. Then the diagnosis and prognosis can be more accurately assessed paving the way for better treatment selection and research methods.