Beyond the well-known concept of lesion-symptom mapping, some lesion in a single location in the brain would disrupt brain functions routed to widespread neural networks [1,30]. Our analysis conformed that local destruction of certain anatomic regions can affect remote areas in brain.
White matter degeneration in CST pathway of stroke patients
The degree of anisotropy depends on the level of organization and the integrity of the white matter tract, and on the degree of freedom of water diffusion movement caused by the oriented axonal membranes and myelin sheaths . Reduced anisotropy along the corticospinal tract (CST) remote from a cerebral infarct has been interpreted as Wallerian degeneration (WD) . DTI can quantify the fractional anisotropy (FA) values to evaluate the pathology change of the cerebral white matter, such as WD. By the good classification ability of MVPA, we reported that apart from the basal ganglia region with direct infarcts, brain areas with significantly decreased FA value in the stroke patients were also distributed in the brainstem of lesioned hemisphere, and a few in bilateral frontal lobes, which may be degenerative lesions caused by Wallerian degeneration.
Neural changes contains anterograde, retrograde degeneration or refactoring, acute and chronic phases of stroke probably differ in the white matter changes. However, no matter what kind of alteration in brain generates specific structure with corresponding function. Therefore we did pattern recognition classification using the whole brain FA map and explored brain regions important for distinguishing patients with motor impairment from healthy controls.
Our study verified degenerative changes in white matter of stroke patients. The patients were infarcted mainly 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, so the changes have generality in some way.
Decreased WM connection in widely distributed brain areas of stroke patients
Many patients left with motor dysfunction after the occurrence of cerebral infarction. Usually, it is related to the injury of the corticospinal tract. The CST mainly 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. CST is crucial for proper execution of a volitional movement [33,34]. Apart from CST and the motor areas of cortex, the proper execution of movements containing balance and coordination also requires extrapyramidal tract and other brain regions such as nucleus in basal ganglia and cerebellum . Since the 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 corticospinal tract passing 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 tissue involved a wide range of brain regions (Fig. 5).
NBS analysis showed 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) were involved in the subnetwork, but also some regions that may participate in the regulation of motor control.
Next, we briefly discuss the brain regions contained in the subnetwork of NBS results.
The bilateral frontal lobe
Similar to the previous study, infarcts cause motor area focal thinning in remote cortex via degeneration of inter-hemispheric connection fiber of the corpus callosum [36,37], we found a change in the connection between the frontal hemispheres, and a small area in contralesional frontal cortex decreased in FA value. 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 . Now we speculate the degeneration in remote parts of CST occurred in acute and subacute phases of stroke.
In addition to motor related brain areas, the affected brain areas in frontal lobe may generate mild or long-term cognitive changes in patients. Recently, a research reported the Reading the Mind in the Eyes Test (RMET) were associated with damage to white-matter tracts connecting frontal and temporo-parietal components of the RMET functional network . Cognitive impairment still requires sensitive detection of subtle changes by complex experimental design or long-term observation .
Basal ganglia region
The patients were infarcted mainly in the basal ganglia region, the CST passing through posterior limb of internal capsule may receive regulation information from nucleus of basal ganglia or constitute loops with 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 subsequent variations in the brain functioning [41,42]. In the early stage of rehabilitation, stroke patients with hemiplegia often have synergistic movement, which is speculated to be related to this loop.
The occipital lobe
In our study, changes in white matter connections involving the occipital (cuneus and precuneus) are most likely related to visual effects. Voluntary actions modulate perception that follow the anatomical-functional bias of the motor system, in stroke patients with dysfunction of normal voluntary movement, they may develop corresponding abnormal sensory modulation that affect brain structure gradually . A study observed reduced functional connectivity between motor and executive control and visuospatial networks in patients with motor deficits vs. healthy controls .They demonstrated functional connectivity exists between visual cortex and ipsilateral/ contralateral motor cortex and cerebellum. We conformed that this decline in functional connectivity is probably accompanied by a decrease in white matter structural connectivity.
Cerebellum is often related to balance adjustment, patients with hemiplegia after stroke usually have problems in walk stability and coordination. The connections between the cerebrum and the cerebellum pass through the cerebral peduncle in brainstem, so we assume that the weakening of connections to the cerebellum is partially consistent with the decrease in FA in brainstem. Previous DTI studies also found a decrease in FA in midbrain after stroke by manually plotting ROI . A recent study found the role of the cerebellum for residual motor output by facilitating cortical excitability in chronic stroke . The changes of cortico-cerebellar structural connectivity was probably caused by brain injuries related to the neural fibers connecting to cerebellum, but the inability of normal movement may gradually lead to abnormal balance that reflected in the decreases 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 range of MRI scan time from disease onset was wide and the phases of stroke rehabilitation may influence some white matter organization in an unexplored way, although we only discussed the stroke patients with motor impairment 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. And it should be emphasized on the classification and refinement of clinical behavior in stroke patients, with the changes of brain features 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 area of damage. These results link key organizational features of brain networks to brain behavior relationships in stroke .
By now, there is no large-scale post-stroke structural network analysis similar to the above functional analysis in quantity and method. In this study, only stroke patients with motor dysfunction were recruited for analysis using DTI data. By MVPA and NBS, we detected distribution of abnormal FA values and white matter connections in the whole brain of the stroke patients.
We need further investigate the changes of the brain structure or functional network in the natural process of different types of brain injuries. Then the diagnosis and prognosis can be concluded more precisely, the basis theory and guidance for the selection of treatment and research methods be provided more reasonably.