Studying the functional organization of the brain in stroke and neurodegenerative diseases has sparked the interest of many researchers in recent years. Although there have been several studies applying functional MRI techniques in the realm of MMD to explore ‘small-world’ network topologies, dynamic functional connectivity networks, and modularity in MMD patients(7, 16, 17), the current study performed ROI-based analyses via functional connectivity for the first time and further combined tensor metrics to provide additional evidence for our findings.
Our study showed that the functional connectivity of several paired regions decreased in MMD patients. There is increasing evidence that intrahemispheric or interhemispheric connectivity changes that occur in ischemic disease(18) are linked to cognitive decline(19). Here, we also confirmed that changes in functional connectivity were correlated with cognitive performances in MMD, although significant correlation was only demonstrated in the functional connectivity between the SMA and the IFGorb.
The SMA complex is located in the posterior part of the superior frontal gyrus, which is bounded by the cingulate gyrus, anterior central gyrus, and superior frontal gyrus(20). Neuroimaging studies have confirmed that the SMA is involved in the cognitive process of working memory, executive control and processing speed (21–23). Through fiber tracking imaging, researchers found that the most important subcortical connection with the SMA included the primary motor area, the cingulate, the corpus callosum, the inferior frontal gyrus (IFG), and the striatal complex-internal capsule(24). It is important to mention that the frontal aslant tract (FAT) has been identified as a white matter tract connecting the SMA to the IFG, and it was shown to have a role in language function, working memory, social community tasks, attention, and music processing.(25). Our results were consistent with the abovementioned anatomical and imaging studies of the SMA.
MMD is an ischemic disease that affects patients for a long period of time, and chronic insufficient blood supply leads to demyelination of white matter fibers and destruction of axon integrity. However, such patterns of subtle damage referred to as NAWM are usually not demonstrated in the structural images, thus preventing us from detecting the brain abnormalities that are caused by MMD on conventional MRI sequences. Fortunately, with the development of MR technology, we can use emerging methods to elucidate brain damage by capitalizing on many different aspects other than structure.
Currently, there is intense research being conducted on white matter integrity and brain functional connectivity in neurological diseases. Studies have shown that white matter abnormalities are correlated with disrupted functional connectivity, suggesting that common mechanisms may underlie fibers and functional connectivity(26). Our study revealed that the fiber integrity and functional connectivity between the SMA and the IFGorb in the left hemisphere were disrupted before the development of a significant brain lesion in MMD patients. Such early detection of brain abnormalities at the preclinical stage is conducive for implementing preventive interventions to abate cognitive decline in MMD.
FA, MD, RD, and AD are the main tensor metrics that are derived from DTI. When the white matter fibers are damaged, the diffusion range of water molecules in the fibers increase, and the values of FA, MD, and RD will also increase accordingly. Our study showed that the FA of the fibers between the SMA and the IFGorb were not significantly different between MMD patients and HCs. This might be the result of the existence of cross fibers between the two brain regions, or it is highly likely that it occurred because the disruption of the fibers happened in all directions.
The interpretations for the changes in the AD are controversial. Theoretically, the AD values decrease when axons are injured, but other studies report that the AD increases in damaged white matter regions(27, 28). The potential mechanism consists of increased extracellular water content that is secondary to atrophy of white matter fibers, and alterations in the water flow in the axons occur due to the breakdown of certain components of the cytoskeleton, which allows water molecules to move more rapidly parallel to the axons(27, 29). To summarize, in the case of intensive axonal loss, the increased isotropic diffusion is likely to enhance both RD and AD(28).
CONN is Matlab-based software that has been widely used for the calculation, demonstration, and investigation of brain network connectivity. Connectivity assessment techniques include seed-to-voxel network maps, ROI-to-ROI connectivity matrixes, graph characteristics of network systems, brain interconnection, inherent connectivity, generalized psychophysiological interaction models, and other voxel-to-voxel measures. Unlike seed-based correlation analysis, which is a hypothesis-driven approach based on a chosen region, ROI-to-ROI analysis is a data-driven method that can produce information regarding the entire brain connectivity pattern. Therefore, we used ROI-based analyses in this study, which we considered to be more powerful for investigating the abnormal brain functional connectivity at the regional level.
White matter integrity impairment and cognitive disruption in MMD have been demonstrated in several studies, aberrant functional connectivity is another form of brain damage caused by MMD(2, 7, 16, 30). The impaired brain functional and structural connectivity between the SMA and IFG in the left hemisphere provides us a novel perception of the pathophysiology of MMD and might be applied as the hallmark in the evaluation of disease progression and prognosis of MMD in the future.
There are some limitations to our study that must be mentioned. First, like other MMD imaging studies, a small number of patients were investigated due to the rare incidence of the disease, which limits the generalizability of our results. It is necessary to conduct a multi-center, large-sample study to confirm our results. Second, vascular abnormalities of MMD mainly involve the anterior circulation of the brain, and therefore, our study did not include the cerebellum as a ROI. It is worth noting that some studies indicate the existence of a functional connection between the cerebellum and the brain(5). Third, anatomical and imaging studies have shown rich fiber connections between the SMA and the IFG that are associated with cognitive functioning, whereas our results show only that the breakdown of the connection between the SMA and the IFGorb in the left hemisphere is significantly correlated with the cognitive performance of MMD patients. Fourth, further studies are required to determine whether functional or structural connectivity is initially damaged before the onset of cognitive dysfunction in patients with MMD.