Resting-state neural activity
It has been reported that patients with subcortical infarct exhibit increased ALFF in the bilateral primary motor cortex (PMC) despite cortical thinning in the early stage of stroke (Liu et al., 2015). However, the findings were contradicted by a study that reported no significant increase in ALFF in the contralesional PMC in patients with chronic stroke, with only a few increases in brain activity in the ipsilesional PMC (Zhang et al., 2014). The fALFF reflects the regional slow-wave brain activity strength and gives an advantage over ALFF because it can reduce the contribution of irrelevant physiological noise to the signal of interest and provide improved sensitivity and specificity in detecting spontaneous brain activities (Song et al., 2019; Zou et al., 2008). In our study, the fALFF was increased in the contralesional parietal lobe, and significant correlations between fALFF in this area and movement scores were detected in stroke patients. Studies in heathy subjects have reported that several parietal regions were involved in motor learning (Ma et al., 2011) and the dorsolateral prefrontal cortex contributed to the formation of movement plans (Hartwigsen et al., 2012). We speculated that the planning of movements was impaired in the stroke patients due to reduced fALFF in the contralesional frontal lobe, and the process of motor learning was more frequent during rehabilitation after the acute stage of stroke.
Changes in FC were identified in multiple functional networks in well-recovered chronic stroke patients with a subcortical lesion in the motor pathway (Wang et al., 2014). The DMN is related to self-consciousness during the resting-state, estimation of acquired experience, and planning of future decisions (Buckner et al., 2008). Consistent with previous findings, our study showed that stroke patients displayed decreased FC within the DMN (Jiang et al., 2018; Zhang et al., 2017). The DAN is involved in the control of visuo-spatial attention and was associated with upper-arm and walking ability in stroke patients (Baldassarre et al., 2016; Carter et al., 2010). This highlights the DAN as a key network for targeting rehabilitation after stroke. Following motor impairment caused by brain lesions and the disuse of the affected limb, brain regions that were originally responsible for motor assistance undergo relative changes, such as attention and motor planning, reflected in the brain functional networks.
In the SMN, the stroke group exhibited increased FC in the contralesional parietal lobe and ipsilesional frontal lobe, coupled with decreased FC in several regions, including the medial parietal lobe. The parietal cortex is comprised of primary somatosensory areas and an associative cortical region. Different portions of the posterior parietal cortex engage in multiple movement-related processes, such as sensorimotor integration, spatial attention, working memory, and early motor planning (Fogassi and Luppino, 2005; Whitlock, 2017). Combined with the increase in nearby fALFF, we considered that the contralesional parietal lobe played an important role in the reuse of motor function after stroke with hemiplegia. Widespread lesions in the fronto-parietal network are associated with working memory deficits. Stroke patients show decrements of moderate magnitude in all subsystems of working memory (Lugtmeijer et al., 2020). The RFPN and the LFPN are largely left-right mirrors of each other. The connectivity changes within the RFPN and the LFPN are probably linked to limb pain and paradigms in motor-related cognition (Smith et al., 2009).
Conjoint analysis of resting-state neural activity and tractography
The fibers connecting the two hemispheres increased in the stroke group across the frontal lobe with reduced fALFF. The resting-state fMRI measures the temporal correlation of blood-oxygenated-level-dependent (BOLD) signals between different brain regions (Power et al., 2011). There are fewer neurons in the regions with higher fiber concentration, for fibers require less blood supply and lower oxygen levels than neurons (Gu et al., 2018). These regions with reduced activity probably result from the structural remodeling of white matter in the brain (Carmichael, 2003). Because of the structural changes in white matter or cortical thickness, the brain exhibits corresponding BOLD signal changes.
Most regions with reduced FC in the RSNs were accompanied by a growing number of fibers, especially the SMN and DAN in stroke subjects. The DAN showed reduced FC in the bilateral cingulate gyrus and the SMN showed reduced FC in the bilateral medial parietal lobe. Most of the fibers passing through these areas are interhemispheric connections. According to previous studies, white matter remodeling occurs in specific regions of the ipsilesional and contralesional hemispheres during the recovery period after stroke (Schaechter et al., 2009; Koch et al., 2016; Umarova et al., 2017). The interhemispheric connections between the motor regions have been reported to be significantly reduced after stroke (Duering et al., 2015), but recovery from motor deficits is typically associated with a steady increase of resting-state connectivity, particularly between the ipsilesional PMC and contralesional areas (Wang et al., 2010; Park et al., 2011). Then how the FC between the hemispheres was increased? It can potentially be answered by the growth of interhemispheric connections besides major motor regions (e.g. PMC). Our research did not calculate functional networks by parcellation of motor regions based on atlas. The increased inter-hemisphere fibers were not necessarily across the specified motor regions, but across the regions for motor assistance, or the changed parts of the motor areas after stroke. It was found due to the benefit of the multi-modal fMRI analyses.
There were no significant changes of fiber bundles passing through the regions with stronger FC in the studied RSNs, but fiber increment occurred in reduced FC regions in the stroke group. Each RSN map was defined by ICA, and a group comparison of the spatial maps reflected a group difference in the connectivity strength or signal synchronization of each voxel to the whole spatial component (Mueller et al., 2014). In other words, significantly reduced synchronization in the bilateral parietal lobe and the cingulate gyrus in the DAN, and increased fiber tracks across these regions were detected. Structure leaves an indelible mark on function, though the relationship between brain structure and function is complex (Suarez et al., 2020). In stroke patients, brain regions with significantly reduced synchronization in the RSNs, such as the parietal lobe in the SMN, were defined as ROIs to track the fibers across them. Brain regions with intensified fibers were decoupled to some extent with the overall functional network. Combined with the increased fALFF in the contralesional parietal lobe, which correlated with motor scores in stroke patients, we speculate that it was the structural basis for the enhancement of the contralateral brain activity.
A finding suggest that the intact hemisphere contributes to the functional recovery early after stroke probably via the transcallosal rather than the corticospinal signals (Zaaimi et al., 2012). The variation theory suggested that recovery of function could be driven by intact areas. The important mechanisms supporting recovery contain the formation of new synapses and collateral sprouting of axons to rewire surviving tissues, especially in peri-infarct cortex (Wiesendanger et al., 2012; Finger et al., 2010). It could be concluded that the increased connections between the contralesional lobe and the ipsilesional regions through the corpus callosum were prepared to complement the functions of the lesioned side.
Motor attention and sensory-motor networks were originally associated and coordinated in the bilateral hemispheres. Loss of function in the lesioned hemisphere would stimulate the contralateral cortex to exert corresponding effects on the related regions, leading to the activation of a compensatory pathway and increase connections between hemispheres. The higher contralesional neural activity might not necessarily be adjacent to the increased fiber tracks, but the need for signal transmission could result in a proliferation of inferior nerve fibers.
Previous studies have shown that there is no unique reorganization scheme in certain brain areas after stroke (Koch et al., 2016). But it is difficult to accurately locate all the microstructural changes in the brain of every patient. Variations after stroke onset, individual differences, and the interaction between the two factors make it difficult to perform precise researches and generate effective personalized therapy. Overall, our results were similar to those of previous studies indicating elevated activity in the contralateral cortex after stroke and suggest a possible structural basis in the brain (Riecker et al., 2010; Gerloff et al., 2006). We made a relatively specific analysis at the group level and integrated it with previous reports to determine the possible mechanisms underlying reorganization after brain lesions.
The roles of the contralesional cortex and interhemispheric relationships in recovery are highly correlated to the efficiency of new treatment approaches, such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) (Grefkes and Fink, 2014). A well-balanced interhemispheric control of excitatory and inhibitory connections is required for sensorimotor function. So far, data about the treatment reactions of these approaches are inconsistent. Interindividual differences in treatment efficacy require precision medicine to seek the variable mechanisms in the reorganization patterns of the brain after stroke. Future longitudinal studies would help to investigate key neural alterations in well-recovered patients and provide insights for treatment implications.