To the best of our knowledge, this is the first study to investigate the intrinsic FC in IXT patients through ICA. Compared with HCs, we observed significant alterations of intranetwork FC in the IXT patients within several RSNs including the VN, SMN, DMN, DAN, ECN, FPN and AN, where these networks are involved in binocular fusion, stereopsis, oculomotor and emotional processes and social cognition. Moreover, FNC analysis also revealed significant differences in SMN–VN, DAN–FPN and FPN–SMN connectivity between the two groups.
Abnormal Intranetwork FC Analysis
Currently, we found decreased FC in right calcarine cortex and left MOG within VN, right PCUN within SMN, left PCUN and bilateral MTG within DMN, right SOG within DAN and right CUN within ECN, which could play a role in dysfunction in various facets of visual perception, including binocular fusion, visuospatial processing, and stereopsis.
Using task-based fMRI, Li et al. demonstrated an increase in bilateral PCUN activity, and suggested that the PCUN plays a role in binocular fusion [14]. The calcarine plays a critical role in the processing of spatial visual information. Wu et al. reported that patients with concomitant exotropia patients showed decreased ALFF values in the calcarine sulcus, and implicated abnormalities herein in visual processing impairments and stereovision [23]. Additionally, within the DMN, bilateral MTG activity was shown to be associated with three-dimensional surface orientation and retinal image velocities[24]. The SOG within DAN is the most important structure in the parietal eye field for visual function, and is also thought to be associated with saccades and in visuo-spatial information processing [25, 26]. Yu et al. suggested that impairment of the right MOG, bilateral calcarine and bilateral CUN may disrupt the integrity of the neural circuitry for vision, resulting in visuospatial impairment [17]. The right CUN within the ECN in IXT patients was shown to be associated with the abnormality of stereopsis and ocular movement [13]. It can be inferred that the CUN is heavily implicated in stereopsis impairment. The MOG within the VN plays an important role in the stereovision function, spatial processing, and so-called “category-selective attention-modulated face/tool processing” [27, 28]. Yan et al. also found that structural abnormalities in the MOG of individuals with concomitant exotropia were related to abnormalities in the dorsal visual pathway [29]. Decreased FC in the left MOG and calcarine (within the VN) may underlie dysfunction of binocular fusion, which is a feature of IXT [15]. It can be deducted that the above altered brain regions within RSNs could prompt the impairment of visuo-spatial processing, binocular fusion and stereopsis function, and may represent the underlying mechanism of IXT. Furthermore, the positive correlation between the FC value of MOG within VN and the degree of exodeviation observed in this study suggests that, to maintain normal binocular fusion and stereopsis during the progression of IXT, the MOG engages in compensatory processes.
Decreased FC in the right PosCG within the SMN and left AG within the FPN were observed in our IXT patients in association with eye movement. In our previous study, we observed abnormal FC between the left primary visual cortex(V1) and right PosCG, along with decreased ALFF values in the PosCG of IXT patients, consistent with the present results; which suggested that the PosCG was related to the ocular movements[27]. Moreover, we noted decreased FC in the right PosCG within the SMN. A previous study reported functional connections between many brain regions in SMN and the primary motor cortex(M1) [30]. The development of motor control is related to changes in synaptic strength in the primary motor cortex [31–35]. The decreased FC between PosCG and V1 and M1 seen in IXT patients indicates that ocular movement impairment may disrupt the processing of binocular visual information. The AG is also important for ocular movement; it processes visual information and passes it to the frontal lobe [25]. We observed decreased FC in the left AG within the FPN, which may impair ocular movement control and accelerate the progression of IXT. Long-standing oculomotor abnormalities can disturbed the normal pattern of retinal correspondence [36]. We proposed that a decrease in in right PosCG within the SMN and left AG within the FPN may lead to the dysfunction in oculomotor control and coordination, which would in turn exacerbate exodeviation. Furthermore, we also found a negative correlation between the FC of AG within the FPN and the degree of exodeviation. Taken together, the results suggest that FC of the AG within the FPN could serve as a biomarker of the severity of oculomotor cortex impairment in IXT patients.
Besides, decreased FC was observed in the left STG within AN, right SMA within the SMN and right SMG within the DAN. Conversely, the FC value of right ACG and PCG within the DMN and left ACG and PCG within the DAN presented increase in IXT patients. All of these brain regions are involved in cognition, attention and emotion. The top-down attentional control is mediated by the ACG [37], and the SMA is fundamental for the processing of information related to emotions and cognitive functions; a decrease in SMA activity can result in attention deficits[34, 35]. Jonathan et al. found that attention-drawing auditory stimuli can deactivate the visual association cortex [38]. Bilateral STGs within the AN play an important role in the monitoring and reassessment of behavior[39]. Increased activity within the DMN is closely associated with increased sensitivity to both the external environment and self-referential/reflective thought [40]; in particular, increased connectivity in affective regions may reduce connectivity in regions associated with cognitive processing, such as the ACG [41], which may help explain why IXT patients are more vulnerable to depression and anxiety. Additionally, the right SMG is crucial for overcoming egocentricity and developing the ability to recognize emotions [42], and is also associated with mind or empathy [43] and social communication [44]. Therefore, the above brain regions may be related to the impairments in emotional cognition, social communication and attention seen in IXT patients, which can lead to various psychological problems. It can be indirectly proved by a cross-sectional study which found a moderate association between strabismus and a series of mental and psychological problem such as anxiety disorder and schizophrenia[8].
Functional Network Connectivity Analysis
Finally, our FNC analysis showed that the DAN -RFPN, RFPN -SMN and SMN-VN were found significantly altered in IXT patients. Since the FPN is critical in visual-spatial attention and motor function [45], and excessive connection of the SMN-RFPN, RFPN-DAN pathways might represent a compensatory mechanism for visual perception impairments in IXT patients. Moreover, disruption of the VN–SMN pathway may lead to binocular fusion and stereoscopic vision impairments, thus accelerating the progress of IXT. Studying altered interactions between RSNs may provide further insight into visuomotor and cortical plasticity.
Limitations
The current study had several limitations that should be acknowledged. First, we only investigated brain function changes in adult IXT patients, and the results may not apply to their pediatric counterparts. Second, although some changes in some brain regions involved in cognition, attention, and emotion were found, we did not evaluate the psychosocial status of the participants with dedicated scales. Finally, the sample size was not large.