In this study, we used DTI parameters to evaluate the association between white matter maturation and ROP. We found significant differences in the DTI parameters of several white matter regions among the preterm and full-term infants, but we observed fewer differences between preterm infants with and without ROP from our analyses. Structural network analyses revealed a significant difference in small-world index values between those with and without severe ROP. Our results may indicate maturational delay of the specific white matter regions in infants with ROP and the reorganized structural brain network after birth in infants with severe ROP.
As previous studies have reported the association between white matter maturation delay and cognitive outcomes in children born preterm,
12,29 our findings may provide functional implications in preterm infants with ROP. Clinical outcomes of ROP have improved greatly since the introduction of laser and anti-vascular endothelial growth factor therapy for severe retinopathy. Therefore, in infants with ROP, clinicians or parents might believe that the condition is no longer associated with childhood visual or nonvisual impairments, in cases of regression or successful treatment. However, our results on white matter maturation in infants with ROP indicate that these infants may retain an increased risk of cognitive or motor impairment. Mechanistically, our results might also suggest a possible association between ROP and white matter maturation in certain areas of the brain. However, as motor and cognitive outcomes were not assessed in this cross-sectional study, further studies are required to validate the clinical and mechanistic implications our study.
Hellstrom et al.
2 suggested ROP as a window into the postnatal development of the brain, and because ROP is associated with neurologic dysfunction and poor brain growth. White matter analyses in our study suggest that white matter injury can occur as a comorbidity of the CNS system in infants with ROP and should be considered carefully. However, we used two control groups (full-term and preterm controls) and a general linear model to discriminate the effects of ROP/severe ROP from those of GA (preterm birth). The results indicated that the microstructural integrity of the white matter significantly differed among the groups in several areas, but relatively fewer differences were observed between preterm infants with and without ROP. These findings suggest that preterm birth may exert a greater effect on white matter microstructural development than ROP does.
However, previous studies have reported an association between delays in microstructural development of the white matter and ROP.
7 Thompson et al.
23 observed an association between severe ROP and microscopic alterations in the optic radiations in very preterm children. Additional studies have revealed that FA values in the posterior limb of the internal capsule, external capsule, and optic radiations are decreased in infants with severe ROP.
29 Functionally, these differences, in addition to the ocular complications of ROP, may lead to visual impairment.
2,12,30 In the present study, we analyzed microstructural integrity in a greater number of white matter areas (
n = 23), adjusting our analyses for GA, GA at the time of MRI, and IVH. ROP was significantly associated with MD values in the superior longitudinal fasciculus, an association fiber tract that synapses on neurons in the occipital lobe and cerebral peduncle, which refines motor movements and uses proprioceptive information to maintain balance and posture. Furthermore, infants with and without severe ROP exhibited significant differences in FA values within the anterior limb of the internal capsule, which contains thalamic fibers that project to the cingulate and prefrontal cortex. These patients also exhibited significant differences in MD values within the stria terminalis, a band of fibers running along the ventricular surface of the thalamus serving as a major output pathway of the amygdala.
There are two distinct pathways of neural processing of vision: the dorsal and ventral pathways. The ventral visual pathway carries information about perceptual features, allowing the creation of long-term representations necessary to identify and recognize objects, whereas the dorsal pathway processes information about objects and their locations in a moment-to-moment manner and mediates the visual control of skilled actions. Among the areas investigated in this study, the inferior frontooccipital fasciculus is the white matter region consisting of the ventral stream of the visual pathway, whereas superior longitudinal fasciculus and superior frontooccipital fasciculus are the regions consisting of the dorsal pathway. In these white matter regions, preterm infants with and without ROP exhibit nonsignificant differences in DTI parameters. In contrast, there were remarkable differences in FA and MD values among preterm infants with and without ROP and full-term infants. This suggests maturational delay of the dorsal and ventral pathways in infants with ROP might be attributed to preterm birth, rather than ROP. The maturation of the two pathways and associated functional deficits in infants with ROP should be investigated further, as these pathways are important for visual perceptual function in infants with ROP.
Changes in DTI parameters may reflect alterations in white matter fiber diameter/density, myelination, or membrane permeability.
31 Therefore, our results may indicate differences in white matter maturation between preterm and full-term infants and between infants with and without severe ROP. The observed associations between altered white matter microstructure and preterm birth/ROP may reflect common etiologic factors, such as hypoxic-ischemic insult in preterm infants, for both ROP and white matter injury.
32,33 Furthermore, hyperoxia can activate signaling pathways, resulting in pathologic angiogenesis via reactive oxygen species, the key pathogenesis of ROP.
34 The oxidative stress caused by hyperoxia may also be relevant to white matter injury in premature infants as it also induces apoptosis in the brain, leading to white matter injury in the neonatal brain.
35 In addition, we detected differences in structural connectivity alterations between preterm infants with and without severe ROP, supporting our findings regarding differences in DTI parameters between these groups. The brain networks of patients with severe ROP exhibited significant decreases in small-worldness, suggesting that severe ROP exerts an impact on the development of integrated and segregated networks. Our results are in concordance with recent findings that early developmental connectivity is altered by preterm birth and adverse neonatal conditions.
36,37 As these significant associations between connectivity and ROP may be predictive of behavioral performance and cognitive capacity later in life,
38 infants with severe ROP may be at risk for poorer behavioral and cognitive outcomes. However, our cross-sectional data do not reveal the precise effect of ROP or severe ROP on white matter development during the post-term period, so further studies are necessary.
Currently, anti-vascular endothelial growth factor treatment is widely performed in cases of severe ROP, such as zone I or zone II posterior stage 3 with plus disease.
39 Due to the possibility of its systemic antiangiogenic effect, it is very important to assess systemic side effects of the therapy. As antiangiogenic effects can be detrimental to brain development, it might anatomically affect the brain microstructure and functionally result in adverse motor, sensory, or cognitive outcomes. However, its effect has been debated and not been extensively studied for brain white matter. In our subgroup comparison between the preterm infants with and without bevacizumab therapy, there was no parameter showing a statistically significant difference between the two groups. This comparison might indicate that the short-term effect of bevacizumab therapy at term equivalent ages is minimal in terms of brain white matter integrity; however, due to the limitation of the small number of patients who underwent this therapy, its long-term effect on the brain should be evaluated further.
The present study possesses several limitations of note. First, our study used a cross-sectional design, and we were, thus, unable to determine the causal relationship between ROP and white matter maturation. Although we controlled for important confounding variables such as GA, age at MRI, and mild IVH, significant differences in clinical characteristics among the groups may have affected our results. Furthermore, our evaluations of the effect of ROP on postnatal development were somewhat limited, as we assessed DTI parameters obtained at term-equivalent ages. Further studies using data obtained at greater ages are required to provide more conclusive data regarding post-term white matter development. Additionally, the subgroup comparison of the DTI parameters between the infants treated with and without bevacizumab therapy involved a small number of treated infants, particularly those who received bevacizumab therapy; thus, this comparison might not have sufficient power to show statistical significance. Furthermore, as visual outcomes could not be assessed at term-equivalent ages, we were unable to evaluate the relationship between white matter abnormalities and visual function. Future studies should examine the associations between various cognitive functions and white matter abnormalities at later time points in infants with ROP, as these associations may elucidate ROP's effects on brain structure and cognition.
In conclusion, our findings demonstrated that white matter microstructural abnormalities were associated with preterm birth in multiple areas of the brain and with ROP in a few areas at term-equivalent ages. Our results suggest that preterm birth exerts a greater effect on white matter maturation than ROP up to the point of term-equivalent ages. Future studies should investigate the association between ROP and CNS development in further detail by evaluating post-term neural development.