As a prevalent, chronic and progressive disease of the macula, age-related macular degeneration (AMD) is the leading cause of central vision impairment worldwide. The prevalence of AMD ranges from 6.8% in Asians to 12.3% in Europeans, is lower in Africans than in Europeans, but similar between Asians and Africans (Kawasaki et al., 2010; Laude et al., 2010; Wong et al., 2014). Major visual impairment occurs mainly in the late stages of AMD in one of two forms: neovascular (wet) AMD and geographic (dry) atrophy. Age is an important risk factor for AMD, other strong and consistent risk factors being darker iris pigmentation (Chakravarthy et al., 2010), previous cataract surgery (Cugati et al., 2006), cigarette smoking (Seddon et al., 1996), and obesity (Seddon et al., 2003). In clinical practice, fundus fluorescein angiography (FFA), optical coherence tomography, and fundus autofluorescence imaging are now extensively applied in diagnosis and to guide management of AMD (Lim et al., 2012). However, these examinations may not be suitable for patients with severe ocular media opacity or significant disease such as heart or renal failure. Advances have been made in disease detection and diagnosis allowing for rapid intervention, monitoring, and amelioration of the disease, improving prognosis, and evaluation.

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely performed to assess cerebrum functional connectivity (FC), which is temporally correlated within resting state functional networks. rs-fMRI is increasingly applied to map the representation of cerebral function in many diseases, such as amyotrophic lateral sclerosis (Douaud et al., 2011), traumatic brain injury (Mayer et al., 2015), stroke (Puig et al., 2018), and Alzheimer’s disease (Zhao et al., 2020), and has proven valuable for characterizing and analyzing cerebral activity in the resting state (Damoiseaux et al., 2006; De Luca et al., 2006) and in task performance (Spreng and Grady, 2010). Based on the correlation between the anatomical structure and physiological functions of the retina and cerebrum (Wong et al., 2001b; Patton et al., 2005), the potential of retinopathy to provide indirect indicators of intracerebral lesions has attracted extensive attention (Fuller et al., 2001; Wong et al., 2001a,2002; Yatsuya et al., 2010). Abnormal spontaneous FC has been observed in ophthalmic diseases such as glaucoma (Li et al., 2017), amblyopia (Ding et al., 2013; Liang et al., 2017), and strabismus (Yan et al., 2019). The frontal, thalamic and temporal cerebral regions comprise the default mode network, which participates in memory, emotional, and cognitive functions (Raichle, 2010; Zhang and Raichle, 2010). Therefore, we hypothesize that FC is abnormal in AMD patients, and that relevant cognition-related or connectivity changes in visual areas may result in anxiety and depression.

To explore this possibility, rs-fMRI was used to measure cerebral FC, promoting an in-depth understanding of the potential neural mechanism of cerebrum visual pathway injury in patients with AMD (Figure 1), and allowing better evaluation and improved prognosis for patients.

Foveal scotoma due to macular photoreceptor atrophy in AMD has caused vision loss and blindness for a large number of individuals globally, particularly in developed countries (Rosengarth et al., 2013; Wong et al., 2014). Previous studies in animals (Kaas et al., 1990; Darian-Smith and Gilbert, 1995; Giannikopoulos and Eysel, 2006) and humans (Pascual-Leone et al., 2005; Liu et al., 2007) have demonstrated altered cerebral functions in response to reduced visual input, but the extent of cerebral changes associated with AMD remains unclear and has attracted the attention of many researchers. Our study has indicated that FC values are significantly increased in the IFG, SFG, IPL, RTG, and SPL, and decreased in the CPL, MCG, MDL, CAL, and TLM in AMDs compared with HCs (Figure 6). These findings may reflect compensatory changes supporting cerebral performance in AMD patients with vision loss.

Previous MRI research on the impact of AMD on cerebral regions is shown in Table 3 and the underlying functions of specific areas of the cerebrum are shown in Table 4. We could hypothesize that AMD not only causes changes in cerebral FC patterns affecting visual pathways, language, cognitive and memory, but also strengthens internetwork connections via a loss of inhibitory signals that accompany visual stimulation or contribute to recruitment of new networks to support and complete visually mediated tasks. Whitson et al. (2015) found relatively high resting-state FC values in AMD patients in the IFG, superior temporal gyrus (STG), inferior parietal lobe (IPL), superior parietal lobe (SPL), supramarginal gyrus (SMG), supplementary motor area (SMA), and precentral gyrus (preCG). They also found high connectivity between SMA and SPL as well as SMA, IPL and IFG which are implicated in motor/visuospatial function, with strong connectivity within the reference links and default mode network compared to HCs. Furthermore, the AMDs showed stronger relationships between connectivity and memory performance in the inferior and medial temporal gyri, temporal pole, IFG, SFG, MFG, posterior cingulate cortex, and medial prefrontal cortex compared to control participants, while the resting default mode network in the bilateral posterior cingulate cortex, anterior cingulate cortices, and precuneus were similar in these groups (Zuo et al., 2020). One study indicates that AMDs exhibit increased cerebral activation in a widely distributed cortical network including SPL, IPL, the frontal eye fields, and the prefrontal cortex (Szlyk and Little, 2009). These results directly and indirectly support our findings that the mean FC values in IFG, SFG, IPL, RTG, and SPL are significantly higher in AMDs than in HCs, suggesting that a positively FC was correlated with these specific cerebral regions involved in the regulatory mechanism of AMD to achieve adaptability and plasticity in various functions such as vision, cognition, and memory.

In addition, one study showed significantly increased gray and white matter in the CPL during a period of oculomotor training in AMD compared with controls (Rosengarth et al., 2013), while no difference was found in white matter of the cingulum hippocampus, cingulate, or the thalamus (Yoshimine et al., 2018). In addition, volumetric reductions were found in the optic radiations, lateral geniculate bodies and visual cortex in AMD patients, as the white matter in frontal lobe was decreased in AMD but not in juvenile macular degeneration (Hernowo et al., 2014). The activation with significant clusters showed marked reduction in the parietal lobules in AMD patients (Little et al., 2008). Since the lateral geniculate body, optic radiation, and visual cortex are vital parts of the visual pathways, AMD patients may have changes in these specific areas. Szlyk and Little (2009) found decreased activation in the left SPL and IPL, primary and secondary visual cortices, frontal eye fields, bilateral superior parietal regions, supplementary motor regions, eye fields, and left fusiform gyrus in AMD patients relative to controls. However, the results of the present study differ from the above findings due to differences in race, geographical region, inter-individual variations and image data processing, but can fully supplement their research. Previous studies (Hernowo et al., 2014; Prins et al., 2016a,b) reported reduced cortical volume and abnormality of white matter in the visual cortex in AMD. The results of these studies suggest that AMD may cause widespread changes in cerebral regions and suggest a strong association between AMD and changes in specific cerebral regions, and their corresponding major effects, and are further supported by the current work.

Whether changes in cerebral activity are consequential or adaptive in AMD and the exact mechanism underpinning them remains unclear. Apoptosis of retinal nerve cells, especially in the macular area, could affect changes in cerebral tissue properties through transsynaptic degeneration in AMD (Haak et al., 2016; Prins et al., 2016a). This would lead to decreased visual signaling from the defective macula and behavioral factors correlated with loss of visually dependent activities, such as social interaction and reading (Zuo et al., 2020). The frontal lobe, cingulate gyrus, temporal gyrus, and thalamus are involved in cognitive, emotional, and memory functions (Critchley et al., 2004; Seitz et al., 2006; Raichle, 2010; Zhang and Raichle, 2010). Lesions of these cerebral regions are connected with social and emotional behavior, and could lead to anxiety and depression. The AMD group in this study showed significant correlations between connectivity in cerebral regions and HADS scores, indicating that anxiety and depression scores are linked with overall FC values, and that abnormal neural electrical activity may occur in brain regions associated with emotional activity (Figure 7). Moreover, AMD may result in specific cerebral regional changes through a variety of mechanisms, including the loss of cognitive stimulation (a consequence of sensory disorder), adaptive restructuring of visual pathways, decreased feedback regulatory signals from visual cortical regions, or by increased metabolic demand in specific cerebral regions, which would present alterations in FC and diminished cognitive ability (Whitson et al., 2015). These changes may promote functional cerebral reorganization in the fronto-parietal control networks (Zhuang et al., 2018) and primary visual cortex (Masuda et al., 2008) in AMD to improve vision and prognosis. The mechanism of cerebral regional changes caused by AMD is a complex process involving many different brain regions and requires more in-depth and comprehensive research.

Based on the above studies (Table 4 and Figure 8), it could be suggested that AMD patients have abnormalities in several cerebral regions. The current study has some limitations. A cross-sectional and observational approach was adopted in this study, and the sample size was small, making it difficult to observe the possible development of cognitive impairment and fMRI changes associated with AMD, so we have not drawn firm conclusions about causality of the described relationships. Therefore, an in-depth, comprehensive and systematic study is needed to elucidate the mechanisms and correlations of AMD-induced changes in brain regions.

Our study demonstrated abnormal FC values in specific cerebral regions of AMD patients. These findings can not only supplement the theoretical basis for research on the mechanisms of AMD nerve injury and repair process, but also form a basis for further exploration of the potential pathophysiological mechanisms of AMD-induced functional changes in cerebral regions.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and all research methods were approved by the Committee of the Medical Ethics of the First Affiliated Hospital of Nanchang University and were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The patients/participants provided their written informed consent to participate in this study.

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.