Glaucoma refers to a series of ocular diseases characterized by progressive optic nerve head (ONH) degeneration retinal ganglion cell (RGC) loss, and concomitant defects of the visual field (VF) [1]. Glaucoma is the leading global cause of irreversible blindness, with an estimated 76 million patients throughout the world and a projected increase in this number to 112 million as of 2040 [2]. Glaucoma causes the blindness of 5.1–6.8 million individuals each year, often resulting in bilateral blindness that causes extensive harm to individuals, their families, and societies [3]. Glaucoma primarily causes selective RGC death within the human retina, with RGC dendrites comprising the optic nerve and providing the majority of the inputs to the primary visual cortex. As RGC viability declines, optic dendrite counts thus decrease, leading to a drop in sensory input to the primary motor cortex and a concomitant drop in functional connectivity (FC) to the secondary visual cortex. As such, the damage associated with glaucoma may extend beyond ONH or RGC degeneration, causing the deterioration of the optic nerve, visual cortex, and potentially even certain non-visual areas of the brain [4, 5]. In light of this evidence, some scholars have suggested regarding glaucoma as a form of neurodegenerative disease [6].

In most prior magnetic resonance imaging (MRI) studies, primary open-angle glaucoma (POAG) patients have been the primary focus. However, the most common glaucoma subtype in East Asia and other portions of Asia is primary angle-closure glaucoma (PACG) [7], and blindness rates in these regions are higher than those in Western nations [8]. Resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as an invaluable tool for studies of intrinsic brain activity in glaucoma patients, offering key insights into the pathological basis for different conditions. In PACG patients, recent studies have revealed abnormal regional homogeneity (ReHo) [9] and low-frequency fluctuation amplitude (ALFF) [10] in several regions of the brain. Cai et al. [11] observed compensatory increases in the degree centrality (DC) values of the bilateral visual cortex and left anterior central gyrus following surgery in patients with PACG, while Chen et al. [12]determined that short- and long-range functional connectivity density spatial distributions differed in PACG patients. Wang et al. [13] observed extensive resting-state FC (rs-FC) abnormalities between the thalamus and other brain regions in individuals with PACG. In another report, changes in information interaction and integration between cerebral hemispheres have been detected in PACG patients, suggesting that this condition may be associated with the impaired interaction and integration of visual information [14]. These reports offer a range of perspectives on PACG-associated characteristics and spontaneous activity changes.

In addition to the ophthalmic changes characteristic of glaucoma, a growing number of studies have indicated that affected patients experience higher rates of a range of other debilitating symptoms including depression and anxiety [15, 16, 17]. Indeed, studies of a large population have revealed a significant correlation between glaucoma and anxiety/depression [18, 19]. Relative to patients with POAG, PACG patients reportedly experience more serious symptoms of depression [20]. The amygdala has been found to serve as an important regulator of emotional activity [21], with MRI scanning having revealed depression-related decreases in amygdalar volume [22]. Limited studies have also explored the neuroimaging basis for psychiatric symptoms in glaucoma patients. One 3T MRI study, for example, found that reductions in left amygdalar volume in POAG patients were related to changes in mood [23]. At present, however, there remains relatively little neuroimaging research focused on psychiatric symptoms in patients with PACG. However, amygdalar abnormalities may be involved in the incidence of depression in PACG patients, highlighting a need for further research on this topic.

In light of the above research findings, the present study sought to employ rs-FC measurements as an approach to detecting abnormal amygdalar FC in patients with PACG. These studies were conducted based on the hypothesis that PACG patients exhibit changes in FC between the amygdala and other regions of the brain, and that these changes are associated with PACG-related clinical parameters.

Here, rs-fMRI approaches were used to evaluate alterations in whole brain and amygdalar FC in patients with PACG. This is the first systematic examination of such changes in the rs-FC of the amygdala in PACG patients to our knowledge. Overall, these analyses revealed extensive alterations in such amygdalar rs-FC in these individuals as compared to control subjects, consistent with the status of glaucoma as a degenerative disease that impacts higher-order cognitive brain functions rather than being restricted to those networks related to the visual field.

Relative to control subjects, patients with PACG exhibited reductions in FC between the right amygdala and bilateral PreCG, right SMA, and between the left amygdala and left PreCG. Both the PreCG and the SMA are components of the sensorimotor network (SMN). Prior reports have documented structural and functional associations between the amygdala and the PreCG [28, 29], which is a component of the amygdaloid-sensorimotor pathway that received amygdala-derived social-emotional stimulus-related inputs [30, 31]. A small number of studies have consistently found that the amygdala can facilitate and coordinate motor tasks via the SMA in the SMN of experimental animals [32, 33]. Glaucoma patients also reportedly exhibit dysregulated SMN function and structural characteristics. Huang et al. [34], for instance, determined that the ALFF area of the left precentral gyrus was reduced in PACG patients, with a corresponding increase in the PreCG ALFF area. Moreover, Dai et al. [35] determined that POAG patients exhibited reductions in FC between the primary visual cortex and the right PreCG, while Fu et al. [9] observed aberrant SMA ReHo values in individuals with PACG. The observed decrease in FC between the amygdala and these brain regions may thus be indicative of the PACG-related impairment of amygdala-sensorimotor pathways.

The left amygdala of individuals with PACG was also found to exhibit reduced FC with the left PCG and left MFG, which are both components of the default mode network (DMN) [36]. The DMN exhibits higher activity levels at rest, while it is less active when attention-demanding tasks are being performed [37]. It is also vital for emotional regulation, internal speech, the retrieval of episodic memories, planning for the future, and the contextualization of specific information [38]. Reductions in DMN activity have been linked to pain, sleep, cognitive impairment, and depression. In other studies, impaired FC between the amygdala and the DMN has been reported in hemodialysis patients with depression [39], childhood emotional abuse [40], major depressive disorder [41], and Alzheimer’s disease with comorbid depression [36, 42]. This suggests that DMN connectivity impairments are closely tied to the pathogenesis of depression. The present results align well with these past findings, suggesting that the reduced FC between the amygdala and the DMN may be reflective of the impairment of memory and emotional organization in PACG patients together with other potential self-cognitive processing defects. However, these explanations remain speculative at present, underscoring a need for future research more directly addressing the basis for these findings.

A reduction in FC was herein detected between the right amygdala and the left PCL in PACG patients. The PCL exhibits functional connections with other parietal and functional areas, and is responsible for controlling sensory and motor innervation while shaping spatial attention and motor functionality [43]. Decreased amygdalar FC with the PCL may be indicative of impaired attention and motor function in individuals diagnosed with PACG. In line with these findings, prior reports have indicated that PCL function may exhibit impairments in patients with glaucoma [44, 45, 46]. Although these data highlight the possibility that reductions in PCL FC values may be predictive of other forms of functional decline, additional research will be vital to clarify the ability of such reductions to predict PACG patient functional outcomes.

PACG patients enrolled in this study also exhibited reductions in rs-FC between the left amygdala and bilateral putamen. The putamen is a key component of the striatum, which comprises the reward network core and amplifies responses to negative emotions [47]. Much as is observed in Alzheimer’s disease and other neurodegenerative conditions [48], the putamen of patients with glaucoma exhibits altered structural and functional characteristics [49, 50]. Yang et al. [51] noted a reduction in putamen and amygdala volume in females with major depression together with a drop in amygdalar rs-FC with the putamen. Similarly, Dombrovski et al. [52] reported that major depressive disorder patients exhibiting suicidal ideation preented with a decrease in putamen bolume consistent with a potential link between depression-related loss of pleasure and reward network abnormalities. These results are consistent with the present findings, raising the possibility that the amygdala and striatal system in PACG patients present with functional and structural defects, ultimately compromising the amygdalostriatal circuits and thus potentially contributing to psychomotor dysfunction and anhedonia.

PACG patients also exhibited reductions in left amygdalar FC with the right cerebellum_8 and vermis_4_5, and in right amygdalar FC with the bilateral cerebellum_8 and vermis_4_5. Anatomical connections linking the amygdala and the cerebellar vermis have been documented previously [53]. The cerebellum is a central regulator of balance, motor control [54], and higher cognition [55]. The cerebellum is thus vital for effectively processing visual information [56, 57]. The observed PACG-related reductions in amygdalar FC with the cerebellum and vermis may thus be reflective of the impairment of cognitive function and visual attention in these patients. Chen et al. [58] previously documented a significant increase in DC values in the left cerebellum of individuals with PACG as compared to healthy subjects, while Fu et al. [9] noted significant cerebellar increases in ReHo values in patients with this form of glaucoma. Moreover, Dai et al. [35] observed a reduction in FC between the primary visual cortex and the left anterior cerebellum and verma in individuals diagnosed with POAG, while Song et al. [59] additionally detected a reduction in Right anterior cerebellar ReHo values and an increase in left posterior cerebellar ReHo values in POAG patients. The present data to not fully align with these prior results, potneitally suggesting that different subregions of the cerebellum play distinct roles in particular intrinsic connectivity networks [60].

Lastly, these results revealed the enhancement of FC between the left and right amygdala in individuals with PACG. High levels of interhemispheric amygdalar FC have previously been reported for weeks to months following pontine infarction in patients, raising the possibility that such abnormal connectivity may represent a neurological mechanism involved in cognitive compensation for motor impairment [61]. Localized neural plasticity may be similarly compensatory in the context of PACG. Such neuroplasticity refers to the selective ability of the nervous system to undergo structural and functional changes in response to injuries or experiences [62]. The decreased functionality of the amygdala and other regions of the brain in patients with PACG may thus trigger compensatory increases in bilateral amygdalar FC.

This study is subject to multiple limitations. For one, the degree of damage to retinal ganglion cells varies markedly among patients with glaucoma, and this damage can impair light perception, mood, and potentially amygdalar function in these patients. This variability may complicate efforts to clearly detect changes attributable to such retinal ganglion cell damage. In addition, light signals have been shown to impact amygdalar activity in a complex manner. In an effort to mitigate this effect, HCs and PACG patients in this study were exposed to similar lighting conditions. A mood scale was also not used to assess study participants, precluding any potential analysis of the relationship between changes in amygdalar FC and patient affective state. Lastly, this was a cross-sectional study such that the causal or temporal relationships between changes in brain activity and disease duration could not be established owing to the absence of appropriate neuroimaging follow-up data.

In conclusion, these results suggest that patients with PACG exhibit a reduction in FC between the amygdala and multiple regions of the grain including the cerebellum, SMA, putamen, MFG, PCG, anterior central gyrus, and paracentral lobule, whereas enhanced connectivity with the contralateral amygdala was detected in these same patients. As such, the pathophysiology of PACG may be associated with the disconnection and compensatory changes of higher-order regions of the amygdala. may be involved in the pathophysiological basis of PACG.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

XZ and LC guided and designed the MRI experiment, besides, they reviewed and revised the manuscript. YC and YW analyzed the resting-state fMRI data. YC unscrambled the results and wrote the manuscript. LL, FO, ZX, and MY collected resting fMRI data and applied for the ethics. JL helped with statistics and graphing. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The studies involving human participants were reviewed and approved by the Medical Research Ethics Committee of The First Affiliated Hospital of Nanchang University. The patients/participants provided their written informed consent to participate in this study (NO.2022 (3-008)).

The authors would like to thank all the patients and volunteers in the study for their helpful participation.

This study was supported by the Clinical Research Center for Medical Imaging in Jiangxi Province (No.20223BCG74001).

The authors declare no conflict of interest.