Retinal-brain structural associations: inner macular GCIPL thickness relates to frontal gray matter volume

Background: The retina has been proposed as a promising biomarker of brain structure due to its embryological origin and close anatomical relationship with the central nervous system. As an accessible extension of the brain, retinal layers, particularly the ganglion cell layer and inner plexiform layer (GCIPL), have been increasingly studied in neuropsychiatric disorders. However, it remains unclear to what extent retinal measures are associated with structural brain alterations, and whether these associations differ depending on the neuroanatomical metric considered. In particular, it is unknown whether retinal thickness is more closely related to volumetric measures, such as gray matter volume, or to cortical thickness, which may reflect distinct biological processes. Clarifying these relationships is crucial to determine the potential utility of retinal imaging as a non-invasive proxy for brain structural integrity and its potential application in clinical and research settings.

Methods: A total of 80 participants (31 patients and 49 healthy controls; 48.8% female; mean age = 30.64 ± 6.39 years) underwent optical coherence tomography (OCT) and structural magnetic resonance imaging (MRI). Retinal measures included macular GCIPL thickness extracted from four inner macular sectors (nasal, temporal, superior, and inferior). Neuroimaging data were processed to obtain frontal gray matter volume and cortical thickness measures. Pearson correlation analyses were conducted to examine bivariate associations between retinal and brain metrics. Additionally, linear regression models adjusted for age and sex were performed to assess whether retinal measures predicted brain structure independently of these covariates. Analyses were conducted separately for each retinal sector, hemisphere, and eye to ensure robustness of findings.

Results: Significant positive associations were observed between GCIPL thickness in the nasal and temporal sectors and frontal gray matter volume. These associations were consistent across both hemispheres and both eyes, with correlation coefficients ranging from r = 0.33 to r = 0.37 (p < 0.05). Regression analyses confirmed that GCIPL thickness in the nasal and temporal sectors significantly predicted frontal gray matter volume after controlling for age and sex (p < 0.05). In contrast, no significant associations were found between GCIPL thickness in any sector and cortical thickness measures. This pattern of results suggests a selective relationship between retinal structure and volumetric, but not cortical thickness, brain metrics.

Conclusions: The present findings support a specific association between retinal GCIPL thickness and frontal gray matter volume, particularly in the nasal and temporal macular sectors. This pattern of results suggests a selective relationship between retinal structure and volumetric, but not cortical thickness, brain metrics. The absence of associations with cortical thickness suggests that retinal measures may preferentially reflect volumetric aspects of brain structure rather than cortical microstructural properties. These results reinforce the potential of retinal imaging as a non-invasive and accessible proxy for brain structural integrity. Further research is needed to determine the longitudinal and clinical relevance of these associations in neuropsychiatric populations.

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