Despite a great number of research, our knowledge of the molecular pathways of schizophrenia pathophysiology remains unclear. Nevertheless, numerous structural changes such as gray matter and total brain volume decreases, reductions in the anterior cingulate cortex, corpus callosum, thalamus, and hippocampus volumes, enlargement of the lateral ventricles that were shown by neuroimaging studies suggest that biological changes at structural levels start at the earliest stages of the disease [1,2]. These changes were correlated with deterioration in neurocognitive tests, mainly executive functions, attention, and verbal memory [3,4]. Additionally, these structural (especially gray matter loss) and cognitive alterations have been demonstrated in every phase of disease, such as both in patients with chronic schizophrenia, first episode of psychosis, prodromal stage of psychosis, and even in individuals with a high genetic risk for schizophrenia [5-7]. These findings make many researchers consider that schizophrenia is not only neurodegenerative but also a neurodevelopmental disease that begins long before the onset of clinical manifestations and that core cognitive deficits are the consequences of an abnormal development of the brain, leading to cognitive dysfunctions.

The retina, which is the only part of the central nervous system that allows examining with the naked eye, emerges from the forebrain ectodermal tissue during neurodevelopment, later becomes a part of the eye, and therefore it is referred to as “a window into the brain.” Optical coherence tomography (OCT) is a noninvasive, fast imaging technique that provides high-resolution and cross-sectional images of the retina. There are no contraindications to OCT, which measures specific retinal structures such as peripapillary retinal nerve fiber layer (RNFL, axon layer of retinal ganglion cells), peripapillary ganglion cell layer (GCL, bodies of ganglion cells), and inner plexiform layer (IPL, synaptic connections between the axons of bipolar cells and dendrites of ganglion cells). There is growing evidence suggesting that retinal abnormalities may be present in psychiatric disorders. Visual impairments including poor visual acuity, cataracts, strabismus, nystagmus, retinal venulae widening, various retinopathies and maculopathies, and dopamine and glutamate abnormalities in the retina are also important features of schizophrenia and could serve to define the disease state [8]. In recent years, several studies have assessed retinal findings of patients with schizophrenia by using OCT and showed a significant deterioration in overall and different quadrants of RNFL thickness and macular volume (MV) [9-11]. The studies also demonstrated the inverse correlation between layer thickness and disease characteristics, including disease duration, symptom severity, and the number of hospitalizations [10,12]. Additionally, negative symptom severity was found to be related to outer nuclear layer and inner segment layer thinning in multiple regions [13].

Additionally, there are studies that investigated cognitive performance in relation to retinal thickness. Recently, a prospective analysis of participants from the UK aged 40-69 years without neurodegenerative disease, determined that thinning of specific retinal segments was related to worse cognitive functioning, and greater likelihood of future cognitive decline. Since cognitive dysfunction is a core feature of schizophrenia, the correlation with retinal findings and cognitive functions may contribute to a better understanding of some neurodevelopmental aberrations in the disorder [14]. Liu et al. [15] found the reduction of the RNFL was significantly correlated with the impairments of immediate memory and visuospatial function in schizophrenia patients.

There are limited number of studies that assessed retinal layer changes in unaffected siblings of schizophrenia patients and no previous study examined the correlation of cognitive functions of the healthy siblings with retinal findings. Here, we present the first study to our knowledge, comparing the patients with schizophrenia and their unaffected siblings in terms of the relationship between retinal layer thicknesses and cognitive decline. We hypothesized that the relationship between retinal changes and cognitive parameters would be stronger in both patients and their healthy siblings, decisively.

In our study, we hypothesized that retinal layer thickness would be decreased more in patients with schizophrenia than healthy siblings and this reduction would be related to the severity of cognitive dysfunctions. According to results, the groups were similar in terms of mean RNFL. However, all GCL-IPL thicknesses were lower in the patient group, and a mild-to-moderate correlation between phonemic verbal fluency from cognitive functions and GCL-IPL’s mean values of total and all subregion thicknesses for both eyes in patient group was demonstrated.

There are a few studies comparing patients with schizophrenia and their first-degree relatives in terms of OCT findings [28]. Kurtulmus et al. [28] found that there was no difference between mean RNFL, GCL and macular thicknesses between groups but only IPL was significantly lower in both patients and first degree relatives than healthy controls. Similar to this study, we found all GCL-IPL thicknesses to be lower in the patient group. GCL-IPL consists of the ganglion cell bodies, dendrites, and synaptic connections. Thinning of GCL-IPL could reflect neuronal atrophy and synaptic losses of schizophrenia [11]. Differently to several recent studies comparing retinal layers via only RNFL structures, in our study spectral-OCT, which has a higher spatial resolution than time domain OCT to investigate GCL-IPL segments and MV in addition to RNFL has been used. González-López et al. [29] demonstrated that the sensitivity of the GCL-IPL in detecting retinal impairment in relapsing-remitting multiple sclerosis (MS) was higher than that of the RNFL measurements. Also, measurements of GCL and IPL in patients with neurodegenerative diseases such as Parkinson’s disease, MS, and optic neuritis have showed correlation with disease severity rather than RNFL thickness [30,31]. Celik et al. [12] found not only decreased GCL and IPL volumes in patients with schizophrenia compared with controls but also stronger correlations between GCL and IPL volumes and disease severity and duration, than RNFL thicknesses. The significant GCL-IPL thinning in the patient group indicates the presence of abnormal synaptic organization during the course of disease, thus GCL-IPL may be more important region than RNFL reflecting retinal changes during the course of psychosis.

In addition to GCL-IPL changes, MVs were significantly lower in patients in our study. A study conducted with MS patients reported that MV reduction is a parameter that demostrates neuronal loss [32]. Two studies [9,32] conducted with schizophrenia patients found no difference between MVs, whereas in one study [33], MVs were lower in the patient group than in controls. Despite few and conflicting results in the literature, our findings support the notion that MV may indicate neuronal loss in patients with schizophrenia, but further studies are needed for better understanding on this topic.

Deficits in neurocognitive functions are considered to be a primary symptom cluster in patients with schizophrenia [34]. Neurocognitive deficits are observed not only in the patients but also in their first-degree relatives and individuals at risk states [35]. In schizophrenia, significant deficits in attention, memory, and executive functions have been found prior to the occurrence of manifest symptoms [36]. It is established that cognitive symptoms worsen with the onset of the disease, and cognitive deficits deteriorate with the duration of the disease. In our study, Trail Making Test- A and B, verbal fluency test, and Digit Span Test-backward performances were significantly worse in the patient group than in siblings. These results are consistent with the previous studies [34,37].

In recent years, studies examining the relationship between retinal structures and cognitive functions have been increasing. A population-based study investigating 11,124 eyes of 6,471 subjects found that low cognitive performance was mainly associated with thinner RNFL thickness and suggested that RNFL thickness would be an indicator for cognitive performance and present the potential for prediction of future cognitive decline [38]. We found that both the right and left eye RNFL thickness and the Digit Span Test performances were moderately correlated in patients. The Digit Span Test evaluates working memory, attention, and short-term auditory recall functions [39]. Similarly, in a follow-up study conducted in 2017, the thickness of the RNFL was associated with the test scores that evaluated episodic memory, and it was emphasized that the RNLF thickness could be a marker reflecting the cognitive deficits in geriatric population [40]. Another large scale population study (n=2,483) reduction of GCL volume is more strongly related to adult cognitive functioning especially in processing speed and verbal episodic memory than RNFL thickness [41]. The studies investigating this relationship in neurological diseases showed different results. A longitudinal population study demonstrated that thinner RNFL and GCL-IPL were associated with different cognitive tests similar to our results and found the association of GCL-IPL with prevalent dementia [42]. The studies exploring the relationship of retinal structures with cognitive functions in schizophrenia patients are limited. In two recent studies, Liu et al. [15] compared thickness of RNFL and neurocognitive tests via the Stroop Color Word Test and Repeatable Battery for the Assessment of Neuropsychology Status in schizophrenia patients and healthy controls and found that in schizophrenia patients there was a significant relationship with impairments of immediate memory, visuospatial functions, and reduction of RNFL thickness. However, differently to these studies, in our study, not only RNFL but also GCL-IPL thickness of the retina was investigated and found correlations with cognitive impairment.

In our study, there was a strong relationship between verbal fluency performances and thickness of GCL-IPL in patient group. The verbal fluency test is used to evaluate language skills, especially speed of processing and sustained attention [43]. In recent studies, verbal fluency performance in schizophrenia patients presented one of the largest mean effect sizes among other neurocognitive test variables [44]. It has consistently found to be affected in both patients and healthy first-degree relatives, supporting its value as a vulnerability marker [45]. The studies investigating verbal fluency as a possible predictor for transition to schizophrenia in first episode psychosis and in ultrahigh risk (UHR) patients concluded that verbal fluency was disrupted prior to the outbreak of psychosis and could contribute to an improved prediction of transition to psychosis in patients with UHR symptoms within two years [46]. We created a model to determine the variables (such as BMI, age, gender, and being sick) affecting retinal measurement and verbal fluency results and found that only being sick and GCL-IPL thicknesses significantly predicted test performance. These results are compatible with studies emphasizing that verbal fluency can be an important predictor in determining the cognitive symptoms of psychosis patients. Several studies in recent years have reported IPL thinning independently of confounders in patients with schizophrenia and suggested that it may be a potential endophenotype candidate. Our results have shown that GCL-IPL thinning is related to some cognitive domains, especially to processing speed. From this point of view, GCL-IPL could be an important layer in terms of evaluating cognitive functions in patients. Additionally, the detection of cognitive impairments and retinal findings in healthy siblings of patients who have a similar genetic predisposition with patients but are not affected by disease-related confounders such as sympthoms of the disease or medication, and the fact that the impairment of patients cannot be found to be associated with disease severity, duration or treatment response, contribute to the neurodevelopmental hypothesis of schizophrenia rather than neurodegenerative processes. Further larger sample studies including healthy control groups with healthy siblings and patients may illuminate these issues.

Our study has some limitations. First of all, our results may not be representative of the general population due to the relatively small size of our sample, besides; as this is a cross-sectional study, the causality is not clear. Second, we examined the relatively limited number of retinal layers in our study, so examining deeper retinal layers may help developing different perspectives on this issue. Additionally, since there was no healthy control group in the study, OCT and neurocognitive parameters could not be compared with those who were not affected by the disease or genetic vulnerability, further studies including the participants from different phases of the disorder for example patients at first psychotic episode may provide better understanding about these connections. Finally, there may be the possible effects of psychotropics used by patients and differences in BMI between groups on retinal structures. Despite these limitations, our study is the first study that evaluates OCT parameters and neurocognitive impairment in the healthy siblings of schizophrenia patients and investigates the correlation of retinal findings in both patients with schizophrenia and their healthy siblings to cognitive functions.

In conclusion, these results indicate that different structural changes in the retinal nerve are associated with some specific cognitive domains in schizophrenia patients. OCT measurements may play an essential role in tracking neurocognitive symptoms which are the important causes of disability in patients. Our findings imply that these structural changes in the retinal nerve are related to possible structural changes in the brain that cause cognitive symptoms.