Oculomics in Schizophrenia Research

Over the past 15 years, there has been an exponential increase in the number of publications focusing on altered retinal structure, function, and vasculature, in addition to other eye problems, in people with schizophrenia and those at high-risk for psychosis. In this editorial, we highlight some reasons for this increase and emphasize the contributions that studies of these issues might make to understanding the development and prevention of schizophrenia.

The retina is a part of the central nervous system (CNS) that is an outgrowth of the brain and shares many features with the brain (eg, neurons, layered architecture, neurotransmitters). It both provides input to and receives input from the brain. Studies of neurological disorders (eg, multiple sclerosis, Parkinson’s disease) and normal aging have revealed similarities between changes in retinal structure and function and changes in brain structure and function (eg, reduced activity, volume loss, alterations in blood vessels), along with correlations between retinal impairments and indicators of illness progression. It is now common to see papers in which the retina is referred to as a “window into the brain” (reviewed in ref. ¹). Changes to the retina predict both cardiovascular disease and cognitive decline in the general population, increasing the focus on oculomics² in medicine and neurology. One potentially important development suggests that glaucoma is a neurodegenerative disease and that it increases the risk for a later diagnosis of schizophrenia,³ perhaps via excessive activation of microglia and the subsequent onset of a neurodegenerative process.⁴ More fundamentally, the retina is the most accessible aspect of the CNS. It can be imaged directly, and electrophysiological studies can identify activity in specific neural cell types (eg, photoreceptors, ganglion cells). Retinal imaging and electrophysiology can also be accomplished more rapidly and less expensively than brain imaging or EEG, and with fewer exclusionary criteria than these techniques. Finally, the increase in studies of the retina in schizophrenia may be driven by the consistently observed abnormalities across a range of measures (reviewed in ref.⁵) in patients and familial high-risk samples (where impaired retinal function predicts impaired cognition). Retinal markers indicate genetic vulnerability, illness state, progression, and dopamine activity,⁵ with relevance to a range of questions salient to those who research schizophrenia spectrum conditions.

A second reason for studying the eye is that there is an increased rate of eye abnormalities in children who later develop schizophrenia, including poor visual acuity, and conditions that cause abnormal visual input (eg, strabismus), and these relationships are stronger than for other sensory anomalies, motor or language disturbances.⁶ A large study (N = 1 140 710) of 18- to 19-year-old military conscripts replicated the link between poor visual acuity and later onset of schizophrenia, and found the link strongest for those whose vision could not be normalized by lenses.⁷ Thus, abnormal visual input may contribute to schizophrenia, and/or the altered neurodevelopment that characterizes schizophrenia may be expressed especially strongly in the eye.

Third, there is a high rate (approximately two-thirds) of visual anomalies (eg, distortion of form, brightness, color, motion) in people with schizophrenia,⁸ and many of these resemble what is found in retinal disease. Moreover, the rate of visual distortions is positively correlated with the rate of visual hallucinations (VH) in schizophrenia patients,⁸ which may suggest that VH involve cortical compensatory responses to altered retinal input. Consistent with this, impaired retinal function is related to an increased rate of VH.⁹

Fourth, there are hypothesized protective effects of congenital blindness against schizophrenia but not other psychiatric disorders.¹⁰ From the 1950s to the present, papers report that in samples of people born blind, or who became blind very early in life, there are extremely few cases of peripheral blindness and no cases of cortical blindness in people who later developed schizophrenia. Notably, this is within the context of many reports of rare cases of schizophrenia with a comorbid condition involving later blindness (eg, retinitis pigmentosa, Usher syndrome), combinations which, incidentally, suggest a genetic relationship between schizophrenia and these degenerative eye conditions. A recent study (N = 467 945),¹¹ found that 0% of the children diagnosed with cortical blindness prior to age 6 had developed schizophrenia or another psychotic disorder, whereas less than 0.66% of the children with peripheral blindness had developed schizophrenia. It must be noted that the strongest test of the congenital blindness and schizophrenia hypothesis is achieved by studying people with blindness onset closer to birth, and many studies showing strong compensatory effects in other sensory domains do not include people with onset after ages 5, 3, or 1. Importantly, after 3 years of age, higher level language functions and retention of vivid visual memories emerge, functions which can be confounded when grouping together subjects with a blindness onset before and after age 3. Thus, the rate of schizophrenia in cases of peripheral blindness in ref.¹¹ might have been lower if the inclusion age for blindness onset was reduced to a lower age. A similar issue applies to the recently published analysis of a larger dataset (~2.5 million),¹² that could neither confirm nor disconfirm a reduced rate of schizophrenia in people who were blind before age 6. That paper rightly argued that due to the relative rarity of schizophrenia and congenital blindness, an even larger study than they performed would be needed for enough power to confirm the protective hypothesis. On the other hand, the hypothesis can be readily tested by combining cohort studies, by more targeted recruitment (eg, at blindness or behavioral health agencies in large metropolitan areas), or by examining more common but related disorders, such as schizotypal personality disorder. The “black swan”—a case of schizophrenia in a congenitally blind person - remains elusive.

Prevalence rates are not the only evidence relevant to the blindness-schizophrenia hypothesis, however. Early total non-visual sensory impairments are not associated with decreased risk for schizophrenia (eg, both congenital and later deafness increase risk), and this discrepancy is worth exploring. Brain development in response to congenital blindness is, in many ways, the opposite of what occurs in schizophrenia (eg, enhancements in auditory spatial localization and temporal resolution, pitch discrimination, selective and divided attention, and working memory, more stable body image, increased neural connectivity, etc.),¹³ which suggests protective mechanisms—involving expansion of cortical maps and unmasking of normally unused connections—that may be harnessed therapeutically. Intriguingly, moderate (but not absent, mild, or severe) visual impairment is associated with psychosis, consistent with the hypothesis that consistently abnormal visual input exacerbates risk, whereas congenital blindness and exceptional acuity are protective.^14,15

Finally, VH in cases of severe vision loss appear to arise due to spontaneous activity in visual cortex subsequent to deprivation of external input¹⁶ (presumably via predictive matching of existing visual representations onto spontanenous activity). Such experiences have not been reported in people who are congenitally blind, even when taking hallucinogenic drugs,¹⁰ perhaps due to a lack of stored visual representations, and/or because the recruitment of visual cortex by other senses reduces the likelihood of predictive visual activity.

In sum, much evidence suggests that schizophrenia is a neural (but not only a brain) systems disorder, and that retinal and other eye markers may have utility for a range of clinical and research applications. Increased incorporation of retinal markers into high risk and longitudinal studies is likely to accelerate the discovery process, and an eye test for psychosis risk remains a tantalizing but real possibility.