{"title":"Roles of the nonvisual opsins in the mammalian retina.","authors":"Russell N VAN Gelder","doi":"10.1016/B978-0-443-22193-4.00021-4","DOIUrl":"10.1016/B978-0-443-22193-4.00021-4","url":null,"abstract":"<p><p>In addition to the rods and cones that subserve vision, several classes of mammalian retinal ganglion cells are also directly photoreceptive. These \"intrinsically photosensitive\" retinal ganglion cells (\"ipRGCs\") utilize the nonvisual photopigments melanopsin (Opn4), neuropsin (Opn5), and encephalopsin (Opn3), which are expressed in largely nonoverlapping ganglion cell populations. Remarkably, all three nonvisual opsins appear to influence the circadian clock, but in different ways. Opn4-expressing cells project from the retina to brain regions regulating circadian rhythms, such as the suprachiasmatic nuclei, and are necessary for entrainment of the behavioral clock in mammals to external light-dark cycles. The retina itself is also a functioning circadian clock, and its local entrainment is mediated by Opn5-dependent photoreception. While evidence for Opn3 functioning as a nonvisual photoreceptor is more limited, loss of its function impairs the amplitude of the circadian clock in multiple tissues, including the retina. These opsins also have other functions within and outside the eye, with Opn4-expressing cells in particular having been shown to influence form vision. This review summarizes current understanding of the biochemistry, cell biology, and physiology of the three nonvisual opsins in the retina.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"217 ","pages":"169-177"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Retinal cell types: Rod and cone photoreceptors.","authors":"Zander Esh, Vladimir J Kefalov","doi":"10.1016/B978-0-443-22193-4.00011-1","DOIUrl":"10.1016/B978-0-443-22193-4.00011-1","url":null,"abstract":"<p><p>This chapter outlines the current understanding on several key topics in the field of rod and cone photoreceptor research. First, we discuss the research techniques that have led to the knowledge accumulated to date, as well as novel approaches to studying photoreceptors. Next, we outline photoreceptor development followed by the mature photoreceptor anatomy. The bulk of the chapter addresses the physiology of photoreceptors, first examining the unique electrophysiologic properties of rod and cone photoreceptors and then discussing their functional characteristics that enable dim- and bright-light vision. We then discuss cellular metabolism and the unique energy requirement of photoreceptors for sustaining their function. Finally, we examine diseases that affect the human photoreceptors, with an emphasis on the genetic bases and pathophysiology as it relates to the functional characteristics described earlier in the chapter. The chapter ends with a short note on the future directions of photoreceptor research and the emerging therapeutics that will be available to clinicians in the coming years.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"217 ","pages":"113-128"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Genetics of the retina.","authors":"Yasmine Zaydon, Fabiha Ahmed, Stephen Tsang","doi":"10.1016/B978-0-443-22193-4.00012-3","DOIUrl":"10.1016/B978-0-443-22193-4.00012-3","url":null,"abstract":"<p><p>The retina is a vital component of the visual system, converting light into neural signals processed by the brain. Its structure includes photoreceptors, bipolar cells, and ganglion cells, each contributing to vision. Genetics play a critical role in retinal development and health, with mutations in over 270 genes linked to inherited retinal diseases, such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Leber congenital amaurosis (LCA). These conditions range from mild visual impairment to complete blindness, reflecting the genetic diversity underlying retinal diseases. Progress in molecular biology has improved understanding of how genetic mutations disrupt retinal function. For example, RP involves mutations in RHO, USH2A, and RPGR, leading to progressive photoreceptor degeneration. AMD is associated with variations in CFH and ARMS2, driven by both genetic and environmental factors. Next-generation sequencing and gene therapy have enabled more targeted treatments. Continued research into retinal implants, pharmacologic interventions, and mitochondrial therapies is expanding therapeutic options, providing hope for improved outcomes and preservation of vision in individuals with these genetic conditions.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"217 ","pages":"21-33"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Fundus autofluorescence imaging.","authors":"Jodi Hwang, Hossein Ameri","doi":"10.1016/B978-0-443-22212-2.00023-9","DOIUrl":"10.1016/B978-0-443-22212-2.00023-9","url":null,"abstract":"<p><p>Fundus autofluorescence (FAF) is a widely utilized method of imaging the retina. It provides a quick and noninvasive method to assess the health of the photoreceptor and retinal pigment epithelium. FAF enables topographic mapping of the metabolic profile of the retina, allowing for disease detection, prognosis, and guidance for the management of a variety of retinal and choroidal diseases. Short-wavelength autofluorescence is the most widely used and studied method of FAF, though advanced techniques such as near-infrared autofluorescence may further expand the clinical utilities of FAF.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"218 ","pages":"87-108"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Human brain evolution: Role of SINE-VNTR-Alu retrotransposons and SINE-VNTR-Alu long noncoding RNA AK057321.","authors":"Matthew P Anderson, Y I Nong","doi":"10.1016/B978-0-443-19043-8.00025-6","DOIUrl":"https://doi.org/10.1016/B978-0-443-19043-8.00025-6","url":null,"abstract":"<p><p>Humans differ remarkably from great apes, with advanced cognitive abilities correlated to enlarged brains resulting from prolonged neurodevelopment. The SINE-VNTR-Alu (SVA) retrotransposons are candidate genetic drivers of these differences. Human genes with intronic SVAs are enriched for neurodevelopmental diseases; the microcephaly gene CDK5 regulatory subunit associated protein 2 (CDK5RAP2) and epilepsy/intellectual disability gene SCN8A coding for sodium channel subunit contain human-specific, intronic SVAs. Deleting gene ZNF91 coding for the SVA-binding zinc finger protein 91 or the intronic SVAs upregulate gene expression to accelerate functional and structural neuron maturation. We also discovered the function of AK057321, duplicated in ultrarare autism, founding a new gene family of long noncoding RNAs containing SVA sequences. AK057321 increases 10-fold as progenitors mature into glutamatergic neurons, and its premature increase upregulates CDK5RAP2 and SCN8A to accelerate neuron maturation. As anticipated by its sequence complementarity, AK057321 forms RNA:DNA heteroduplexes with genomic SVAs and decoy-binds the ZNF91 repressive complex. SVA-mediated block of CDK5RAP2-induced neuron maturation could prolong progenitor proliferation to increase neuron numbers and cerebral cortex size. SVA-lncRNA AK057321 also acts in adulthood to promote threefold enriched expression of Huntington (containing an SVA) in the frontal cortex relative to the brain stem. The large number of neurologic genes regulated by SVA-lncRNA AK057321 suggests the retrotransposon-based gene regulatory mechanism shaped human brain development and functions to advance cognitive abilities.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"219 ","pages":"57-74"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Epigenetic processes in neurodevelopmental disorders.","authors":"Elisa Ventura, Alessandro Sessa","doi":"10.1016/B978-0-443-19043-8.00003-7","DOIUrl":"https://doi.org/10.1016/B978-0-443-19043-8.00003-7","url":null,"abstract":"<p><p>Epigenetic factors control the pattern of gene expression during brain development, introducing epigenetic modifications that can be maintained and transmitted from one cell generation to the next one or modified in response to external stimuli. Such modifications are fundamental for the correct timing and spatial regulation of the critical processes that follow one another during brain development. Proper DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs function are required for the formation of a functional cortex. Since epigenetic factors control the expression of multiple genes, their alteration usually has pleiotropic effects and impacts on multiple biologic processes. Alterations affecting epigenetic factors that are relevant for brain development translate into defects in key processes, including neuronal stem cell proliferation, differentiation and maturation, neuron migration, and synapse formation/function. The dysregulation of all these processes leads to neurodevelopmental disorders with different etiology, age onset, and severity of the clinical manifestations. Despite the heterogeneity of these disorders, neurodevelopmental disorders of different origin can feature overlapping phenotypes and common symptoms, depending on the neurodevelopmental mechanisms that are impacted by the specific altered epigenetic factor.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"219 ","pages":"187-203"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Brainstem evoked responses.","authors":"Gabriel Byczynski, Sven Vanneste","doi":"10.1016/B978-0-443-15736-3.00007-X","DOIUrl":"10.1016/B978-0-443-15736-3.00007-X","url":null,"abstract":"<p><p>The brainstem's activity and control over both central and peripheral functioning is notably widespread, yet difficult to quantify due to its location and size. Methods have been developed to improve our understanding of the brainstem's activity, particularly through the use of proxy-measures, via physiologic imaging. Heart rate variation, pupillometry, skin conduction, P300 alterations, and salivary α-amylase are popular measures which allow for a determination of brainstem activity. This chapter discusses the use and findings of physiologic imaging for brainstem activity. It also discusses how researchers may attempt to alter brainstem activity with stimulation. Vagus nerve, occipital nerve, and auditory nerve stimulation are discussed, with their therapeutic contributions and functional effects for context. We discuss evoked brainstem responses including brainstem evoked audiometry, which additionally provide valuable information as a direct representation of brainstem activation and pathology. Lastly, we discuss the application of brainstem responses and nerve stimulation in a surgical setting via intraoperative recording. We conclude by discussing the value of these measures and methods in brainstem research.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"216 ","pages":"317-327"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147528299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Heidi I L Jacobs, Prokopis C Prokopiou, Tarun Singhal
{"title":"Functional and molecular brainstem imaging.","authors":"Heidi I L Jacobs, Prokopis C Prokopiou, Tarun Singhal","doi":"10.1016/B978-0-443-15736-3.00009-3","DOIUrl":"10.1016/B978-0-443-15736-3.00009-3","url":null,"abstract":"<p><p>The brainstem connects the cerebrum, cerebellum, and spinal cord and includes several nuclei that produce key neurotransmitters important for the modulation of behavior and cognition. Since the 16th century, humans have tried to understand the importance of the brainstem in health and disease. The development of modern neuroimaging methods, using functional magnetic resonance imaging or positron emission tomography, has ushered in an era of understanding function and molecular changes in the brainstem in many neurologic diseases. This chapter discusses the methodologic complexities of imaging the neuromodulatory subcortical nuclei in the brainstem. Furthermore, we discuss the current state-of-the-art clinical applications using these techniques for early detection, differential diagnostics, monitoring of disease and intervention, and drug development, highlighting future perspectives for the field.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"216 ","pages":"329-344"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147528340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Color vision.","authors":"Kassandra R Lee, Michael A Webster","doi":"10.1016/B978-0-443-22193-4.00017-2","DOIUrl":"10.1016/B978-0-443-22193-4.00017-2","url":null,"abstract":"<p><p>Color vision has been studied for centuries, but many fundamental questions remain about the nature of color perception and its neural underpinnings. Typical human color vision is trichromatic - based on three types of cone receptors - yet manifests in a wide variety of individual variations. Similarly, the processing of the cone signals depends on opponent mechanisms that compare the signals from different cone classes. However, the types of comparisons and how they ultimately relate to color appearance or different perceptual tasks are still shrouded in mystery. This review focuses on the processing of color in the retina within the context of the broader goals of color perception and highlights recent insights and questions.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"217 ","pages":"307-316"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Adaptive optics scanning light ophthalmoscopy.","authors":"Austin Roorda","doi":"10.1016/B978-0-443-22212-2.00008-2","DOIUrl":"10.1016/B978-0-443-22212-2.00008-2","url":null,"abstract":"<p><p>Scanning light imaging systems are broadly useful in many applications, especially when applied to ophthalmoscopy and vision science. This chapter aims to explain how and why they are useful. It starts by covering the basic principles of scanning systems and their history. Then it covers the ways in which scanning imaging systems are used in ophthalmoscopy, why they are so effective for ophthalmoscopy, and how the addition of adaptive optics has driven a paradigm shift in how scanning light ophthalmoscopes are used to study vision in health and disease. An adaptive optics scanning light ophthalmoscope is readily adaptable for many imaging modalities, including fluorescence, phase contrast, and even as a basic platform for optical coherence tomographic imaging. Applications beyond imaging include fast and accurate measurement of eye movements and the ability to administer functional tests, like acuity, sensitivity, and fixation. It is a technology that will continue to evolve and find use in ophthalmology and vision science.</p>","PeriodicalId":12907,"journal":{"name":"Handbook of clinical neurology","volume":"218 ","pages":"51-71"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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