The Cognitive-Emotional Design and Study of Architectural Space: A Scoping Review of Neuroarchitecture and Its Precursor Approaches.

Humans respond cognitively and emotionally to the built environment. The modern possibility of recording the neural activity of subjects during exposure to environmental situations, using neuroscientific techniques and virtual reality, provides a promising framework for future design and studies of the built environment. The discipline derived is termed "neuroarchitecture". Given neuroarchitecture's transdisciplinary nature, it progresses needs to be reviewed in a contextualised way, together with its precursor approaches. The present article presents a scoping review, which maps out the broad areas on which the new discipline is based. The limitations, controversies, benefits, impact on the professional sectors involved, and potential of neuroarchitecture and its precursors' approaches are critically addressed.

Purinergic modulation of neuronal gap junction circuits in the CNS of the leech.

Gap junctions (GJs) are widely distributed in brains across the animal kingdom. To visualize the GJ- coupled networks of two major mechanosensory neurons in the ganglia of medicinal leeches, we injected these cells with the GJ-permeable tracer Neurobiotin. When diffusion time was limited to only 30 min, tracer coupling was highly variable for both cells, suggesting a possible modulation of GJ permeability. In invertebrates the innexins (homologs of vertebrate pannexins) form the GJs. Because extracellular adenosine triphosphate (ATP) modulates pannexin and leech innexin hemichannel permeability and is released by leech glial cells following injury, we tested the effects of bath application of ATP after the injection of Neurobiotin and observed a significant increase in the number of neurons tracer coupled to the sensory neurons. This effect required the elevation of intracellular Ca2+ and could be produced by bath application of caffeine. Conversely, scavenging endogenous extracellular ATP with the ATPase apyrase decreased the number of coupled cells. ATP also increased electrical conductance and tracer permeability between the bilateral Retzius neurons. This modulatory effect of ATP on GJ coupling was blocked by siRNA knockdown of a P1-like adenosine receptor. Finally, exposure of leech ganglia to extracellular ATP induced a characteristic low frequency (<0.3 Hz) rhythmic bursting activity that was roughly synchronous among multiple neurons, a behavior that was significantly attenuated by the GJ blocker octanol. These findings highlight the mediation by ATP of a robust physiological mechanism for modifying neuronal circuits by rapidly recruiting neurons into active networks and entraining synchronized bursting activity.

Individual differences in level of wisdom are associated with brain activation during a moral decision-making task.

INTRODUCTION: Wisdom is reportedly associated with better health and quality of life. However, our knowledge of the neurobiology of wisdom is still in the early stages of development. We aimed to improve our understanding by correlating a psychometric measure of the trait with patterns of brain activation produced by a cognitive task theorized to be relevant to wisdom: moral decision-making. In particular, we aimed to determine whether individual differences in wisdom interact with moral task complexity in relation to brain activation. METHODS: Participants were 39 community-dwelling men and women aged 27-76 years, who completed moral and nonmoral decision-making tasks while undergoing functional magnetic resonance imaging. Brain activation in select regions of interest was correlated with participants' scores on the San Diego Wisdom Scale (SD-WISE). RESULTS: Individual differences in wisdom were found to interact with brain response to moral versus nonmoral and moral personal versus impersonal dilemmas, particularly in regions in or near the default mode network. Persons with higher scores on the SD-WISE had less contrast between moral and nonmoral dilemmas and greater contrast between moral-personal and moral-impersonal dilemmas than individuals with lower SD-WISE scores. CONCLUSIONS: Results confirmed our hypothesis that individual differences in level of wisdom would interact with moral condition in relation to brain activation, and may underscore the relevance of considering one's own and others' actions and experiences in the context of wise thinking. Future studies are needed to replicate these findings and to examine specific neurocircuits.

Top-Down Atmospheric Ionization Mass Spectrometry Microscopy Combined With Proteogenomics.

Mass spectrometry-based protein analysis has become an important methodology for proteogenomic mapping by providing evidence for the existence of proteins predicted at the genomic level. However, screening and identification of proteins directly on tissue samples, where histological information is preserved, remain challenging. Here we demonstrate that the ambient ionization source, nanospray desorption electrospray ionization (nanoDESI), interfaced with light microscopy allows for protein profiling directly on animal tissues at the microscopic scale. Peptide fragments for mass spectrometry analysis were obtained directly on ganglia of the medicinal leech (Hirudo medicinalis) without in-gel digestion. We found that a hypothetical protein, which is predicted by the leech genome, is highly expressed on the specialized neural cells that are uniquely found in adult sex segmental ganglia. Via this top-down analysis, a post-translational modification (PTM) of tyrosine sulfation to this neuropeptide was resolved. This three-in-one platform, including mass spectrometry, microscopy, and genome mining, provides an effective way for mappings of proteomes under the lens of a light microscope.

Wayfinding and Glaucoma: A Virtual Reality Experiment.

Purpose: Wayfinding, the process of determining and following a route between an origin and a destination, is an integral part of everyday tasks. The purpose of this study was to investigate the impact of glaucomatous visual field loss on wayfinding behavior using an immersive virtual reality (VR) environment. Methods: This cross-sectional study included 31 glaucomatous patients and 20 healthy subjects without evidence of overall cognitive impairment. Wayfinding experiments were modeled after the Morris water maze navigation task and conducted in an immersive VR environment. Two rooms were built varying only in the complexity of the visual scene in order to promote allocentric-based (room A, with multiple visual cues) versus egocentric-based (room B, with single visual cue) spatial representations of the environment. Wayfinding tasks in each room consisted of revisiting previously visible targets that subsequently became invisible. Results: For room A, glaucoma patients spent on average 35.0 seconds to perform the wayfinding task, whereas healthy subjects spent an average of 24.4 seconds (P = 0.001). For room B, no statistically significant difference was seen on average time to complete the task (26.2 seconds versus 23.4 seconds, respectively; P = 0.514). For room A, each 1-dB worse binocular mean sensitivity was associated with 3.4% (P = 0.001) increase in time to complete the task. Conclusions: Glaucoma patients performed significantly worse on allocentric-based wayfinding tasks conducted in a VR environment, suggesting visual field loss may affect the construction of spatial cognitive maps relevant to successful wayfinding. VR environments may represent a useful approach for assessing functional vision endpoints for clinical trials of emerging therapies in ophthalmology.

Electrical transmission: Two structures, same functions?

Electrical synapses are finding increasing representation and importance in our understanding of signaling in the nervous system. In contrast to chemical synapses, at which molecules are evolutionary conserved, vertebrate and invertebrate electrical synapses represent molecularly different structures that share a common communicating strategy that allows them to serve very similar functions. A better understanding of differences and commonalities regarding the structure, function and regulation of vertebrate and invertebrate electrical synapses will lead to a better understanding of the properties and functional diversity of this modality of synaptic communication. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 517-521, 2017.

Gap junction proteins and the wiring (Rewiring) of neuronal circuits.

The unique morphology and pattern of synaptic connections made by a neuron during development arise in part by an extended period of growth in which cell-cell interactions help to sculpt the arbor into its final shape, size, and participation in different synaptic networks. Recent experiments highlight a guiding role played by gap junction proteins in controlling this process. Ectopic and overexpression studies in invertebrates have revealed that the selective expression of distinct gap junction genes in neurons and glial cells is sufficient to establish selective new connections in the central nervous systems of the leech (Firme et al. [2012]: J Neurosci 32:14265-14270), the nematode (Rabinowitch et al. [2014]: Nat Commun 5:4442), and the fruit fly (Pézier et al., 2016: PLoS One 11:e0152211). We present here an overview of this work and suggest that gap junction proteins, in addition to their synaptic/communicative functions, have an instructive role as recognition and adhesion factors. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 575-586, 2017.

NSF workshop report: discovering general principles of nervous system organization by comparing brain maps across species.

Efforts to understand nervous system structure and function have received new impetus from the federal Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Comparative analyses can contribute to this effort by leading to the discovery of general principles of neural circuit design, information processing, and gene-structure-function relationships that are not apparent from studies on single species. We here propose to extend the comparative approach to nervous system 'maps' comprising molecular, anatomical, and physiological data. This research will identify which neural features are likely to generalize across species, and which are unlikely to be broadly conserved. It will also suggest causal relationships between genes, development, adult anatomy, physiology, and, ultimately, behavior. These causal hypotheses can then be tested experimentally. Finally, insights from comparative research can inspire and guide technological development. To promote this research agenda, we recommend that teams of investigators coalesce around specific research questions and select a set of 'reference species' to anchor their comparative analyses. These reference species should be chosen not just for practical advantages, but also with regard for their phylogenetic position, behavioral repertoire, well-annotated genome, or other strategic reasons. We envision that the nervous systems of these reference species will be mapped in more detail than those of other species. The collected data may range from the molecular to the behavioral, depending on the research question. To integrate across levels of analysis and across species, standards for data collection, annotation, archiving, and distribution must be developed and respected. To that end, it will help to form networks or consortia of researchers and centers for science, technology, and education that focus on organized data collection, distribution, and training. These activities could be supported, at least in part, through existing mechanisms at NSF, NIH, and other agencies. It will also be important to develop new integrated software and database systems for cross-species data analyses. Multidisciplinary efforts to develop such analytical tools should be supported financially. Finally, training opportunities should be created to stimulate multidisciplinary, integrative research into brain structure, function, and evolution.

NSF workshop report: discovering general principles of nervous system organization by comparing brain maps across species.

Efforts to understand nervous system structure and function have received new impetus from the federal Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Comparative analyses can contribute to this effort by leading to the discovery of general principles of neural circuit design, information processing, and gene-structure-function relationships that are not apparent from studies on single species. We here propose to extend the comparative approach to nervous system 'maps' comprising molecular, anatomical, and physiological data. This research will identify which neural features are likely to generalize across species, and which are unlikely to be broadly conserved. It will also suggest causal relationships between genes, development, adult anatomy, physiology, and, ultimately, behavior. These causal hypotheses can then be tested experimentally. Finally, insights from comparative research can inspire and guide technological development. To promote this research agenda, we recommend that teams of investigators coalesce around specific research questions and select a set of 'reference species' to anchor their comparative analyses. These reference species should be chosen not just for practical advantages, but also with regard for their phylogenetic position, behavioral repertoire, well-annotated genome, or other strategic reasons. We envision that the nervous systems of these reference species will be mapped in more detail than those of other species. The collected data may range from the molecular to the behavioral, depending on the research question. To integrate across levels of analysis and across species, standards for data collection, annotation, archiving, and distribution must be developed and respected. To that end, it will help to form networks or consortia of researchers and centers for science, technology, and education that focus on organized data collection, distribution, and training. These activities could be supported, at least in part, through existing mechanisms at NSF, NIH, and other agencies. It will also be important to develop new integrated software and database systems for cross-species data analyses. Multidisciplinary efforts to develop such analytical tools should be supported financially. Finally, training opportunities should be created to stimulate multidisciplinary, integrative research into brain structure, function, and evolution.

Control of neuronal morphology and connectivity: emerging developmental roles for gap junctional proteins.

Recent evidence indicates that gap junction (GJ) proteins can play a critical role in controlling neuronal connectivity as well as cell morphology in the developing nervous system. GJ proteins may function analogously to cell adhesion molecules, mediating cellular recognition and selective neurite adhesion. Moreover, during synaptogenesis electrical synapses often herald the later establishment of chemical synapses, and thus may help facilitate activity-dependent sculpting of synaptic terminals. Recent findings suggest that the morphology and connectivity of embryonic leech neurons are fundamentally organized by the type and perhaps location of the GJ proteins they express. For example, ectopic expression in embryonic leech neurons of certain innexins that define small GJ-linked networks of cells leads to the novel coupling of the expressing cell into that network. Moreover, gap junctions appear to mediate interactions among homologous neurons that modulate process outgrowth and stability. We propose that the selective formation of GJs between developing neurons and perhaps glial cells in the CNS helps orchestrate not only cellular synaptic connectivity but also can have a pronounced effect on the arborization and morphology of those cells involved.

Gap junction-dependent homolog avoidance in the developing CNS.

Oppositely directed projections of some homologous neurons in the developing CNS of the medicinal leech (Hirudo verbana), such as the AP cells, undergo a form of contact-dependent homolog avoidance. Embryonic APs extend axons within the connective nerve toward adjacent ganglia, in which they meet and form gap junctions (GJs) with the oppositely directed axons of their segmental homologs, stop growing, and are later permanently retracted (Wolszon et al., 1994a,b). However, early deletion of an AP neuron leads to resumed growth and permanent maintenance of the projections of neighboring APs. Here we test the hypothesis that a GJ-based signaling mechanism is responsible for this instance of homolog avoidance. We demonstrate that selective knockdown of GJ gene Hve-inx1 expression in single embryonic APs, by expressing a short-hairpin interfering RNA, leads to continued growth of the projections of the cell toward, into, and beyond adjacent ganglia. Moreover, the projections of the APs in adjacent ganglia also resume growth, mimicking their responses to cell deletion. Continued growth was also observed when two different INX1 mutant transgenes that abolish dye coupling between APs were expressed. These include a mutant transgene that effectively downregulates all GJ plaques that include the INX1 protein and a closed channel INX1 mutant that retains the adhesive cellular binding characteristic of INX1 GJs but not the open channel pore function. Our results add GJ intercellular communication to the list of molecular signaling mechanisms that can act as mediators of growth-inhibiting cell-cell interactions that define the topography of neuronal arbors.

Microscopy ambient ionization top-down mass spectrometry reveals developmental patterning.

There is immense cellular and molecular heterogeneity in biological systems. Here, we demonstrate the utility of integrating an inverted light microscope with an ambient ionization source, nanospray electrospray desorption ionization, attached to a high-resolution mass spectrometer to characterize the molecular composition of mouse spinal cords. We detected a broad range of molecules, including peptides and proteins, as well as metabolites such as lipids, sugars, and other small molecules, including S-adenosyl methionine and glutathione, through top-down MS. Top-down analysis revealed variation in the expression of Hb, including the transition from fetal to adult Hb and heterogeneity in Hb subunits consistent with the genetic diversity of the mouse models. Similarly, temporal changes to actin-sequestering proteins ß-thymosins during development were observed. These results demonstrate that interfacing microscopy with ambient ionization provides the means to perform targeted in situ ambient top-down mass spectral analysis to study the pattern of proteins, lipids, and sugars in biologically heterogeneous samples.

Expression of a dominant negative mutant innexin in identified neurons and glial cells reveals selective interactions among gap junctional proteins.

Neurons and glia of the medicinal leech CNS express different subsets of the 21 innexin genes encoded in its genome. We report here that the punctal distributions of fluorescently tagged innexin transgenes varies in a stereotypical pattern depending on the innexin expressed. Furthermore, whereas certain innexins colocalize extensively (INX1 and INX14), others do not (e.g., INX1 and INX2 or INX6). We then demonstrate that the mutation of a highly conserved proline residue in the second transmembrane domain of innexins creates a gap junction protein with dominant negative properties. Coexpressing the mutated INX1 gene with its wild type blocks the formation of fluorescent puncta and decouples the expressing neuron from its normal gap junction-coupled network of cells. Similarly, expression of an INX2 mutant transgene (a glial cell innexin), blocks endogenous INX2 puncta and wild-type transgene puncta, and decouples the glial cell from the other glial cells in the ganglion. We show in cell culture with dye-uptake and plasma membrane labeling experiments that the mutant innexin transgene is not expressed on the cell membrane but instead appears to accumulate in the cell's perinuclear region. Lastly, we use these mutant innexin transgenes to show that the INX1 mutant transgene blocks not only INX1 puncta formation, but also puncta of INX14, with which INX1 usually colocalizes. By contrast, the formation of INX6 puncta was unaffected by the INX1 mutant. Together, these experiments suggest that leech innexins can selectively interact with one another to form gap junction plaques, which are heterogeneously located in cellular arbors. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 571-586, 2013.

Ectopic expression of select innexins in individual central neurons couples them to pre-existing neuronal or glial networks that express the same innexin.

Fifteen of the 21 innexin (Inx) genes (Hve-inx) found in the genome of the medicinal leech, Hirudo verbana, are expressed in the CNS (Kandarian et al., 2012). Two are expressed pan-neuronally, while the others are restricted in their expression to small numbers of cells, in some cases reflecting the membership of known networks of electrically coupled and dye-coupled neurons or glial cells. We report here that when Hve-inx genes characteristic of discrete coupled networks were expressed ectopically in neurons known not to express them, the experimental cells were found to become dye coupled with the other cells in that network. Hve-inx6 is normally expressed by only three neurons in each ganglion, which form strongly dye-coupled electrical connections with each other [Shortening-Coupling interneuron (S-CI) network] (Muller and Scott, 1981; Dykes and Macagno, 2006). But when Hve-inx6 was ectopically expressed in a variety of central embryonic neurons, those cells became dye coupled with the S-CI network. Similarly, Hve-inx2 is normally uniquely expressed by the ganglion's large glial cells, but when it was ectopically expressed in different central neurons, they became dye coupled to the glial cells. In contrast, overexpression of the pan-neuronal Inx genes Hve-inx1 and Hve-inx14 did not yield any novel instances of dye coupling to pre-existent neuronal networks. These results reveal that expression of certain innexins is sufficient to couple individual neurons to pre-existing networks in the CNS. We propose that a primary determinant of selective neuronal connectivity and circuit formation in the leech is the surface expression of unique subsets of gap junctional proteins.

The medicinal leech genome encodes 21 innexin genes: different combinations are expressed by identified central neurons.

Gap junctional proteins are important components of signaling pathways required for the development and ongoing functions of all animal tissues, particularly the nervous system, where they function in the intracellular and extracellular exchange of small signaling factors and ions. In animals whose genomes have been sufficiently sequenced, large families of these proteins, connexins, pannexins, and innexins, have been found, with 25 innexins in the nematode Caenorhabditis elegans Starich et al. (Cell Commun Adhes 8: 311-314, 2001) and at least 37 connexins in the zebrafish Danio rerio Cruciani and Mikalsen (Biol Chem 388:253-264, 2009). Having recently sequenced the medicinal leech Hirudo verbana genome, we now report the presence of 21 innexin genes in this species, nine more than we had previously reported from the analysis of an EST-derived transcriptomic database Dykes and Macagno (Dev Genes Evol 216: 185-97, 2006); Macagno et al. (BMC Genomics 25:407, 2010). Gene structure analyses show that, depending on the leech innexin gene, they can contain from 0 to 6 introns, with closely related paralogs showing the same number of introns. Phylogenetic trees comparing Hirudo to another distantly related leech species, Helobdella robusta, shows a high degree of orthology, whereas comparison to other annelids shows a relatively low level. Comparisons with other Lophotrochozoans, Ecdyzozoans and with vertebrate pannexins suggest a low number (one to two) of ancestral innexin/pannexins at the protostome/deuterostome split. Whole-mount in situ hybridization for individual genes in early embryos shows that ∼50% of the expressed innexins are detectable in multiple tissues. Expression analyses using quantitative PCR show that ∼70% of the Hirudo innexins are expressed in the nervous system, with most of these detected in early development. Finally, quantitative PCR analysis of several identified adult neurons detects the presence of different combinations of innexin genes, a property that may underlie the participation of these neurons in different adult coupling circuits.

AMASS: algorithm for MSI analysis by semi-supervised segmentation.

Mass Spectrometric Imaging (MSI) is a molecular imaging technique that allows the generation of 2D ion density maps for a large complement of the active molecules present in cells and sectioned tissues. Automatic segmentation of such maps according to patterns of co-expression of individual molecules can be used for discovery of novel molecular signatures (molecules that are specifically expressed in particular spatial regions). However, current segmentation techniques are biased toward the discovery of higher abundance molecules and large segments; they allow limited opportunity for user interaction, and validation is usually performed by similarity to known anatomical features. We describe here a novel method, AMASS (Algorithm for MSI Analysis by Semi-supervised Segmentation). AMASS relies on the discriminating power of a molecular signal instead of its intensity as a key feature, uses an internal consistency measure for validation, and allows significant user interaction and supervision as options. An automated segmentation of entire leech embryo data images resulted in segmentation domains congruent with many known organs, including heart, CNS ganglia, nephridia, nephridiopores, and lateral and ventral regions, each with a distinct molecular signature. Likewise, segmentation of a rat brain MSI slice data set yielded known brain features and provided interesting examples of co-expression between distinct brain regions. AMASS represents a new approach for the discovery of peptide masses with distinct spatial features of expression. Software source code and installation and usage guide are available at http://bix.ucsd.edu/AMASS/ .

Multiple changes in peptide and lipid expression associated with regeneration in the nervous system of the medicinal leech.

BACKGROUND: The adult medicinal leech central nervous system (CNS) is capable of regenerating specific synaptic circuitry after a mechanical lesion, displaying evidence of anatomical repair within a few days and functional recovery within a few weeks. In the present work, spatiotemporal changes in molecular distributions during this phenomenon are explored. Moreover, the hypothesis that neural regeneration involves some molecular factors initially employed during embryonic neural development is tested. RESULTS: Imaging mass spectrometry coupled to peptidomic and lipidomic methodologies allowed the selection of molecules whose spatiotemporal pattern of expression was of potential interest. The identification of peptides was aided by comparing MS/MS spectra obtained for the peptidome extracted from embryonic and adult tissues to leech transcriptome and genome databases. Through the parallel use of a classical lipidomic approach and secondary ion mass spectrometry, specific lipids, including cannabinoids, gangliosides and several other types, were detected in adult ganglia following mechanical damage to connected nerves. These observations motivated a search for possible effects of cannabinoids on neurite outgrowth. Exposing nervous tissues to Transient Receptor Potential Vanilloid (TRPV) receptor agonists resulted in enhanced neurite outgrowth from a cut nerve, while exposure to antagonists blocked such outgrowth. CONCLUSION: The experiments on the regenerating adult leech CNS reported here provide direct evidence of increased titers of proteins that are thought to play important roles in early stages of neural development. Our data further suggest that endocannabinoids also play key roles in CNS regeneration, mediated through the activation of leech TRPVs, as a thorough search of leech genome databases failed to reveal any leech orthologs of the mammalian cannabinoid receptors but revealed putative TRPVs. In sum, our observations identify a number of lipids and proteins that may contribute to different aspects of the complex phenomenon of leech nerve regeneration, establishing an important base for future functional assays.

Automated querying and identification of novel peptides using MALDI mass spectrometric imaging.

MSI is a molecular imaging technique that allows for the generation of topographic 2D maps for various endogenous and some exogenous molecules without prior specification of the molecule. In this paper, we start with the premise that a region of interest (ROI) is given to us based on preselected morphological criteria. Given an ROI, we develop a pipeline, first to determine mass values with distinct expression signatures, localized to the ROI, and second to identify the peptides corresponding to these mass values. To identify spatially differentiated masses, we implement a statistic that allows us to estimate, for each spectral peak, the probability that it is over- or under-expressed within the ROI versus outside. To identify peptides corresponding to these masses, we apply LC-MS/MS to fragment endogenous (nonprotease digested) peptides. A novel pipeline based on constructing sequence tags de novo from both original and decharged spectra and a subsequent database search is used to identify peptides. As the MSI signal and the identified peptide are only related by a single mass value, we isolate the corresponding transcript and perform a second validation via in situ hybridization of the transcript. We tested our approach, MSI-Query, on a number of ROIs in the medicinal leech, Hirudo medicinalis, including the central nervous system (CNS). The Hirudo CNS is capable of regenerating itself after injury, thus forming an important model system for neuropeptide identification. The pipeline helps identify a number of novel peptides. Specifically, we identify a gene that we name HmIF4, which is a member of the intermediate filament family involved in neural development and a second novel, uncharacterized peptide. A third peptide, derived from the histone H2B, is also identified, in agreement with the previously suggested role of histone H2B in axon targeting.

Wireless physiological monitoring and ocular tracking: 3D calibration in a fully-immersive virtual health care environment.

Wireless physiological/neurological monitoring in virtual reality (VR) offers a unique opportunity for unobtrusively quantifying human responses to precisely controlled and readily modulated VR representations of health care environments. Here we present such a wireless, light-weight head-mounted system for measuring electrooculogram (EOG) and electroencephalogram (EEG) activity in human subjects interacting with and navigating in the Calit2 StarCAVE, a five-sided immersive 3-D visualization VR environment. The system can be easily expanded to include other measurements, such as cardiac activity and galvanic skin responses. We demonstrate the capacity of the system to track focus of gaze in 3-D and report a novel calibration procedure for estimating eye movements from responses to the presentation of a set of dynamic visual cues in the StarCAVE. We discuss cyber and clinical applications that include a 3-D cursor for visual navigation in VR interactive environments, and the monitoring of neurological and ocular dysfunction in vision/attention disorders.