The authors would like to thank Rabih Dow, Padma Rajagopal, Molly Connors and the staff of the Carroll Center for the Blind (Newton MA, USA) for their support in carrying out this research. This work was supported by the NIH/NEI grant: RO1 EY019924.

1. Participant Demographics
This is an on-going study that recruits blind male and female participants aged between 18-45 years. All participants are legally blind of early onset (documented prior to the age of 3) and of varying ocular etiologies. None of the study participants were previously familiar with the spatial layout of the target physical building.
2. Preparation and Familiarization with AbES
<ol>
	<li> Provide the participant with a blindfold and headphones to be worn throughout the training and assessment process. Ensure that the blindfold is comfortably placed over the eyes and the headphones are properly oriented and positioned over the ears (i.e. left speaker over left ear).</li>
 <li>Train participant how to use assigned keys and the information represented by the audio cues in AbES. Using specific key strokes (Figure 3), a user navigates through and explores the building virtually (moving forward, right or left). Each virtual step approximates one step in the real physical building. </li>
 <li>Familiarize with rules and premise of the game.</li>
 <li>Familiarize with audio cues specific to game play (e.g. sound of locating jewels and sound of monsters nearby). As the user navigates through the building, auditory-based and contextual spatial information is acquired sequentially and is dynamically updated. Spatial and situational information is based on iconic and spatialized sound cues provided after each step taken. Orientation is based on cardinal compass headings (e.g. "north" or "east") and text through speech (TTS) is used to provide further information regarding a user's current location, orientation and heading (e.g. "you are in the corridor on the first floor, facing west") as well as the identity of objects and obstacles in their path (e.g. "this is a door"). Distance cues are provided based on modulating sound intensity. The spatial localization of the sounds is updated to match the user's egocentric heading. Essentially, the software is designed to play an appropriate audio file as a function of the location and egocentric heading of the user and keeps track of the user's position as they move through the environment. For example, if a door is located on the person's right side, the knocking sound is heard in the user's right ear (i.e. the software plays an audio file of a knocking sound in the right channel). If the person now turns around 180 degrees so that the same door is now located on their left side, the same knocking sound is now heard in the left channel (i.e. the software plays an audio file of a knocking sound in the left channel). Finally, if the user is facing the door, the same knocking sound is heard in both ears equally. By keeping track of the user's egocentric heading, the software can play the appropriate spatial localized sounds that identify the presence and location of objects and keep track of these changes as the user moves through the virtual environment. See Figure 4.</li>
</ol>
3. Training and Game Play with AbES (3 Sessions Each Lasting 30 min for a Total of 1.5 hr)
<ol>
	<li>Allow for free game play and note any difficulties and challenges (i.e. use of key strokes, audio cues, areas of difficult navigation). Positive reinforcement and clarifications are provided at the end of each training session.</li>
 <li>Record game performance (e.g. number, time and location where a participant finds a jewel).</li>
</ol>
4. Assess Virtual Navigation Task Performance
<ol>
	<li>Explain to participant the details of the testing and provide instructions on how to complete the virtual navigation tasks. The participant will complete 10 predetermined navigation tasks presented sequentially using the AbES software (i.e. once the participant successfully completes the first task, the computer will automatically re-locate them to the starting point of the following task).</li>
 <li>Inform the participant that they will have a maximum of 6 min to complete each navigation task.</li>
 <li>10 virtual navigation paths of comparable difficulty (i.e. distance traveled and number of turns) are chosen based on predetermined pairings of 10 start and stop locations (i.e. rooms). Specifically, the range of steps needed to navigate the target route ranged between 25-35 steps (in the virtual environment) and incorporated between 3-4 turns of 90 degrees.</li>
 <li>Load the 10 navigation pairs into AbES for automated presentation and data capture of performance.</li>
 <li>Outcome measures are automatically recorded using AbES' internal software. Outcome measures include: successful completion of the navigation task and time taken to reach target. See Figure 5A.</li>
 <li>Instructions describing the start location and the target destination are provided automatically by the AbES software at the start of each task. Timing begins immediately once the subject takes their first virtual step from the starting location and ends once arriving at the target location (unless time takes longer than 6 min, for which the run is scored as incomplete and the next path is presented). Captured data is automatically sent to a text file and opened subsequently in database/statistical software for further analysis. </li>
</ol>
5. Assess Physical Navigation Task Performance
<ol>
	<li>Explain to participant the details of the testing and provide instructions on how to complete the physical navigation tasks. The participant will complete 10 predetermined navigation tasks (presented in scrambled order from the previous virtual performance assessment) and under the supervision of an experienced investigator.</li>
 <li>Inform the participant they will have a maximum of 6 min to complete each navigation task. For the purposes of the physical navigation task, the participant is allowed to use their white cane for mobility support.</li>
 <li>10 physical navigation paths are chosen based on predetermined pairings of 10 start and stop locations (i.e. rooms) of comparable difficulty (i.e. distance traveled and number of turns).</li>
 <li>Investigator prepares stopwatch and clipboard with list of navigation tasks for manual scoring of performance. </li>
 <li>Outcome measures are manually recorded by the investigator. Outcome measures include: successful completion of the navigation task and time taken to reach target.</li>
 <li>"Square-off" the participant (i.e. position the participant with the door of the starting location behind them). Instructions describing the start location and the target destination are provided by the investigator at the start of each task. Timing begins immediately once the subject takes their first physical step from the starting location and ends when the participant verbally reports arriving at the destination (unless time takes longer than 6 min, for which the run is scored as an incomplete and the next path is presented). Captured data is recorded manually and subsequently transferred to database/statistical software for further analysis. See Figure 5B.</li>
</ol>
6. Assess Physical Drop off Task Performance
<ol>
	<li>Explain to participant the details of the testing and provide instructions on how to complete the physical drop off navigation tasks. The participant will complete 5 navigation tasks with the goals of exiting the building using the shortest route possible and under the supervision of an experienced investigator. </li>
 <li>Inform the participant that they will have a maximum of 6 min to complete each navigation task. For the purposes of the physical drop off navigation task, the participant is allowed to use their white cane for mobility support.</li>
 <li>5 predetermined physical starting locations are used such that 3 exit paths of different lengths are possible.</li>
 <li>Investigator prepares stopwatch and clipboard with list of navigation tasks for manual scoring of performance. </li>
 <li>Outcome measures are manually recorded by the investigator. Outcome measures include: successful completion of the navigation task and time taken to reach target. Furthermore, paths are scored such that the shortest path taken is given maximum points (i.e. 3 for shortest path, 2 for the second, 1 for the longest, and 0 for not being able to complete the task). See Figure 5C.</li>
 <li>"Square-off" the participant at the first starting location. Instructions describing the start location are provided by the investigator at the start of each task. Timing begins immediately once the subject takes their first physical step from the starting location and ends when the participant verbally reports arriving to an exit door of the building (unless time takes longer than 6 min, for which the run is scored as incomplete and the next start location is presented). Captured data is recorded manually and subsequently transferred to database/statistical software for further analysis.</li>
</ol>

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	<li>Loomis, J. M., Klatzky, R. L., Golledge, R. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Navigating+without+vision:+basic+and+applied+research.">Navigating without vision: basic and applied research.</a> Optom. Vis. Sci. 78, 282-289 (2001).</li><li>Siegel, A. W., White, S. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+development+of+spatial+representations+of+large-scale+environments.">The development of spatial representations of large-scale environments.</a> Adv. Child Dev. Behav. 10, 9-55 (1975).</li><li>Strelow, E. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=What+is+needed+for+a+theory+of+mobility:+direct+perception+and+cognitive+maps--lessons+from+the+blind.">What is needed for a theory of mobility: direct perception and cognitive maps--lessons from the blind.</a> Psychol. Rev. 92, 226-248 (1985).</li><li>Giudice, N. A., Bakdash, J. Z., Legge, G. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wayfinding+with+words:+spatial+learning+and+navigation+using+dynamically+updated+verbal+descriptions.">Wayfinding with words: spatial learning and navigation using dynamically updated verbal descriptions.</a> Psychol. Res. 71, 347-358 (2007).</li><li>Ashmead, D. H., Hill, E. W., Talor, C. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Obstacle+perception+by+congenitally+blind+children.">Obstacle perception by congenitally blind children.</a> Percept. Psychophys. 46, 425-433 (1989).</li><li>Dede, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Immersive+interfaces+for+engagement+and+learning.">Immersive interfaces for engagement and learning.</a> Science. 323, 66-69 (2009).</li><li>Bavelier, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Brains+on+video+games.">Brains on video games.</a> Nat. Rev. Neurosci. 12, 763-768 (2011).</li><li>Bavelier, D., Green, C. S., Dye, M. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Children,+wired:+for+better+and+for+worse.">Children, wired: for better and for worse.</a> Neuron. 67, 692-701 (2010).</li><li>Lange, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Designing+informed+game-based+rehabilitation+tasks+leveraging+advances+in+virtual+reality.">Designing informed game-based rehabilitation tasks leveraging advances in virtual reality.</a> Disabil. Rehabil. , (2012).</li><li>Merabet, L., S&#225;nchez, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Audio-based+Navigation+Using+Virtual+Environments:+Combining+Technology+and+Neuroscience.">Audio-based Navigation Using Virtual Environments: Combining Technology and Neuroscience.</a> AER Journal: Research and Practice in Visual Impairment and Blindness. 2, 128-137 (2009).</li><li>Kalia, A. A., Legge, G. E., Roy, R., Ogale, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+Indoor+Route-finding+Technology+for+People+with+Visual+Impairment.">Assessment of Indoor Route-finding Technology for People with Visual Impairment.</a> J. Vis. Impair. Blind. 104, 135-147 (2010).</li><li>Lahav, O., Schloerb, D. W., Srinivasan, M. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Newly+blind+persons+using+virtual+environment+system+in+a+traditional+orientation+and+mobility+rehabilitation+program:+a+case+study.">Newly blind persons using virtual environment system in a traditional orientation and mobility rehabilitation program: a case study.</a> Disabil. Rehabil. Assist Technol. , (2011).</li></ol>

The authors declare no conflicts of interests.

We describe an interactive audio-based virtual environment simulator designed to improve general spatial awareness and navigation skills in the blind. We demonstrate that interacting with AbES provides accurate cues that describe the spatial relationships between objects and the overall layout of the target environment. Blind users can generate accurate spatial cognitive maps based on this auditory information and by interacting with the immersive virtual environment. Furthermore, interacting with AbES within the context of a game metaphor demonstrates that spatial cognitive constructs can be learned implicitly and rather simply through causal interaction with the software. As demonstrated in this initial phase of the study, the interactive and immersive nature of the game can improve the individual's spatial awareness of a new environment, provide a platform for creating an accurate spatial cognitive map, and may reduce the insecurity associated with independent navigation prior to arriving at an unfamiliar building. 
Typically, individuals with visual impairment can gain functional independence through orientation and mobility (O&amp;M) training. It is important however that training strategies remain flexible and adaptable so that they can be applied to novel and unfamiliar situations and tailored to a person's own strengths and weaknesses so as to address their particular challenges, needs and learning strategies. The creative use of interactive virtual navigation environments such as AbES may provide for this flexibility and supplement current O&amp;M training curriculum. This software represents an adjunctive strategy that not only draws upon the benefits of high motivational drive, but also provides for a testing platform to carry out more controlled and quantifiable studies to test and validate the effectiveness of these training approaches.
Current and future investigations will include a large-scale study where participants are randomized to differing methods of training (e.g. gaming compared to direct serial route learning) and navigation (i.e. route finding) performance will be compared. We will also investigate differences between early and late blind as well as the relationship between additional factors of interest including age and gender. 
Finally, given the apparently engaging nature of this combined virtual environment and gaming approach, it would also be of interest to investigate the potential benefit of AbES on navigation skill development in blind individuals beyond the profile described here. For example, the largest (and fastest growing) segment of visual impairment is in the aging population and current trends are expected to increase13. Thus, it would seem highly relevant to explore the effectiveness of this approach for the non-visual acquisition of spatial information supporting navigation skills in this demographic group. Given that AbES is a computer based approach, it is difficult to speculate at this time on its effectiveness on non-digital natives. Along similar lines, developing AbES in manner that would be amenable to individuals with residual vision (i.e. low vision) could also be worthwhile. Given that the majority of individuals who are legally blind fall under this category13, training in virtual environments prior to actual physical travel may also be of benefit to plan routes and avoid difficulties associated with trying to access information in an unfamiliar environment. In this direction, current work is aimed at developing AbES features such as zooming (i.e. high magnification) and high a contrast display to support individuals with low vision.

Finding one's way in an unfamiliar environment presents as a significant challenge for the blind. Navigating successfully requires an understanding of the spatial relationships that exist between one's self and objects in the environment1,2. The mental representation that describes surrounding space is referred to as a spatial cognitive map3. Blind individuals can gather relevant spatial information regarding their surrounding environment through other sensory channels (such as hearing) allowing for the generation of an accurate spatial cognitive map for the purposes of real world navigation tasks4,5. 
Considerable interest has arisen regarding the educative potential of virtual environments and action video games as a means to learn and master skills6-9. Indeed, many strategies and approaches have been developed for the blind for this purpose (see 4,10-12). We have developed Audio-based Environment Simulator (AbES); a user-centered audio-based virtual environment that allows for simulated navigation and exploration of an existing physical building. Drawing from original architectural floor plans, a virtual rendering of a modern two-story building (located at the Carroll Center for the Blind; Newton, MA) was generated with the AbES software (Figures 1A and B). AbES incorporates an action game metaphor with a premise designed to promote full exploration of the building space. Using simple key strokes and spatialized sound cues, users navigate and explore the entire building to collect a maximum number of jewels hidden in various rooms. Users must avoid roving monsters that can take them away and hide them elsewhere in the building (Figure 1C).
We demonstrate that interacting with AbES allows a blind user to generate an accurate spatial cognitive map of a target building based on auditory information acquired within the context of an action game metaphor. This is confirmed by a series of post-training behavioral performance tests designed to assess the transfer of acquired spatial information from a virtual environment to a real-world and large scale indoor navigation task (see Figure 2 for overall study design). Our results show that blind users are able to successfully navigate throughout a building for which they were previously unfamiliar, despite the fact that at no time were they informed of the overall purpose of the study, nor were they instructed to recall the spatial layout of the building while playing the game.

<table border="1">
<tbody>
 <tr>
 <td>Name of Equipment</td>
 <th >Comments</td>
 </tr>
 <tr>
 <td>Laptop computer</td>
 <td >Laptop used exclusively for training participants and collecting data</td>
 </tr>
 <tr>
 <td>Stereo Head phones (fully enclosed circumaural design)</td>
 <td >Worn by all participants during training</td>
 </tr>
 <tr>
 <td>Blindfold</td>
 <td >Worn by all participants during training and testing</td>
 </tr>
 </tbody>
</table>

development of an audio-based virtual gaming environment to assist with navigation skills in the blind

Audio-based Environment Simulator (AbES) is virtual environment software designed to improve real world navigation skills in the blind. Using only audio based cues and set within the context of a video game metaphor, users gather relevant spatial information regarding a building's layout. This allows the user to develop an accurate spatial cognitive map of a large-scale three-dimensional space that can be manipulated for the purposes of a real indoor navigation task. After game play, participants are then assessed on their ability to navigate within the target physical building represented in the game. Preliminary results suggest that early blind users were able to acquire relevant information regarding the spatial layout of a previously unfamiliar building as indexed by their performance on a series of navigation tasks. These tasks included path finding through the virtual and physical building, as well as a series of drop off tasks. We find that the immersive and highly interactive nature of the AbES software appears to greatly engage the blind user to actively explore the virtual environment. Applications of this approach may extend to larger populations of visually impaired individuals.

Results from three early blind participants (aged between 19 and 22 years) are shown (see Table 1 for participant characteristics). In summary, all three participants showed a high level of success on all three navigation tasks following game play with the AbES software. This was confirmed by the performance scores (group mean and individual) on all three behavioral tasks (see Figure 6). The percentage correct performance for the virtual (mean: 90%) followed by the physical (mean: 88.7%) navigation tasks illustrates a high level of success and comparable performance for both tasks (Figure 6A). Performance on the drop off experiments suggests that participants often selected the shortest route possible to exit the building (mean score: 3.0) (Figure 6B). Finally, the average time taken to navigate to target is shown for all three navigation tasks is shown in Figure 6C. Virtual navigation time (assessed first) was typically longer (mean: 137.3 sec) than physical (73.8 sec) navigation performance. The shorter mean navigation times observed in the drop off task (mean: 37.3 sec) are consistent with the fact that participants were likely to choose the shortest possible path to exit the building. 
Assessing individual results from one representative study participant and navigation route on all three tasks assessed revealed that virtual navigation from a start to end point located on the first floor took 79 sec (Figure 7A; path shown in yellow). Assessment of performance on the same path in the physical building took 46 sec (Figure 7B). Assessment of drop off task performance illustrates that the participant took the shortest path possible (scoring 3 points and a taking navigation time of 48 sec) (Figure 7C). 
<table border="1">
<tbody>
 <tr>
 <td>subject</td>
 <td>age (years)</td>
 <td>etiology of blindness</td>
 <td>level of visual function</td>
 </tr>
 <tr>
 <td >1</td>
 <td >22</td>
 <td >retinopathy of prematurity</td>
 <td >residual (light perception)</td>
 </tr>
 <tr>
 <td >2</td>
 <td >19</td>
 <td >Peters anomaly; bilateral retinal detachment; end stage glaucoma</td>
 <td >profound (no light perception)</td>
 </tr>
 <tr>
 <td >3</td>
 <td >19</td>
 <td >retinopathy of prematurity</td>
 <td >residual (light perception)</td>
 </tr>
 </tbody>
</table>
Table 1. Participant characteristics.
<img src="/files/ftp_upload/50272/50272fig1.jpg" alt="Figure 1" fo:content-width="5in" fo:src="/files/ftp_upload/50272/50272fig1highres.jpg"/> Figure 1. Virtual environment rendered in AbES. A) original two-story building floor plan. The building includes 23 rooms and a series of connecting corridors as well as 3 separate entrances and 2 stairwells. Given the existing spatial layout, there are multiple route possibilities to enter and exit the building, B) virtual rendering of target building in AbES, C) objects encountered while playing AbES in game mode. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/50272/50272fig1large.jpg" target="_blank">Click here to view larger figure</a>.
<img src="/files/ftp_upload/50272/50272fig2.jpg" alt="Figure 2"/> Figure 2. Overall Study Design. All participants undergo a fixed training and game play period with AbES followed by a series of navigation assessments (always in sequential order). Assessments of performance include virtual, physical, and drop off navigation tasks.
<img src="/files/ftp_upload/50272/50272fig3.jpg" alt="Figure 3"/> Figure 3. AbES keystrokes.
<img src="/files/ftp_upload/50272/50272fig4.jpg" alt="Figure 4"/> Figure 4. Training and game play with AbES. A) Participants sit at a computer terminal wearing a blindfold and stereo headphones. B) Photo of an investigator with a study participant.
<img src="/files/ftp_upload/50272/50272fig5.jpg" alt="Figure 5" fo:content-width="5in" fo:src="/files/ftp_upload/50272/50272fig5highres.jpg"/> Figure 5. Summary of navigation task assessments. A) Data capture from virtual navigation path assessment. The start and end points are read to the participant and the next path is loaded automatically after completion. The path taken (shown in yellow) and time to target are collected automatically by the software. B) Investigator assesses performance in a physical navigation task. Timing (using a stopwatch) commences with the participant's first step and ends when the participant reports arriving to the target end point. C) Sample route and scoring strategy for drop off navigation task. There are three exit doors and thus multiple possible routes to exit the building. Based on the starting point, the path taken (shown in yellow) is scored. Three (3) points are given for using the shortest exit, followed by 2 and 1 point (a score of zero indicates unable to find an exit). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/50272/50272fig5large.jpg" target="_blank"> Click here to view larger figure</a>.
<img src="/files/ftp_upload/50272/50272fig6.jpg" alt="Figure 6" fo:content-width="5in" fo:src="/files/ftp_upload/50272/50272fig6highres.jpg"/> Figure 6. Summary results from navigation task assessments. Results (group means and individual results from 10 tested navigation routes) from 3 representative participants in the study are shown. A) Percentage correct performance for the virtual followed by the physical navigation tasks. B) Performance results (average number of points) on drop off tasks. C) Average time taken to navigate to target is shown for all three navigation assessments. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/50272/50272fig6large.jpg" target="_blank">Click here to view larger figure</a>.
<img src="/files/ftp_upload/50272/50272fig7.jpg" alt="Figure 7" fo:content-width="5in" fo:src="/files/ftp_upload/50272/50272fig7highres.jpg"/> Figure 7. Individual results from navigation task assessments. Representative results are shown from one study participant on all three navigation tasks assessed. A) virtual navigation (path shown on yellow). B) assessment of performance on the same path in the physical building. C) assessment of a drop off task illustrates that the participant took the shortest path possible. The alternative potential paths (yellow dotted lines) and score value relative to the given starting point are also shown. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/50272/50272fig7large.jpg" target="_blank">Click here to view larger figure</a>.
Supplmental Movie 1. Supplementary video of annotated video game play. Video sequence showing a player (yellow moving icon) entering a room located on the first floor where a jewel is hidden. Spatialized sounds (left and right channel) allow the player to orient and identify the location of objects (e.g. doors and obstacles) in their surrounding environment. Once a jewel is found, the player exits the building and they must avoid roving monsters (red moving icons). The player then continues to explore the building (first and second floors) to find more hidden jewels. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/50272/50272movie1.wmv" target="_blank">Click here to view supplemental movie</a>.

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Development of an Audio-based Virtual Gaming Environment to Assist with Navigation Skills in the Blind

Audio-based Environment Simulator (AbES) is virtual environment software designed to improve real world navigation skills in the blind.

Audio-based Environment Simulator (AbES) is virtual environment software designed to improve real world navigation skills in the blind. Using only audio ...

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14.2K Views.  Massachusetts Eye and Ear Infirmary, Harvard Medical School. Audio-based Environment Simulator (AbES) is virtual environment software designed to improve real world navigation skills in the blind.

Video: Development of an Audio-based Virtual Gaming Environment to Assist with Navigation Skills in the Blind

The Measurement and Treatment of Suppression in Amblyopia

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current estimates put the prevalence of amblyopia at approximately 1-3%1-3, the majority of cases being monocular2. Amblyopia is most frequently caused by ocular misalignment (strabismus), blur induced by unequal refractive error (anisometropia), and in some cases by form deprivation.
Although amblyopia is initially caused by abnormal visual input in infancy, once established, the visual deficit often remains when normal visual input has been restored using surgery and/or refractive correction. This is because amblyopia is the result of abnormal visual cortex development rather than a problem with the amblyopic eye itself4,5 . Amblyopia is characterized by both monocular and binocular deficits6,7 which include impaired visual acuity and poor or absent stereopsis respectively. The visual dysfunction in amblyopia is often associated with a strong suppression of the inputs from the amblyopic eye under binocular viewing conditions8. Recent work has indicated that suppression may play a central role in both the monocular and binocular deficits associated with amblyopia9,10 .
Current clinical tests for suppression tend to verify the presence or absence of suppression rather than giving a quantitative measurement of the degree of suppression. Here we describe a technique for measuring amblyopic suppression with a compact, portable device11,12 . The device consists of a laptop computer connected to a pair of virtual reality goggles. The novelty of the technique lies in the way we present visual stimuli to measure suppression. Stimuli are shown to the amblyopic eye at high contrast while the contrast of the stimuli shown to the non-amblyopic eye are varied. Patients perform a simple signal/noise task that allows for a precise measurement of the strength of excitatory binocular interactions. The contrast offset at which neither eye has a performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control13,14 and patient6,9,11 populations.
In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia12,15,16 . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device15.

Amblyopia is a developmental disorder of the visual cortex that is often accompanied by strong suppression of one eye. We present a new technique for measuring and treating interocular suppression in patients with amblyopia that can be deployed using virtual reality goggles or a portable iPod Touch device.

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current ...

Using Quantitative Real-time PCR to Determine Donor Cell Engraftment in a Competitive Murine Bone Marrow Transplantation Model

Murine bone marrow transplantation models provide an important tool in measuring hematopoietic stem cell (HSC) functions and determining genes/molecules that regulate HSCs. In these transplant model systems, the function of HSCs is determined by the ability of these cells to engraft and reconstitute lethally irradiated recipient mice. Commonly, the donor cell contribution/engraftment is measured by antibodies to donor- specific cell surface proteins using flow cytometry. However, this method heavily depends on the specificity and the ability of the cell surface marker to differentiate donor-derived cells from recipient-originated cells, which may not be available for all mouse strains. Considering the various backgrounds of genetically modified mouse strains in the market, this cell surface/ flow cytometry-based method has significant limitations especially in mouse strains that lack well-defined surface markers to separate donor cells from congenic recipient cells. Here, we reported a PCR-based technique to determine donor cell engraftment/contribution in transplant recipient mice. We transplanted male donor bone marrow HSCs to lethally irradiated congenic female mice. Peripheral blood samples were collected at different time points post transplantation. Bone marrow samples were obtained at the end of the experiments. Genomic DNA was isolated and the Y chromosome specific gene, Zfy1, was amplified using quantitative Real time PCR. The engraftment of male donor-derived cells in the female recipient mice was calculated against standard curve with known percentage of male vs. female DNAs. Bcl2 was used as a reference gene to normalize the total DNA amount. Our data suggested that this approach reliably determines donor cell engraftment and provides a useful, yet simple method in measuring hematopoietic cell reconstitution in murine bone marrow transplantation models. Our method can be routinely performed in most laboratories because no costly equipment such as flow cytometry is required.

Determining donor cell engraftment presents a challenge in mouse bone marrow transplant models that lack well-defined phenotypical markers. We described a methodology to quantify male donor cell engraftment in female transplant recipient mice. This method can be used in all mouse strains for the study of HSC functions.

Murine bone marrow transplantation models provide an important tool in measuring hematopoietic stem cell (HSC) functions and determining genes/molecules ...

An Improved Method for Rapid Intubation of the Trachea in Mice

Despite some anatomical and physiological differences, mouse models continue to be an essential tool for studying human lung disease. Bleomycin toxicity is a commonly used model to study both acute lung injury and fibrosis, and multiple methods have been developed for administering bleomycin (and other toxic agents) into the lungs. However, many of these approaches, such as transtracheal instillation, have inherent drawbacks, including the need for strong anesthetics and survival surgery. This paper reports a quick, reproducible method of intratracheal intubation that involves mild inhaled anesthesia, visualization of the trachea, and the use of a surrogate spirometer to confirm exposure. As a proof of concept, 8-12 week old C57BL/6 mice were administered either 2.0 U/kg of bleomycin or an equivalent volume of PBS, and both damage and fibrotic endpoints were measured post-exposure. This procedure allows researchers to treat a large cohort of mice in a relatively short period with little expense and minimal post-procedure care.

This article presents a rapid and simple method for administering bleomycin directly into the mouse trachea via intubation. Key advantages of this method are that it is highly reproducible, easy to master, and does not require specialized equipment or lengthy recovery times.

Despite some anatomical and physiological differences, mouse models continue to be an essential tool for studying human lung disease. Bleomycin toxicity ...

Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method

This protocol shows the measurement of the apoptotic activity neutralization of TNF&#945; in a mouse fibroblast cell model (WEHI 164) using an anti-TNF&#945; mAb. In addition, this protocol can be used to evaluate other anti-TNF&#945; molecules, such as fusion proteins. The cellular model employed here is sensitive to TNF&#945;-mediated apoptosis when an additional stress factor is induced in cell culture conditions (e.g., serum deprivation). This procedure exemplifies how to execute this analytical assay, highlighting the key operations relating to the sample preparation, cell dilution, apoptosis induction, and spectrophotometric measurements that are critical to ensure successful results. This protocol reveals the best-performance conditions relating to apoptosis induction and efficient signal recording, leading to low uncertainty values.

Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody mAb by Neutralizing TNF Using an In Vitro Bioanalytical Method

A protocol for the determination of the relative anti-apoptotic activity of an anti-TNF&#945; mAb using a neutralization mechanism with WEHI 164 cells is presented here. This protocol is useful for comparing the neutralization strength of different molecules with the same biological functionality.

This protocol shows the measurement of the apoptotic activity neutralization of TNF&#945; in a mouse fibroblast cell model (WEHI 164) using an ...

Re-Arterialized Rat Partial Liver Transplantation with an in vivo Vessel-Oriented 70% Hepatectomy

Split liver transplantation and living liver donor liver transplantation were developed in the clinic to utilize liver organs in a more efficient manner. To better understand the mechanism behind these surgical procedures, a rat partial liver transplantation (PLTx) model was established for relevant surgical studies. Because of the complexity of the rat PLTx model, a protocol with detailed descriptions is required. An article published previously reported a protocol in which ex vivo hepatectomy was used to achieve 50% rat PLTx. In contrast to this protocol, we introduced a re-arterialized PLTx with an in vivo 70% hepatectomy. An updated vessel-oriented hepatectomy was incorporated into the rat PLTx to refine the microsurgical procedure. The portal veins and hepatic arteries of the left lateral lobe and the median lobe were individually dissected and ligated before removal of the liver parenchyma, thereby decreasing the probability of bleeding in the remnant liver stump. Furthermore, an end-to-side vessel anastomosis between the common hepatic artery and the enlarged proper hepatic artery was introduced to re-arterialize the hepatic artery. By using this end-to-side vessel anastomosis technique, the diameter of the anastomosis was enlarged, thereby decreasing the difficulty of hand suture and maintaining a high rate of anastomotic patency. Moreover, the cuff anastomosis of the infrahepatic vena cava was slightly modified. A section of circumferential liver parenchyma around the vena cava of a recipient was preserved during cuff anastomosis to maintain the three-dimensional shape of the vascular lumen. This section of liver parenchyma was removed after completing the anastomosis. With this modification, the step involving placement of stay sutures was omitted, thereby further shortening the cuff anastomosis time. By using this protocol of rat PLTx, a low liver enzyme level, an intact liver lobular architecture and a high survival rate were achieved after microsurgery.

Re-Arterialized Rat Partial Liver Transplantation with an in vivo Vessel-Oriented 70% Hepatectomy

Here, a protocol involving re-arterialized rat partial liver transplantation is presented. Specifically, 70% liver was resected in vivo by using an updated technique of vessel-oriented hepatectomy. The hepatic artery was reconstructed in an end-to-side manner. The cuff technique was modified to shorten the anastomosis time of the infrahepatic vena cava.

Split liver transplantation and living liver donor liver transplantation were developed in the clinic to utilize liver organs in a more efficient manner. ...

Assessment of the Efficacy of An Osteopathic Treatment in Infants with Biomechanical Impairments to Suckling

Breastfeeding can be challenging for mother-infant dyads experiencing biomechanical suckling difficulties. Although lactation consultants (LCs) all over the world have increased their skills in this field and can provide support to help position the infant at the breast, the impact of their intervention might be limited in the presence of stiff structures in the infants. Here we present a protocol for a randomized controlled trial to assess the efficacy of osteopathic treatment, coupled with lactation consultation, for infants&#39; biomechanical suckling difficulties. It proposes a set-up and a sequence of actions to ensure an optimal context for treatment, as well as a blinding of parents and LCs to the intervention. Data such as the infant&#39;s latch ability measured with the LATCH Assessment Tool, the mother&#39;s nipple pain with a visual analog scale (VAS), and the mother&#39;s perceptions are collected by LCs four times over a 10-day period. Osteopathic lesions are documented by the osteopath, using a standardized assessment grid. Structures of interest are coherent with the anatomical zones involved in latching onto the breast. This protocol also proposes a strategy to document systematically an osteopathic profile of infants with biomechanical suckling difficulties in their first weeks of life. The implementation of this protocol confirms its feasibility for osteopathic assessment and treatment and paves the way for future trials to further explore the efficacy of osteopathic techniques for infants with biomechanical suckling difficulties.

Osteopathy is an emerging field of clinical research. Here we present a protocol to assess the efficacy of an osteopathic intervention coupled with lactation consultation, in infants with biomechanical issues impeding breastfeeding.

Breastfeeding can be challenging for mother-infant dyads experiencing biomechanical suckling difficulties. Although lactation consultants (LCs) all over ...

Blind Endotracheal Intubation in Neonatal Rabbits

The newborn rabbit is a useful animal model for various pathologies and procedures. Airway management of the rabbit is complex due to its anatomical characteristics, which is further complicated in the case of the newborn. Of the different methods of advanced airway management, endotracheal intubation is less aggressive than tracheostomy, and is more feasible than supraglottic management given the lack of supraglottic devices of such a small size. As direct glottis visualization is very difficult in animals this size, this blind intubation model is presented as an effective alternative, especially for experiments requiring prolonged anesthesia. Using this method, we performed blind intubations with a 90% success rate.

We describe a technique of endotracheal intubation in newborn rabbits after esophageal catheterization with a gastric tube.

The newborn rabbit is a useful animal model for various pathologies and procedures. Airway management of the rabbit is complex due to its anatomical ...

Real-Time Dynamic Navigation System for the Precise Quad-Zygomatic Implant Placement in a Patient with a Severely Atrophic Maxilla

Zygomatic implants (ZIs) are an ideal way to address cases of a severely atrophic edentulous maxilla and maxilla defects because they replace extensive bone augmentation and shorten the treatment cycle. However, there are risks associated with the placement of ZIs, such as penetration of the orbital cavity or infra-temporal fossa. Furthermore, the placement of multiple ZIs makes this surgery risky and more difficult to perform. Potential intraoperative complications are extremely dangerous and may cause irreparable losses. Here, we describe a practical, feasible, and reproducible protocol for a real-time surgical navigation system for precisely placing quad-zygomatic implants in the severely atrophic maxilla of patients with residual bone that does not meet the requirements of conventional implants. Hundreds of patients have received ZIs at our department based on this protocol. The clinical outcomes have been satisfactory, the intraoperative and postoperative complications have been low, and the accuracy indicated by infusion of the designed image and postoperative three-dimensional image has been high. This method should be utilized during the entire surgical procedure to ensure ZI placement safety.

Here, we present a protocol to achieve precise quad-zygomatic implant placement in patients with severely atrophic maxilla using a real-time dynamic navigation system.

Zygomatic implants (ZIs) are an ideal way to address cases of a severely atrophic edentulous maxilla and maxilla defects because they replace extensive ...

Dynamic Navigation in Endodontics: Guided Access Cavity Preparation by Means of a Miniaturized Navigation System

In the case of teeth with pulp canal calcification (PCC) and apical pathology or pulpitis, root canal treatment can be very challenging. PCC are common sequelae of dental trauma but can also occur with stimuli such as caries, bruxism, or after placing a restoration. In order to access the root canal as minimally invasive as possible in case of a necessary root canal treatment, dynamic navigation has recently been introduced in endodontics in addition to static navigation. The use of a dynamic navigation system (DNS) requires pre-operative cone-beam computed tomography (CBCT) imaging and a digital surface scan. If necessary, reference markers must be placed on the teeth before the CBCT scan; with some systems, these can also be planned and created digitally afterward. By means of a stereo camera connected to the planning software, the drill can now be coordinated with the help of reference markers and virtual planning. As a result, the position of the drill can be displayed on the monitor in real-time during preparation in different planes. In addition, the spatial displacement, the angular deviation, and the depth position are also displayed separately. The few commercially available DNS mostly consist of relatively large camera-marker-systems. Here, the DNS contains miniaturized components: a low-weight camera (97 g) mounted on the micromotor of the electric handpiece utilizing a manufacturer-specific connecting mechanism and a small marker (10 mm x 15 mm), which can be easily attached to an individually manufactured intraoral tray. For research purposes, a post-operative CBCT scan can be matched with the pre-operative one, and the volume of tooth structure removed can be calculated by the software. This work aims to present the technique of guided access cavity preparation by means of a miniaturized navigation system from imaging to clinical implementation.

Dynamic navigation systems (DNS) provide real-time visualization and guidance to the operator during endodontic access cavities preparation. The planning of the procedure requires three-dimensional imaging utilizing cone beam computed tomography and surface scans. After the export of the planning data to the DNS, access cavities can be prepared with minimal invasion.

In the case of teeth with pulp canal calcification (PCC) and apical pathology or pulpitis, root canal treatment can be very challenging. PCC are common ...

Vessel-Sparing Microsurgical Longitudinal Intussusception Vasoepididymostomy to Treat Epididymal Obstructive Azoospermia

The epididymis is a common site of obstruction in obstructive azoospermia (OA). Vasoepididymostomy has become an important method for the treatment of epididymal OA since 2000. There are two challenges in classic microscopic vasoepididymostomy. First, anastomosis of the vas deferens and epididymis is performed with double-needle sutures. However, there is a lack of good-quality and cost-effective double-needle sutures in China, which leads to increased difficulty and poor success rates of anastomosis. Second, the separation of the vas deferens does not retain vasculature, although the vas deferens vasculature plays an important role in the blood supply to the vas deferens, epididymis, and testis. This affects the blood supply to the anastomotic area and epididymis.
Therefore, this team has made innovative improvements to address these problems. Good-quality, cost-effective, single-needle sutures, which are easy to purchase in China and other countries, were used in microsurgical longitudinal intussusception vasoepididymostomy. This can optimize the operation procedure and shorten the operation time while ensuring the success rate of the anastomosis. The surgical method of preserving the vas deferens vessels was innovatively proposed because the etiology of epididymal OA is mostly inflammatory in China. The protection of the blood supply to the vas deferens and epididymis is maximized using microsurgical forceps to separate and protect the vasculature. Patency reached 81.7% in the postoperative follow-up, indicating a better surgical treatment effect.

The present protocol describes a vessel-sparing, longitudinal intussusception vasoepididymostomy using readily available single-needle sutures in China, a safe and effective procedure, which may improve patients' patency and natural pregnancy rates.

The epididymis is a common site of obstruction in obstructive azoospermia (OA). Vasoepididymostomy has become an important method for the treatment of ...