This work was supported by the University Research Fund (URF) from the University of Pennsylvania, and the American Heart Association&#39;s Student Scholarships in Cerebrovascular Disease &#38; Stroke. Special thanks to the researchers, clinicians and staff of the Laboratory for Cognition and Neural Stimulation for their ongoing support.

This study was approved by the local Institutional Review Board and meets all criteria set forth by Good Clinical Practice Guidelines. All participants provided informed consent before any study procedures began. Study participants were expected to participate in three separate sessions (outlined in Table 1). The elements of the experiment are described in stepwise fashion below. Session order was randomized.
<table border="1" fo:keep-together.within-page="always" fo:keep-with-next.within-page="always">
	<tb...

We successfully induced and measured USN symptoms with TMS and VR, respectively. While we did not have significant results when compared to sham trials, we were able to compare multiple metrics of egocentric neglect (average head angle, time spent looking at flowers in either hemispace) and allocentric neglect (performance in selecting flowers with asymmetric petals on the left vs. the right side) between the different experimental groups, and found significant differences in average head angle between subjects stimulate...

Unilateral spatial neglect (USN) is a syndrome characterized by inattention to or inaction in one side of space that affects between 23-46% of acute stroke survivors, most commonly involving injury to the right cerebral hemisphere and resulting in a tendency to ignore the left side of space and/or the survivor&#39;s body1,2. Although the majority of patients with USN experience significant recovery in the short term, subtle USN symptoms often persist3. USN can increase patient risk for falls and impede activities of daily living2,4 It has also been shown to negatively impact both motor and global functional outcomes5,6.
Deficits in USN can be conceptualized as existing across multiple dimensions, such as whether a person ignores one side of space with respect to their own body (egocentric) or with respect to an external stimulus (allocentric)7,8,9, or whether a person is unable to direct their attention (attentional) or actions (intentional) toward one side of space10. Patients often exhibit a complex constellation of symptoms that can be characterized along more than one of these dimensions. This variability of USN syndromes is thought to result from varying degrees of injury to specific neuroanatomical structures and neuronal networks, which are complex11. Allocentric neglect has been associated with lesions of the angular gyrus (AG) and superior temporal gyrus (STG), while the posterior parietal cortex (PPC) including the supramarginal gyrus (SMG) has been implicated in egocentric processing12,13,14,15. Attentional neglect is thought to involve lesions in the right IPL16, while intentional neglect is thought to be secondary to damage of the right frontal lobe17 or basal ganglia18.
Clinical assessment of USN currently relies on pen-and-paper neuropsychological instruments. These conventional assessment tools may be less sensitive than more technologically sophisticated tools, resulting in misdiagnosing or under-diagnosing some patients with USN19. Better characterization of residual deficits could facilitate the delivery of therapy to patients with milder USN and potentially improve their overall recovery, but such characterization would require very sensitive diagnostic tools. USN poses similar challenges in the laboratory setting, where it can be difficult to isolate from the motor and visual impairments that commonly accompany USN among stroke patients.
Virtual reality (VR) presents a unique opportunity to develop new tools for the diagnosis and characterization of USN. VR is a multisensory 3D environment presented in the first person with real time interactions in which individuals are able to perform tasks involving ecologically valid objects20. It is a promising tool for assessing USN; the ability to precisely control what the user sees and hears allows developers to present a wide variety of virtual tasks to the user. In addition, the sophisticated hardware and software packages currently available allow for real-time collection of a wealth of data about the user&#39;s actions, including eye, head, and limb movements, far exceeding the metrics offered by traditional diagnostic tests21. These data streams are instantaneously available, opening up the possibility for real-time adjustment of diagnostic tasks based on user performance (e.g. targeting the ideal difficulty level for a given task). This feature can facilitate task adaptation to the wide range of severity seen in USN, which is regarded as a priority in the development of new diagnostic tools for USN22. In addition, immersive VR tasks may impose an increased burden on the patients&#39; attentional resources23,24, resulting in increased errors which can facilitate the detection of neglect symptoms; indeed, some VR tasks have been shown to have increased sensitivity when compared to conventional paper-and-pencil measures of USN24,25.
In this study, the goal was to create an assessment tool that requires no expertise in neurology to operate and that can reliably detect and characterize even subtle cases of USN. We built a virtual reality-based, game-like task. We then induced a USN-like syndrome in healthy subjects with transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique that utilizes electromagnetic pulses emitted from a handheld stimulation coil, which pass through the scalp and skull of the subject and induce electric currents in the subject&#39;s brain that stimulate neurons26,27. This technique has been utilized in the study of USN by others13,17,28,29,30, though to our knowledge never in conjunction with a VR-based assessment tool.
Many researchers are already working on diagnostic and therapeutic applications of VR systems. Recent reviews31,32 explored a number of projects aimed at the assessment of USN with VR-based techniques, and a number of other studies with this aim have been published33,34,35,36,37,38,39,40,41. The majority of these studies do not utilize the full complement of VR technology that is currently available to the consumer market (e.g., a head-mounted display (HMD) and eye-tracking inserts), limiting their datasets to a smaller number of easily-quantifiable metrics. In addition, all of these studies were performed on patients with acquired brain injury leading to USN, requiring screening methods to assure that patients could at least participate in the assessment tasks (e.g., excluding patients with large visual field deficits or cognitive impairment). It is possible that more subtle cognitive, motor, or visual deficits passed under the threshold of these screening methods, possibly confounding the results of these studies. It is also possible that such screening biased the samples of participants in these studies toward a particular subtype of USN.
To avoid the screening biases of prior studies, we recruited healthy subjects and artificially simulated USN symptoms with a standard TMS protocol that is well-described in a recent manuscript15, with the goal of inducing allocentric USN-like symptoms by targeting the STG and egocentric USN-like symptoms by targeting the SMG. We designed the task to actively adjust its difficulty trial to trial and to differentiate between different subtypes of USN, specifically allocentric vs. egocentric symptoms. We also used standard paper &#38; pencil assessments of USN to formally demonstrate that the deficits we induced with rTMS are USN-like. We believe the method will be useful to other researchers who want to test novel VR tools for the assessment and rehabilitation of USN.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>AirFilm Coil (AFC) Rapid Version</td>
			<td>Magstim</td>
			<td>N/A</td>
			<td>Air-cooled TMS coil</td>
		</tr>
		<tr>
			<td>Alienware 17 R4 Laptop</td>
			<td>Dell</td>
			<td>N/A</td>
			<td>NVIDIA GeForce GTX 1060 (full specs at https://topics-cdn.dell.com/pdf/alienware-17-laptop_users-guide_en-us.pdf)</td>
		</tr>
		<tr>
			<td>BrainSight 2.0 TMS Neuronavigation Software</td>
			<td>Rogue Research Inc</td>
			<td>N/A</td>
			<td>TMS neural targeting software</td>
		</tr>
		<tr>
			<td>CED 1902 Isolated pre-amplifier</td>
			<td>Cambridge Electronic Design Limted</td>
			<td>N/A</td>
			<td>EMG pre-amplifier</td>
		</tr>
		<tr>
			<td>CED Micro 401 mkII</td>
			<td>Cambridge Electronic Design Limted</td>
			<td>N/A</td>
			<td>Multi-channel waveform data acquisition unit</td>
		</tr>
		<tr>
			<td>CED Signal 5</td>
			<td>Cambridge Electronic Design Limted</td>
			<td>N/A</td>
			<td>Sweep-based data acquisition and analysis software. Used to measure TMS evoked motor responses.</td>
		</tr>
		<tr>
			<td>HTC Vive Binocular Add-on</td>
			<td>Pupil Labs</td>
			<td>N/A</td>
			<td>HTC Vive, Vive Pro, or Vive Cosmos eye tracking add-on with 2 x 200Hz eye cameras.</td>
		</tr>
		<tr>
			<td>Magstim D70 Remote Coil</td>
			<td>Magstim</td>
			<td>N/A</td>
			<td>Hand-held TMS coil</td>
		</tr>
		<tr>
			<td>Magstim Super Rapid 2 plus 1</td>
			<td>Magstim</td>
			<td>N/A</td>
			<td>Transcranial Magnetic Stimulation Unit</td>
		</tr>
		<tr>
			<td>Unity 2018</td>
			<td>Unity</td>
			<td>N/A</td>
			<td>cross-platform VR game engine</td>
		</tr>
		<tr>
			<td>Vive Pro</td>
			<td>HTC Vive</td>
			<td>N/A</td>
			<td>VR hardware system with external motion sensors; 1440x1600 pixels per eye, 90 Hz refresh rate, 110&#176; FoV</td>
		</tr>
	</tbody>
</table>

virtual reality tools for assessing unilateral spatial neglect: a novel opportunity for data collection

Unilateral spatial neglect (USN) is a syndrome characterized by inattention to or inaction in one side of space and affects between 23-46% of acute stroke survivors. The diagnosis and characterization of these symptoms in individual patients can be challenging and often requires skilled clinical staff. Virtual reality (VR) presents an opportunity to develop novel assessment tools for patients with USN.
We aimed to design and build a VR tool to detect and characterize subtle USN symptoms, and to test the tool on subjects treated with inhibitory repetitive transcranial magnetic stimulation (TMS) of cortical regions associated with USN.
We created three experimental conditions by applying TMS to two distinct regions of cortex associated with visuospatial processing- the superior temporal gyrus (STG) and the supramarginal gyrus (SMG) - and applied sham TMS as a control. We then placed subjects in a virtual reality environment in which they were asked to identify the flowers with lateral asymmetries of flowers distributed across bushes in both hemispaces, with dynamic difficulty adjustment based on each subject's performance. 
We found significant differences in average head yaw between subjects stimulated at the STG and those stimulated at the SMG and marginally significant effects in the average visual axis.
VR technology is becoming more accessible, affordable, and robust, presenting an exciting opportunity to create useful and novel game-like tools. In conjunction with TMS, these tools could be used to study specific, isolated, artificial neurological deficits in healthy subjects, informing the creation of VR-based diagnostic tools for patients with deficits due to acquired brain injury. This study is the first to our knowledge in which artificially generated USN symptoms have been evaluated with a VR task.

Data were collected from healthy individuals using the protocol outlined above to demonstrate how the different variables that can be extracted from the virtual reality task can be analyzed to detect subtle differences between groups.
In this study, 7 individuals (2 male) with an average age of 25.6 and an average of 16.8 years of education each underwent three separate sessions of TMS. These subjects were broken into two groups...

Watch this Scientific Journal Video about Virtual Reality Tools for Assessing Unilateral Spatial Neglect: A Novel Opportunity for Data Collection at JoVE.com

Virtual Reality Tools for Assessing Unilateral Spatial Neglect: A Novel Opportunity for Data Collection

The goal was to design, build, and pilot a novel virtual reality task to detect and characterize unilateral spatial neglect, a syndrome affecting 23-46% of acute stroke survivors, expanding the role of virtual reality in the study and management of neurologic disease.

Unilateral spatial neglect (USN) is a syndrome characterized by inattention to or inaction in one side of space and affects between 23-46% of acute stroke ...

Our protocol, investigators can design and validate novel virtual reality tools to assist in the diagnosis and characterization of unilateral spatial neglect. This technique provides a broad array of data sets for the study of unilateral spatial neglect. It also avoids possible confounding effects seen in studies of patients with acquired brain injury.Better characterization of unilateral spatial neglect can facilitate the delivery of therapy to patients with subtle but still debilitating deficits and potentially improve their overall recovery. Demonstrating the procedure will be Sam Cason and Peter Schwab, researchers from my laboratory. To perform the Line Bisection test have the subject sit at a table directly across from the tester and provide the subject with a writing utensil and the stimulus sheet ensuring that the sheet is placed directly in front of the subject.Instruct the subject to quickly and accurately bisect each line printed on the stimulus sheet as close to the middle of each line as possible while keeping their head and shoulders centered as much as possible. To perform the Bells Test provide the subject with the Bells Test stimuli sheet and instruct the subject to circle or cross out all of the bells on the sheet as quickly and accurately as possible while keeping their head and shoulders as centered. To perform the star cancellation test present the subject with the stimulus sheet ensuring that it is placed directly in front of them and instruct the subject to circle or cross out all of the stars on the stimulus sheet as quickly and accurately as possible with their head and shoulders centered.To perform the Otas circle cancellation test provide the subject with the Otas circle cancellation stimulus sheet and instruct the subject to cross out or circle all of the open incomplete circles as quickly and as accurately as possible with their head and shoulders as centered. Before the first TMS session upload the subject's 3TT1 MRI scan into the neuro navigational software and create a 3D representation of the subject's brain. During the first session, have the subject sit in front of an optical tracking camera and use a headband or glasses to place a tracker on the subject.Attach one disposable disc electrode on the subject's right dorsal interosseous, one disc electrode to the subject's second knuckle on the right pointer finger and one ground electrode to the subject's right wrist, right hand, and wrist. Plug the electrodes into an electrode adapter that inputs into an MEP tracking software program and select, new online session to open the subject's project within the neuro navigational software. Select the targets to be stimulated in this session and using a pointer registered to the neuro navigational software touch the subject's face in the same locations that the landmarks were placed.Open the validation tab in the software and use the pointer to touch the subject in various spots on the head, ensuring that the cross hairs on the screen line up with the spot being pointed to on the subject. Plug a handheld TMS coil into the TMS machine and turn on the TMS machine. Set the instrument to single pulse and set an appropriate stimulation intensity.Placing the handheld TMS coil on the left side of the subject's head, deliver stimuli to the motor cortex using TMS single pulses. To identify the location that stimulates the first dorsal interosseous. Alter the stimulation intensity until the stimulation elicits MEP's of at least 50 millivolts exactly five out of 10 times.This intensity is considered the resting motor threshold. Replace the handheld coil with an air cooled TMS coil with a built-in cooling system targeting the SMG or STG for active sessions or the vertex for sham sessions and set the stimulation parameters to repetitive TMS at a rate of one Hertz for 20 minutes at a 110%intensity of the resting motor threshold. Then start stimulation of the target of interest.To perform the virtual reality behavior test place the VR headset onto the seated subject's head with the straps secured tightly but comfortably. Give the subject both controllers and ensure that both eyes are visible by visually confirming they are centered in the pupil core software camera feeds. In the unity editor, open the virtual reality task and press the play button.Ask the subject to look straight ahead and click the tear camera button. Click the begin tutorial button and wait for the subject to complete the tutorial. When subject is finished, click the calibrate eye tracking button and click next trial to begin the first trial.When the subject has completed the trial click the play button again to end the task. In this analysis the average head angle was examined to determine whether the virtual reality task was sensitive enough to identify a difference between the SMG and STG groups. ANCOVA analysis of head angle differences between groups revealed a significant difference in head angle change scores between the pre and post TMS groups.This finding from the virtual reality task is consistent with the results of the traditional paper and pencil task as both demonstrated a pattern in which the SMG group may have had a subtle neglect and looked more toward the right compared to the STG group. To specifically assess for signs of allocentric neglect on an individual target level flowers can be separated by which side of the flower contains the defective petals. In this analysis, participants in the SMG group had a tendency to look further to the right at a higher flower to head angle when searching for the short petal on the right side of the flower compared to the angle observed when the short petals were on the left side of the flower.When the average number of seconds that participants looked at each flower were analyzed no significant difference in mean head angle change score was observed between the SMG and STG groups. This method is limited by the subtle clinical effects achieved with repetitive transcranial magnetic stimulation. So proper stimulation parameters in cortical region targeting are critical.

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3.7K visualizações.  University of Pennsylvania. Em nosso protocolo, os pesquisadores podem projetar e validar novas ferramentas de realidade virtual para auxiliar no diagnóstico e caracterização da negligência espacial unilateral. Esta técnica fornece uma ampla gama de conjuntos de dados para o estudo da negligência espacial unilateral. Também evita possíveis efeitos de confusão vistos em estudos de pacientes com lesão cerebral adquirida.Uma melhor caracterização da negligência espacial unilateral pode facilitar a entre...