Name: functional mri in conjunction with a novel mri-compatible hand-induced robotic device to evaluate rehabilitation of individuals recovering from hand grip deficits
Uploaded: 2019-11-23T12:30:00
Description: Watch this Scientific Journal Video about Functional MRI in Conjunction with a Novel MRI-compatible Hand-induced Robotic Device to Evaluate Rehabilitation of Individuals Recovering from Hand Grip Defi

This work was supported by a grant from the National Institute of Neurological Disorders and Stroke (Grant number 1R01NS105875-01A1) of the National Institutes of Health to A. Aria Tzika. This work was performed at the Athinoula A. Martinos Center for Biomedical Imaging.&#160; We wish to thank Director Dr. Bruce R. Rosen, M.D., Ph.D. and members of the Martinos Center staff for their support.&#160; We further wish to thank Mr. Christian Pusatere and Mr. Michael Armanini for their assistance in running experiments.&#160; Lastly, we thank Dr. Michael A. Moskowitz and Dr. Rosen for their guidance in the conception and development of the MR_CHIROD series of devices and the associated stroke studies.&#160;

All experiments were approved by the Institutional Review Board at Massachusetts General Hospital and performed as approved at the Athinoula A. Martinos Center for Biomedical Imaging.
1. Subject Preparation
NOTE: Inclusion criteria are: (i) right hand dominance, (ii) ability to give written informed consent. Exclusion was implemented on the basis of screening for contra-indicators in the magnetic resonance environment such as the following: (a) Routin...

<ol>
	<li>Mintzopoulos, 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=Functional+MRI+of+Rehabilitation+in+Chronic+Stroke+Patients+Using+Novel+MR-Compatible+Hand+Robots.">Functional MRI of Rehabilitation in Chronic Stroke Patients Using Novel MR-Compatible Hand Robots.</a> The Open Neuroimaging Journal. 2, 94-101 (2008).</li><li>Khanicheh, A., Mintzopoulos, D., Weinberg, B., Tzika, A. A., Mavroidis, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MR_CHIROD+v.2:+Magnetic+resonance+compatible+smart+hand+rehabilitation+device+for+brain+imaging.">MR_CHIROD v.2: Magnetic resonance compatible smart hand rehabilitation device for brain imaging.</a> IEEE Transactions on Neural Systems and Rehabilitation Engineering. 16 (1), 91-98 (2008).</li><li>Astrakas, L. G., Nagyi, S. H., Kateb, B., Tzika, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Functional+MRI+using+robotic+MRI+compatible+devices+for+monitoring+rehabilitation+from+chronic+stroke+in+the+molecular+medicine+era+(Review).">Functional MRI using robotic MRI compatible devices for monitoring rehabilitation from chronic stroke in the molecular medicine era (Review).</a> IEEE International Journal of Molecular Medicine. 29 (6), 963-973 (2012).</li><li>Lazaridou, A., 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=fMRI+as+a+molecular+imaging+procedure+for+the+functional+reorganization+of+motor+systems+in+chronic+stroke.">fMRI as a molecular imaging procedure for the functional reorganization of motor systems in chronic stroke.</a> Molecular Medicine Reports. 8 (3), 775-779 (2013).</li><li>Lazaridou, A., 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=Diffusion+tensor+and+volumetric+magnetic+resonance+imaging+using+an+MR-compatible+hand-induced+robotic+device+suggests+training-induced+neuroplasticity+in+patients+with+chronic+stroke.">Diffusion tensor and volumetric magnetic resonance imaging using an MR-compatible hand-induced robotic device suggests training-induced neuroplasticity in patients with chronic stroke.</a> International Journal of Molecular Medicine. 32 (5), 995-1000 (2013).</li><li>Mintzopoulos, 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=Connectivity+alterations+assessed+by+combining+fMRI+and+MR-compatible+hand+robots+in+chronic+stroke.">Connectivity alterations assessed by combining fMRI and MR-compatible hand robots in chronic stroke.</a> NeuroImage. 47, T90-T97 (2009).</li><li>Mintzopoulos, 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=fMRI+Using+GRAPPA+EPI+with+High+Spatial+Resolution+Improves+BOLD+Signal+Detection+at+3T.">fMRI Using GRAPPA EPI with High Spatial Resolution Improves BOLD Signal Detection at 3T.</a> The Open Magnetic Resonance Journal. 2, 57-70 (2009).</li><li>Khanicheh, A., Mintzopoulos, D., Weinberg, B., Tzika, A. A., Mavroidis, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+Electrorheological+Fluid+Dampers+for+Applications+at+3-Tesla+MRI+Environment.">Evaluation of Electrorheological Fluid Dampers for Applications at 3-Tesla MRI Environment.</a> IEEE/ASME Transactions on Mechatronics. 13 (3), 286-294 (2008).</li><li>Babaiasl, M., Mahdioun, S. H., Jaryani, P., Yazdani, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+review+of+technological+and+clinical+aspects+of+robot-aided+rehabilitation+of+upper-extremity+after+stroke.">A review of technological and clinical aspects of robot-aided rehabilitation of upper-extremity after stroke.</a> Disability and Rehabilitation Assistive Technology. 11 (4), 263-280 (2016).</li><li>Huang, V. S., Krakauer, J. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Robotic+neurorehabilitation:+a+computational+motor+learning+perspective.">Robotic neurorehabilitation: a computational motor learning perspective.</a> Journal of NeuroEngineering and Rehabilitation. 6, 5 (2009).</li><li>Tsekos, N., Khanicheh, A., Christoforou, E., Mavroidis, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+Resonance-Compatible+Robotic+and+Mechatronics+Systems+for+Image-Guided+Interventions+and+Rehabilitation:+A+Review+Study.">Magnetic Resonance-Compatible Robotic and Mechatronics Systems for Image-Guided Interventions and Rehabilitation: A Review Study.</a> Annual Review of Biomedical Engineering. 9, 351-387 (2007).</li><li>Sivak, M., Unluhisarcikli, O., Weinberg, B., Mirelman-Harari, A., Bonato, P., Mavroidis, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Haptic+system+for+hand+rehabilitation+integrating+an+interactive+game+with+an+advanced+robotic+device.">Haptic system for hand rehabilitation integrating an interactive game with an advanced robotic device.</a> Proceedings of IEEE Haptics Symposium. , (2010).</li><li>Colombo, R., 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=Design+strategies+to+improve+patient+motivation+during+robot-aided+rehabilitation.">Design strategies to improve patient motivation during robot-aided rehabilitation.</a> Journal of NeuroEngineering and Rehabilitation. 4 (1), 3 (2007).</li><li>Unluhisarcikli, O., 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=A+Robotic+Hand+Rehabilitation+System+with+Interactive+Gaming+Using+Novel+Electro-Rheological+Fluid+Based+Actuators.">A Robotic Hand Rehabilitation System with Interactive Gaming Using Novel Electro-Rheological Fluid Based Actuators.</a> Proceedings of IEEE International Conference on Robotics and Automation. , (2010).</li></ol>

We present fMRI of a motor task using the latest version of a novel robotic device, the MR_CHIROD1,2,8. The MR_CHIROD has been designed to execute a hand-squeezing grip task which has can be performed by chronic stroke patients and has been studied previously1,2,3,4,5...

Appropriate imaging metrics may monitor and predict the likelihood of therapy success in individuals better than clinical assessments and provide information to improve and individualize therapy planning. We have developed experience with patients recovering from chronic stroke1,2,3,4,5,6,7,8. Developing optimal individualized strategies that focus on how motor training can influence incremental improvement either in reorganization of neural activity and/or motor function is still challenging. Insights into the underlying structural remodeling and re-organization processes for functional recovery in the brain after neurological disease can allow us to evaluate the relationship between distributed topographic patterns of neural activity and functional recovery via functional neuroimaging methods and brain mapping. Success will facilitate developing personalized treatment strategies optimized to yield improvements in grip strength in broad population with neurological conditions based on magnetic resonance imaging (MRI) metrics9.
Here we present a protocol that employs a newly re-designed robotic hand device that provides a controllable resistance force against which a subject grips and releases a handle in synchrony with an oscillating visual stimulus. The MR_CHIROD v3 (MR-compatible Hand-Induced RObotic Device) is a system for presentation of adjustable forces against which gripping and releasing motions are performed, while measuring and recording applied force, grip displacement and timestamps for each data point (Figure 1). The device was engineered to provide reliable assessments of brain activation images during fMRI (functional Magnetic Resonance Imaging), which can be used to evaluate blood-oxygen-level dependent (BOLD) changes in brain responses of patients recovering from neurological disorders. MR-compatibility is achieved through the use of entirely non-ferrous/non-magnetic components for the structure and pneumatic actuator elements and shielded sensor/electronic components that are positioned on the scanner&#8217;s bed. Figure 2 shows the device attached to an MR scanner bed, and with a subject in the magnet bore grasping the handle of the MR_CHIROD v3 (Figure 3). Interface and control components are positioned outside the MR scanner room (Figure 4).
The device is used simultaneously with brain imaging methods to assess relevant brain activations. The primary use of the system is to provide a motor task that generates activations of the brain&#39;s motor areas, which are detected using fMRI. Brain activation while using the MR_CHIROD during imaging can assess neuroplasticity in neurological disease. By tracking changes in activations in the course of and after motor training using the MR_CHIROD, progress of motor rehabilitation following any neurological disease that leads to motor deficits (e.g., stroke) may be observed.
The MR_CHIROD v3 can also be table-mounted, for use in intra-scan training exercises, in which the subject grips and releases in response to suitable visual stimuli for periods of 45 min, three times per week during the study. Our experience with robotically delivered training, monitored with imaging, suggests that the recovery window for stroke patients for instance may never close1.
Our rationale for building and using an MR-compatible hand-grip robot is that robotic recovery has the potential to produce a great impact on impairment due to its easy deployment, applicability across various motor impairments, high measurement reliability, and capacity to deliver high intensity training protocols10. Our MR-compatible robot can: (a) be set for subject-specific ranges of motion and be programmatically adjusted to apply subject-specific force levels; (b) control, measure and record force and displacement parameters through a host computer; (c) remotely adjust control parameters without requiring interruption of scanning for access to the MR scanner room or repositioning of the subject; and (d) provide therapy via training exercises precisely and consistently for extended periods.
We are aware of no commercially available recovery robotic device that can be used with an MR scanner to measure the subject&#8217;s hand grip force and displacement while applying computer-controlled time-varying force. Tsekos et al.11 have reviewed a variety of primarily research-based, MR-compatible robotic and rehabilitation devices, including earlier iterations of the MR_CHIROD series of devices. Other devices were designed for studying wrist motion, finger motion, isometric grip strength, and multi-joint movements. For devices that actively provide resistive or other forces, a variety of MR-compatible technologies have been employed including hydraulics, pneumatics, mechanical linkages and electrorheological fluid dampers. Some devices include multiple degrees of freedom, including another extension of the earlier MR_CHIROD versions added a rotational degree of freedom and hydraulic force application, however it was not adapted for MR-compatibility12.
Our hand-grip-specific device has the advantages of portability (it is regularly transported between the MR facility and office-based training sites), and capability of producing large, computer-controlled, time-varying resistive forces. Current use of pneumatic technology in the MR_CHIROD avoids the need for high voltage sources necessary for electro-rheological fluid-based systems, the potential for leakage of hydraulic fluid, and complex cable/linkages linking the interface mechanism with external power and control components.
The MR_CHIROD was the first device that was demonstrated to function in conjunction with fMRI for brain mapping in stroke patients1. Importantly, the MR_CHIROD v3 is particularly useful for home- or office-based training, as the system and its software were designed for use without expert clinical support and with motivational elements (&#8220;gamification&#8221;). Relative to physical therapist-facilitated training in a hospital, office- or home-based training is less expensive and more convenient, making it easier for patients to adhere to daily therapy. The device, already relatively inexpensive relative to some of the other research-based devices, can be reengineered to improve the cost-to-benefit ratio. Virtual reality and gamification of training, both of which are compatible with the MR_CHIROD v3, can engage patients, increase their attention during the task, and improve motivation, thus increasing the effectiveness of recovery13.

<table>
	<tbody>
		<tr>
			<td>Ball bearings, plastic with glass balls (8)</td>
			<td>McMaster-Carr</td>
			<td>6455K97</td>
			<td></td>
		</tr>
		<tr>
			<td>Bi-directional logic level converter</td>
			<td>Adafruit</td>
			<td>395</td>
			<td></td>
		</tr>
		<tr>
			<td>Dual LS7366R Quadrature Encoder Buffer</td>
			<td>SuperDroid Robots</td>
			<td>TE-183-002</td>
			<td></td>
		</tr>
		<tr>
			<td>Feather M0 WiFi w/ATWINC1500</td>
			<td>Adafruit</td>
			<td>Adafruit 3010</td>
			<td></td>
		</tr>
		<tr>
			<td>Flanged nuts, fiberglass, 3/8&#8221;-16 (8)</td>
			<td>McMaster-Carr</td>
			<td>98945A041</td>
			<td></td>
		</tr>
		<tr>
			<td>Garolite rod, &#190;&#8221; dia, 4&#8217; long</td>
			<td>McMaster-Carr</td>
			<td>8467K84</td>
			<td></td>
		</tr>
		<tr>
			<td>Laptop</td>
			<td>Various</td>
			<td></td>
			<td>Any laptop with USB2.0 port(s) and MATLAB</td>
		</tr>
		<tr>
			<td>Load Cell (20kg)</td>
			<td>Robotshop</td>
			<td>RB-PHI-119</td>
			<td></td>
		</tr>
		<tr>
			<td>Load Cell Amplifier- HX711</td>
			<td>Mouser</td>
			<td>474-SEN-13879</td>
			<td></td>
		</tr>
		<tr>
			<td>MATLAB</td>
			<td>MathWorks</td>
			<td></td>
			<td>2008 version or later with Psychophysics Toolbox</td>
		</tr>
		<tr>
			<td>Magnetic resonance imaging scanner</td>
			<td>Siemens</td>
			<td>Skyra 3T</td>
			<td>3T full body scanner with BOLD and GRAPPA capabilities</td>
		</tr>
		<tr>
			<td>MR_CHIRODv3</td>
			<td>fabricated in-house</td>
			<td></td>
			<td>Bespoke plastic &#38; 3D printed structure</td>
		</tr>
		<tr>
			<td>Op amp development board</td>
			<td>Schmartboard</td>
			<td>710-0011-01</td>
			<td></td>
		</tr>
		<tr>
			<td>Panel Mount Power Supply</td>
			<td>Delta</td>
			<td>PMT-D2V100W1AA</td>
			<td></td>
		</tr>
		<tr>
			<td>Plastic tubing &#38; tube fittings</td>
			<td>McMaster-Carr</td>
			<td>various</td>
			<td></td>
		</tr>
		<tr>
			<td>Pyrex/graphite piston/cylinder module</td>
			<td>Airpot</td>
			<td>2KS240-3</td>
			<td></td>
		</tr>
		<tr>
			<td>Screws, &#188;&#8221;-20, nylon</td>
			<td>McMaster-Carr</td>
			<td>various</td>
			<td></td>
		</tr>
		<tr>
			<td>Shaft Collars for &#190;&#8221; dia shaft, nylon (2)</td>
			<td>McMaster-Carr</td>
			<td>9410T6</td>
			<td>Stock metal clamping screws replaced with plastic screws</td>
		</tr>
		<tr>
			<td>Shielded cables (2)</td>
			<td>US Digital</td>
			<td>CA-C5-SH-C5-25</td>
			<td></td>
		</tr>
		<tr>
			<td>Threaded rod, fiberglass, 3/8&#8221;-16</td>
			<td>McMaster-Carr</td>
			<td>91315A010</td>
			<td></td>
		</tr>
		<tr>
			<td>Transmissive optical encoder code strip</td>
			<td>US Digital</td>
			<td>LIN-2000-3.5-0.5</td>
			<td></td>
		</tr>
		<tr>
			<td>Transmissive Optical Encoder Module</td>
			<td>US Digital</td>
			<td>EM2-0-2000-I</td>
			<td></td>
		</tr>
		<tr>
			<td>PTFE sleeve bearings</td>
			<td>McMaster-Carr</td>
			<td>2639T32</td>
			<td></td>
		</tr>
	</tbody>
</table>

functional mri in conjunction with a novel mri-compatible hand-induced robotic device to evaluate rehabilitation of individuals recovering from hand grip deficits

Functional magnetic resonance imaging (fMRI) is a non-invasive magnetic resonance imaging technique that images brain activation in vivo, using endogenous deoxyhemoglobin as an endogenous contrast agent to detect changes in blood-level-dependent oxygenation (BOLD effect). We combined fMRI with a novel robotic device (MR-compatible hand-induced robotic device [MR_CHIROD]) so that a person in the scanner can execute a controlled motor task, hand-squeezing, which is a very important hand movement to study in neurological motor disease. We employed parallel imaging (generalized auto-calibrating partially parallel acquisitions [GRAPPA]), which allowed higher spatial resolution resulting in increased sensitivity to BOLD. The combination of fMRI with the hand-induced robotic device allowed precise control and monitoring of the task that was executed while a participant was in the scanner; this may prove to be of utility in rehabilitation of hand motor function in patients recovering from neurological deficits (e.g., stroke). Here we outline the protocol for using the current prototype of the MR_CHIROD during an fMRI scan.

The methodology outlined in the protocol allows the collection of fMRI images while the volunteer is performing the task in real-time in the magnet. Experiments were performed in the Bay 1 facility of the Massachusetts General Hospital Athinoula A. Martinos Center for Biomedical Imaging, using a 3T full-body magnetic resonance scanner. Figure 2 and Figure 3 show the placement of the MR_CHIROD on the table and the patient in place operating it. In <strong class="...

Watch this Scientific Journal Video about Functional MRI in Conjunction with a Novel MRI-compatible Hand-induced Robotic Device to Evaluate Rehabilitation of Individuals Recovering from Hand Grip Defi

Functional MRI in Conjunction with a Novel MRI-compatible Hand-induced Robotic Device to Evaluate Rehabilitation of Individuals Recovering from Hand Grip Deficits

We performed functional MRI using a novel MRI-compatible hand-induced robotic device to evaluate its utility for monitoring hand motor function in individuals recovering from neurological deficits.

Functional magnetic resonance imaging (fMRI) is a non-invasive magnetic resonance imaging technique that images brain activation in vivo, using endogenous ...

This protocol is used to monitor the rehabilitation of patients with hand grip deficits. Chronic stroke patients and those with other neurological diseases involving motor deficits may benefit from this technique. Magnetic Resonance Imaging allows monitoring of the adaptability of the brain.In other words, neuroplasticity in response to rehabilitation of grip performance. With suitable modification of the force stimulus device this method can be applied for rehabilitation of disabilities affecting other regions of the body. This device, and any modifications, must retain MR compatibility.It's important to insure that the MRI rod has been properly connected and it's functions verified before bringing a subject into the MR room. Prior to starting this experiment first obtain informed consent from the subject and thoroughly screen them for MRI safety. Do not proceed with the scan if the participant has any potential MRI contraindications.To begin setup, first bring the magnetic resonance compatible hand induced robotic device into the MRI room and place it near the penetration panel. Then, insert the 3/8 inch pneumatic tube into the pass through tube in the panel, into the adjacent MRI support room. Then, connect the support room fore sensing and encoder cables to the D-sub connector on the external side of the penetration panel as shown here.Connect the 3/8 inch pneumatic tube fitting, emerging from the penetration panel, to the outlet of the interface power unit pressure regulator outlet. Then, connect the four millimeter pneumatic tube to the outlet of the compressor in the inlet of the air filter on the interface power regulator. After extending and lowering the scanner bed attach the bottom half of the head coil and have the volunteer lay down, making sure that they are resting comfortably with their arms extended and use small foam pads to immobilize the participant's head.Attach the communication ball on the volunteer's chest and provide instructions on its use. Also, attach the top of the head coil. Now, loosely install the robotic device on the side of the patient opposite to their brain lesion using the corresponding bed slot.Then, with the volunteer's elbow resting on the table to support their arm, move the device handle to the webbing between thumb and forefinger and help them grab the handles. If the device is on the opposite side of the table from the penetration panel position the cables in the pneumatic tube so that they pass under the table rather than over the patient. Next, instruct the volunteer to squeeze and push or pull the device until they have the most comfortable position for squeezing.Then secure the device firmly in place by tightening the plastic nuts using an MR compatible wrench. Now, run the custom user interface stimulus program. Set the pressure to the minimal set-up level to automatically push the handle to the end stop, verifying display of motion and force waveforms.Next, set the force level and instruct the volunteer to completely squeeze two to three times for approximately two seconds. Observe whether the volunteer can complete a squeeze at that force level. Gradually increase the force level and repeat squeeze attempts until they cannot complete a squeeze.This measurement serves as the volunteer's maximum grip strength. The program will automatically calculate 60%40%and 20%of the maximum force level for use during testing. Next, confirm that the communication ball works, then position using the laser alignment, before moving the table and the participant into the scanner's iso center.Now, using the user interface, generate the instruction and stimulus images and set the system to apply the first force level and wait for a trigger signal from the MRI scanner. The program will display a set of instructions to remind the volunteer how to respond to the visual stimulus. The program will wait for the scanner to provide a trigger signal then remove the instructions and show a fixation cross that the volunteer should focus on.When the fMRI scan acquisition begins a visual metronome will be displayed in the form of a growing and shrinking circle. The volunteer should completely squeeze and release the handle synchronously with the stimulus. Rest periods will separate stimulus periods during which time the fixation cross will again be displayed.Observe the live plots of force and displacement to monitor the force output and participant task performance. Once the experiment is complete let the participant know they can relax and to let go of the handle. Finally, collect a series of anatomical scans.This figure shows typical motor task results. Here we see fMRI activations superimposed on a brain outline and as pseudo-color on a three dimensional, cross-sectional view of the volunteer's anatomical image. M1 indicates the primary motor cortex and SMA indicates the supplementary motor area.This image shows pseudo-color activations rendered on a brain template. This graph shows actual force output measured in units of force as a function of time. The output was recorded in real time.The white bar corresponds with the 60-second stimulus and rest period. Here, a single voxal time course of activation is shown, chosen from a voxal at the somatosensory area at the location of the cross-hairs in this image. All subjects must be properly trained in performing the metronome tracking grip motions in advance.In addition, synchronization between the visual stimulus and the MRI sequence is crucial. Additional imaging modalities can be used in this protocol, including Diffusion Tensor Imaging to detect white matter fiber tract orientation and growth, which is also expected to change with rehabilitation. Performing any MR experiment is hazardous due to the powerful magnetic field generated by the scanner.Therefore, all subjects and experimenters must follow MR safety guidelines including screening for contraindications. Development of this process will allow the demonstration that stroke recovery continues beyond six months post-injury suggesting that therapy and associated insurance reimbursement should continue beyond this time.

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Functional Neuroimaging Using Ultrasonic Blood-brain Barrier Disruption and Manganese-enhanced MRI

Although mice are the dominant model system for studying the genetic and molecular underpinnings of neuroscience, functional neuroimaging in mice remains technically challenging. One approach, Activation-Induced Manganese-enhanced MRI (AIM MRI), has been used successfully to map neuronal activity in rodents 1-5. In AIM MRI, Mn2+ acts a calcium analog and accumulates in depolarized neurons 6,7. Because Mn2+ shortens the T1 tissue property, regions of elevated neuronal activity will enhance in MRI. Furthermore, Mn2+ clears slowly from the activated regions; therefore, stimulation can be performed outside the magnet prior to imaging, enabling greater experimental flexibility. However, because Mn2+ does not readily cross the blood-brain barrier (BBB), the need to open the BBB has limited the use of AIM MRI, especially in mice.
One tool for opening the BBB is ultrasound. Though potentially damaging, if ultrasound is administered in combination with gas-filled microbubbles (i.e., ultrasound contrast agents), the acoustic pressure required for BBB opening is considerably lower. This combination of ultrasound and microbubbles can be used to reliably open the BBB without causing tissue damage 8-11.
Here, a method is presented for performing AIM MRI by using microbubbles and ultrasound to open the BBB. After an intravenous injection of perflutren microbubbles, an unfocused pulsed ultrasound beam is applied to the shaved mouse head for 3 minutes. For simplicity, we refer to this technique of BBB Opening with Microbubbles and UltraSound as BOMUS 12. Using BOMUS to open the BBB throughout both cerebral hemispheres, manganese is administered to the whole mouse brain. After experimental stimulation of the lightly sedated mice, AIM MRI is used to map the neuronal response.
To demonstrate this approach, herein BOMUS and AIM MRI are used to map unilateral mechanical stimulation of the vibrissae in lightly sedated mice 13. Because BOMUS can open the BBB throughout both hemispheres, the unstimulated side of the brain is used to control for nonspecific background stimulation. The resultant 3D activation map agrees well with published representations of the vibrissae regions of the barrel field cortex 14. The ultrasonic opening of the BBB is fast, noninvasive, and reversible; and thus this approach is suitable for high-throughput and/or longitudinal studies in awake mice.

A technique is described for broadly opening the blood-brain barrier in the mouse using microbubbles and ultrasound. Using this technique, manganese can be administered to the mouse brain. Because manganese is an MRI contrast agent that accumulates in depolarized neurons, this approach enables imaging of neuronal activity.

Although mice are the dominant model system for studying the genetic and molecular underpinnings of neuroscience, functional neuroimaging in mice remains ...

Transplantation of Olfactory Ensheathing Cells to Evaluate Functional Recovery after Peripheral Nerve Injury

Olfactory ensheathing cells (OECs) are neural crest cells which allow growth and regrowth of the primary olfactory neurons. Indeed, the primary olfactory system is characterized by its ability to give rise to new neurons even in adult animals. This particular ability is partly due to the presence of OECs which create a favorable microenvironment for neurogenesis. This property of OECs has been used for cellular transplantation such as in spinal cord injury models. Although the peripheral nervous system has a greater capacity to regenerate after nerve injury than the central nervous system, complete sections induce misrouting during axonal regrowth in particular after facial of laryngeal nerve transection. Specifically, full sectioning of the recurrent laryngeal nerve (RLN) induces aberrant axonal regrowth resulting in synkinesis of the vocal cords. In this specific model, we showed that OECs transplantation efficiently increases axonal regrowth.
OECs are constituted of several subpopulations present in both the olfactory mucosa (OM-OECs) and the olfactory bulbs (OB-OECs). We present here a model of cellular transplantation based on the use of these different subpopulations of OECs in a RLN injury model. Using this paradigm, primary cultures of OB-OECs and OM-OECs were transplanted in Matrigel after section and anastomosis of the RLN. Two months after surgery, we evaluated transplanted animals by complementary analyses based on videolaryngoscopy, electromyography (EMG), and histological studies. First, videolaryngoscopy allowed us to evaluate laryngeal functions, in particular muscular cocontractions phenomena. Then, EMG analyses demonstrated richness and synchronization of muscular activities. Finally, histological studies based on toluidine blue staining allowed the quantification of the number and profile of myelinated fibers.
All together, we describe here how to isolate, culture, identify and transplant OECs from OM and OB after RLN section-anastomosis and how to evaluate and analyze the efficiency of these transplanted cells on axonal regrowth and laryngeal functions.

Olfactory ensheathing cells (OECs) are neural crest cells which allow growth of the primary olfactory neurons. This specific property can be used for cellular transplantation. We present here a model of cellular transplantation based on the use of OECs in a laryngeal nerve injury model.

Olfactory ensheathing cells (OECs) are neural crest cells which allow growth and regrowth of the primary olfactory neurons. Indeed, the primary olfactory ...

Optogenetic Functional MRI

The investigation of the functional connectivity of precise neural circuits across the entire intact brain can be achieved through optogenetic functional magnetic resonance imaging (ofMRI), which is a novel technique that combines the relatively high spatial resolution of high-field fMRI with the precision of optogenetic stimulation. Fiber optics that enable delivery of specific wavelengths of light deep into the brain in vivo are implanted into regions of interest in order to specifically stimulate targeted cell types that have been genetically induced to express light-sensitive trans-membrane conductance channels, called opsins. fMRI is used to provide a non-invasive method of determining the brain's global dynamic response to optogenetic stimulation of specific neural circuits through measurement of the blood-oxygen-level-dependent (BOLD) signal, which provides an indirect measurement of neuronal activity. This protocol describes the construction of fiber optic implants, the implantation surgeries, the imaging with photostimulation and the data analysis required to successfully perform ofMRI. In summary, the precise stimulation and whole-brain monitoring ability of ofMRI are crucial factors in making ofMRI a powerful tool for the study of the connectomics of the brain in both healthy and diseased states.

This protocol describes the steps and data analysis required to successfully perform optogenetic functional magnetic resonance imaging (ofMRI). ofMRI is a novel technique that combines high-field fMRI readout with optogenetic stimulation, allowing for cell type-specific mapping of functional neural circuits and their dynamics across the whole living brain.

The investigation of the functional connectivity of precise neural circuits across the entire intact brain can be achieved through optogenetic functional ...

The Combined Use of Transcranial Direct Current Stimulation and Robotic Therapy for the Upper Limb

Neurologic disorders such as stroke and cerebral palsy are leading causes of long-term disability and can lead to severe incapacity and restriction of daily activities due to lower and upper limb impairments. Intensive physical and occupational therapy are still considered main treatments, but new adjunct therapies to standard rehabilitation that may optimize functional outcomes are being studied.
Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that polarizes underlying brain regions through the application of weak direct currents through electrodes on the scalp, modulating cortical excitability. Increased interest in this technique can be attributed to its low cost, ease of use, and effects on human neural plasticity. Recent research has been performed to determine the clinical potential of tDCS in diverse conditions such as depression, Parkinson&#39;s disease, and motor rehabilitation after stroke. tDCS helps enhance brain plasticity and seems to be a promising technique in rehabilitation programs.
A number of robotic devices have been developed to assist in the rehabilitation of upper limb function after stroke. The rehabilitation of motor deficits is often a long process requiring multidisciplinary approaches for a patient to achieve maximum independence. These devices do not intend to replace manual rehabilitation therapy; instead, they were designed as an additional tool to rehabilitation programs, allowing immediate perception of results and tracking of improvements, thus helping patients to stay motivated.
Both tDSC and robot-assisted therapy are promising add-ons to stroke rehabilitation and target the modulation of brain plasticity, with several reports describing their use to be associated with conventional therapy and the improvement of therapeutic outcomes. However, more recently, some small clinical trials have been developed that describe the associated use of tDCS and robot-assisted therapy in stroke rehabilitation. In this article, we describe the combined methods used in our institute for improving motor performance after stroke.

The combined use of transcranial direct current stimulation and robotic therapy as an add-on for conventional rehabilitation therapy may result in improved therapeutic outcomes due to modulation of brain plasticity. In this article, we describe the combined methods used in our institute for improving motor performance after stroke.

Neurologic disorders such as stroke and cerebral palsy are leading causes of long-term disability and can lead to severe incapacity and restriction of ...

Real-time Video Projection in an MRI for Characterization of Neural Correlates Associated with Mirror Therapy for Phantom Limb Pain

Mirror therapy (MT) has been proposed as an effective rehabilitative strategy to alleviate pain symptoms in amputees with phantom limb pain (PLP). However, establishing the neural correlates associated with MT therapy have been challenging given that it is difficult to administer the therapy effectively within a magnetic resonance imaging (MRI) scanner environment. To characterize the functional organization of cortical regions associated with this rehabilitative strategy, we have developed a combined behavioral and functional neuroimaging protocol that can be applied in participants with a leg amputation. This novel approach allows participants to undergo MT within the MRI scanner environment by viewing real-time video images captured by a camera. The images are viewed by the participant through a system of mirrors and a monitor that the participant views while lying on the scanner bed. In this manner, functional changes in cortical areas of interest (e.g., sensorimotor cortex) can be characterized in response to the direct application of MT.

We present a novel combined behavioral and neuroimaging protocol employing real-time video projection for the purpose of characterizing the neural correlates associated with mirror therapy within the magnetic resonance imaging scanner environment in leg amputee subjects with phantom limb pain.

Mirror therapy (MT) has been proposed as an effective rehabilitative strategy to alleviate pain symptoms in amputees with phantom limb pain (PLP). ...

Conducting Hyperscanning Experiments with Functional Near-Infrared Spectroscopy

Concurrent brain recordings of two or more interacting persons, an approach termed hyperscanning, are gaining increasing importance for our understanding of the neurobiological underpinnings of social interactions, and possibly interpersonal relationships. Functional near-infrared spectroscopy (fNIRS) is well suited for conducting hyperscanning experiments because it measures local hemodynamic effects with a high sampling rate and, importantly, it can be applied in natural settings, not requiring strict motion restrictions. In this article, we present a protocol for conducting fNIRS hyperscanning experiments with parent-child dyads and for analyzing brain-to-brain synchrony. Furthermore, we discuss critical issues and future directions, regarding the experimental design, spatial registration of the fNIRS channels, physiological influences and data analysis methods. The described protocol is not specific to parent-child dyads, but can be applied to a variety of different dyadic constellations, such as adult strangers, romantic partners or siblings. To conclude, fNIRS hyperscanning has the potential to yield new insights into the dynamics of the ongoing social interaction, which possibly go beyond what can be studied by examining the activities of individual brains.

The present protocol describes how to conduct fNIRS hyperscanning experiments and analyze brain-to-brain synchrony. Further, we discuss challenges and possible solutions.

Concurrent brain recordings of two or more interacting persons, an approach termed hyperscanning, are gaining increasing importance for our understanding ...

Comprehensive Autopsy Program for Individuals with Multiple Sclerosis

We describe a rapid tissue donation program for individuals with multiple sclerosis (MS) that requires scientists and technicians to be on-call 24/7, 365 days a year. Participants consent to donate their brain and spinal cord. Most patients were followed by neurologists at the Cleveland Clinic Mellen Center for MS Treatment and Research. Their clinical courses and neurological disabilities are well-characterized. Soon after death, the body is transported to the MS Imaging Center, where the brain is scanned in situ by 3 T magnetic resonance imaging (MRI). The body is then transferred to the autopsy room, where the brain and spinal cord are removed. The brain is divided into two hemispheres. One hemisphere is immediately placed in a slicing box and alternate 1 cm-thick slices are either fixed in 4% paraformaldehyde for two days or rapidly frozen in dry ice and 2-methylbutane. The short-fixed brain slices are stored in a cryopreservation solution and used for histological analyses and immunocytochemical detection of sensitive antigens. Frozen slices are stored at -80 &#176;C and used for molecular, immunocytochemical, and in situ hybridization/RNA scope studies. The other hemisphere is placed in 4% paraformaldehyde for several months, placed in the slicing box, re-scanned in the 3 T magnetic resonance (MR) scanner and sliced into centimeter-thick slices. Postmortem in situ MR images (MRIs) are co-registered with 1 cm-thick brain slices to facilitate MRI-pathology correlations. All brain slices are photographed and brain white-matter lesions are identified. The spinal cord is cut into 2 cm segments. Alternate segments are fixed in 4% paraformaldehyde or rapidly frozen. The rapid procurement of postmortem MS tissues allows pathological and molecular analyses of MS brains and spinal cords and pathological correlations of brain MRI abnormalities. The quality of these rapidly-processed postmortem tissues (usually within 6 h of death) is of great value to MS research and has resulted in many high-impact discoveries.

Multiple sclerosis is an inflammatory demyelinating disease with no cure. Analysis of brain tissue provides important clues to understanding the pathogenesis of the disease. Here we discuss the methodology and downstream analysis of MS brain tissue collected through a unique rapid autopsy program in operation at the Cleveland Clinic.

We describe a rapid tissue donation program for individuals with multiple sclerosis (MS) that requires scientists and technicians to be on-call 24/7, 365 ...

Preparation of Peripheral Nerve Stimulation Electrodes for Chronic Implantation in Rats

Peripheral nerve cuff electrodes have long been used in the neurosciences and related fields for stimulation of, for example, vagus or sciatic nerves. Several recent studies have demonstrated the effectiveness of chronic VNS in enhancing central nervous system plasticity to improve motor rehabilitation, extinction learning, and sensory discrimination. Construction of chronically implantable devices for use in such studies is challenging due to rats&#8217; small size, and typical protocols require extensive training of personnel and time-consuming microfabrication methods. Alternatively, commercially available implantable cuff electrodes can be purchased at a significantly higher cost. In this protocol, we present a simple, low-cost method for construction of small, chronically implantable peripheral nerve cuff electrodes for use in rats. We validate the short and long-term reliability of our cuff electrodes by demonstrating that VNS in ketamine/xylazine anesthetized rats produces decreases in breathing rate consistent with activation of the Hering-Breuer reflex, both at the time of implantation and up to 10 weeks after device implantation. We further demonstrate the suitability of the cuff electrodes for use in chronic stimulation studies by pairing VNS with skilled lever press performance to induce motor cortical map plasticity.

Existing approaches for constructing chronically implantable peripheral nerve cuff electrodes for use in small rodents often require specialized equipment and/or highly trained personnel. In this protocol we demonstrate a simple, low-cost approach for fabricating chronically implantable cuff electrodes, and demonstrate their effectiveness for vagus nerve stimulation (VNS) in rats.

Peripheral nerve cuff electrodes have long been used in the neurosciences and related fields for stimulation of, for example, vagus or sciatic nerves. ...

Evaluating Postural Control and Lower-extremity Muscle Activation in Individuals with Chronic Ankle Instability

Computerized dynamic posturography (CDP) is an objective technique for the evaluation of postural stability under static and dynamic conditions and perturbation. CDP is based on the inverted pendulum model that traces the interrelationship between the center of pressure and the center of gravity. CDP can be used to analyze the proportions of vision, proprioception, and vestibular sensation to maintain postural stability. The following characters define chronic ankle instability (CAI): persistent ankle pain, swelling, the feeling of &#8220;giving way,&#8221; and self-reported disability. Postural stability and fibular muscle activation level in individuals with CAI decreased due to lateral ankle ligament complex injuries. Few studies have used CDP to explore the postural stability of individuals with CAI. Studies that investigate postural stability and related muscle activation by using synchronized CDP with surface electromyography are lacking. This CDP protocol includes a sensory organization test (SOT), a motor control test (MCT), and an adaption test (ADT), as well as tests that measure unilateral stance (US) and limit of stability (LOS). The surface electromyography system is synchronized with CDP to collect data on lower limb muscle activation during measurement. This protocol presents a novel approach for evaluating the coordination of the visual, somatosensory, and vestibular systems and related muscle activation to maintain postural stability. Moreover, it provides new insights into the neuromuscular control of individuals with CAI when coping with real complex environments.

Individuals with chronic ankle instability (CAI) exhibit postural control deficiency and delayed muscle activation of lower extremities. Computerized dynamic posturography combined with surface electromyography provides insights into the coordination of the visual, somatosensory, and vestibular systems with muscle activation regulation to maintain postural stability in individuals with CAI.

Computerized dynamic posturography (CDP) is an objective technique for the evaluation of postural stability under static and dynamic conditions and ...

Role of Diffusion MRI Tractography in Endoscopic Endonasal Skull Base Surgery

Endoscopic endonasal surgery has gained a prominent role in the management of complex skull base tumors. It allows the resection of a large group of benign and malignant lesions through a natural anatomical extra-cranial pathway, represented by the nasal cavities, avoiding brain retraction and neurovascular manipulation. This is reflected by the patients' prompt clinical recovery and the low risk of permanent neurological sequelae, representing the main caveat of conventional skull base surgery. This surgery must be tailored to each specific case, considering its features and relationship with surrounding neural structures, mostly based on preoperative neuroimaging. Advanced MRI techniques, such as tractography, have been rarely adopted in skull base surgery due to technical issues: lengthy and complicated processes to generate reliable reconstructions for inclusion in the neuronavigation system. 
This paper aims to present the protocol implemented in the institution and highlights the synergistic collaboration and teamwork between neurosurgeons and the neuroimaging team (neurologists, neuroradiologists, neuropsychologists, physicists, and bioengineers) with the final goal of selecting the optimal treatment for each patient, improving the surgical results and pursuing the advancement of personalized medicine in this field.

We present a protocol to integrate diffusion MRI tractography in patient work-up to endoscopic endonasal surgery for a skull base tumor. The methods for adopting these neuroimaging studies in the pre- and intra-operative phases are described.

Endoscopic endonasal surgery has gained a prominent role in the management of complex skull base tumors. It allows the resection of a large group of ...