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. We wish to thank Director Dr. Bruce R. Rosen, M.D., Ph.D. and members of the Martinos Center staff, and Dr. Michael Moskowitz, M.D., for their advice and support. Lastly, we thank Virtumed, LLC for the manufacture of the device.

All the 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. Subject consent for the use and sharing of de-identified data was obtained.
NOTE: In the current study, the inclusion criteria were as follows: (1) right or left hemiparesis with residual leg movement from an ischemic/MCA stroke incurred &#8805;6 months earlier; (2) a Functional Ambulation Category (FAC) scor...

Critical steps 
The pre-testing of a subject&#39;s ability to generate at least minimal motion of the foot pedal with their paretic foot is crucial. An FAC score of 4 or 5 and the ability to stand for a minimal period reflect a subject&#39;s combined ability between their unaffected and paretic limbs and do not reflect the ability to move the paretic foot alone. In the current study, a primary goal was the stimulation of neuroplastic changes about the region of the injury through intensive therapy i...

The use of quantitative metrics derived from functional and structural brain imaging may be more useful and effective for tracking progress and predicting the outcomes of stroke therapy than assessing clinical scores, and these quantitative metrics could be useful in designing and improving individualized therapy plans1,2. Developing effective, personalized strategies that relate motor training to a measurable reorganization of neural activity and/or improvements in motor function remains challenging. In prior work, insights have been developed regarding how functional neuroimaging methods and brain mapping in patients affected by chronic stroke can show such changes3,4,5,6,7,8. The examination of brain function in relation to hand-grip performance (which is key to patient self-sufficiency and quality of life) has led to the expectation that this technique could also be applied to gait-related foot motion control through the evaluation of the corresponding topographic patterns of neural activity and the recovery of function. It has been posited that the incorporation of MRI-based functional maps of injury may help to characterize neurological deficits more precisely than clinical evaluations9 and that using robotic devices is more effective for brain recovery than conventional paradigms10. Functional maps can provide insight into which parts of a system are functioning, thereby providing information that is not evident from clinical observations11. Success in foot motion and strength rehabilitation with MRI for stroke patients will facilitate the development of personalized treatment strategies based on MRI metrics for a broader population with other neurological conditions.
In the work presented here, the use of the MR-compatible foot-induced robotic device (MR_COFID or foot device) during fMRI scanning is described to examine the effects of post-stroke motor skill training on brain function. The motivation for the development of this controlled-resistance foot device was the critical unmet need for foot-motion rehabilitation in stroke patients. Constructing a system suitable both for home- and office-based training and for the MR-based monitoring of the responses to training activities creates a unified approach that addresses prior limitations in terms of both training and evaluation.
The MR_COFID (Figure 1A) is an adaptation of the prior magnetic resonance-compatible hand-induced robotic device (MR_CHIRODv2)8,12, which employed an electro-rheological fluid (ERF) actuator to provide dynamically controlled, resistive force in response to a subject grasping and squeezing its handle mechanism. The ERF actuator (Figure 1B) is a fluid-filled, bi-directional piston in which the ERF on one side of the piston is forced by piston motion to flow between a pair of electrodes in a channel, which returns the fluid to the other side of the piston. When a high voltage (HV) is applied to the electrodes, particles in the non-conductive, silicone oil align and mechanically bind to each other, thus increasing the viscosity of the fluid and the device&#39;s resistance to motion. In the hand-grip device, the actuator is directly coupled to the grip handles, to a load cell to measure the applied force, and to an optical encoder to measure the displacement of the handle. The new foot device transforms the linear action of the grip device into the angular displacement of the foot in dorsiflexion and plantar flexion using a crank slider mechanism (Figure 1C). The resistance force from the ERF actuator is converted nearly in proportion to the resistance torque about the ankle joint. The pedal&#39;s crank motion is symmetrical about the vector perpendicular to the main actuator axis, thus taking advantage of the approximation that the crank angle and its sine are nearly equal for small angles. As only resistive forces can be exerted by ERF, the system is inherently safe; the actuator cannot actively push or pull the foot, and the force falls to zero when the subject stops moving. The maximum plantar flexion of the foot device is 35&#176;&#160;and the maximum dorsiflexion is 18&#176;. These values are within the range of motion of the foot during normal gait and non-weight-bearing conditions13,14, are nearly the same as the values used in other research15, and were found during preliminary testing to meet or exceed the stroke subjects&#39; ranges of motion on their injury-affected side and to allow for the maximization of the available resistive forces via the linear-angular transmission mechanism. The original grip device and the additional foot motion mechanism were constructed from non-ferrous materials (plastic, aluminum, brass) for MR safety.
The ERF actuator employs variable electrical, rather than magnetic, fields to alter the fluid viscosity and is, thus, unaffected by the magnetic fields of the MR scanner. The ERF actuator is enclosed within a cylindrical copper shell that is connected to the shield conductor of the coaxial HV cable; this cable is, in turn, grounded to the penetration panel of the MR scanner&#39;s Faraday cage. This prevents potential radio frequency noise from the variable voltage applied to the actuator from affecting the scanner and prevents the variable magnetic fields of the scanner from inducing currents in the cables, which could change the ERF viscosity. The HV cable continues outside of the penetration panel to the HV amplifier. Coaxial MHV (miniature high voltage) connectors are used, which provide additional safety when carrying voltages up to 4 kV (Figure 2).
The separate cables from the optical encoder and the load cell have shields that are also grounded to the penetration panel, thus preventing their signals (particularly the digital signals from the encoder channels) from affecting either the scanner or the small voltage load cell output. The shielded and grounded cables outside the penetration panel carry signals to the data acquisition (DAQ) module. The output of the load cell, which uses a temperature-compensated Wheatstone bridge, is amplified by an instrumentation amplifier attached to the analog input terminals of the DAQ, providing a 1,000x amplification factor.
The DAQ module runs firmware using the Lua scripting language (Supplemental Coding File 1). The script loaded onto the DAQ module runs at a loop rate of 500 Hz, and the module reads the encoder and amplified load cell signal, converts the sensor readings to length and force values, and stores them in memory registers for access and logging by an m-file user interface (UI; Figure 3) on the host laptop (Supplemental Coding File 2). The host laptop sends target force values for dorsiflexion and plantar flexion, closed-loop controller parameters, and encoder-reset commands to additional memory registers on the DAQ module when needed. The DAQ script runs a control loop that detects the pedal motion direction to determine which force to exert: dorsiflexion or plantar flexion. It then calculates an output voltage proportional to the difference between the measured and target force values, bounded by 0 V and 4 V, which is the allowable input range of the HV amplifier. The ERF responds to the magnitude of the applied electric field; reversing the voltage does not reduce the viscosity below that of the unenergized (no electric field) fluid, so the DAQ output is limited to a minimum of 0 V. The DAQ quantizes (12 bit resolution) and samples (500 Hz) the analog voltages, resulting in a stair-step output to the HV amplifier that can cause high-frequency components in the HV output due to the rapid changes at each step. The HV amplifier has small and large signal bandwidths of 35 kHz and 8 kHz, respectively, so to reduce the possibility that RF noise&#160;detectable by the scanner is generated, the DAQ output uses a first-order RC filter with a &#8722;3 dB frequency at approximately 900 Hz, so higher frequencies are almost eliminated. In addition, the foot device is positioned outside the bore of the scanner near the foot of the bed, further minimizing any interaction between the device sensors, the actuator, and the scanner. The amplifier, with a gain of 1,000 V/V and a peak output of 4 kV, generates fields across the ERF gap up to 4 kV/mm; although ERF fluid&#39;s breakdown voltage is not reported by the vendor, viscosity and other parameters are described up to this level. The ERF cylinder can exert slightly more than 200 N of force when fully energized and being moved at the target speed. The moment arm length where the connecting rod joins the pedal is 56 mm, resulting in a maximum torque of approximately 11.2 Nm. This is more than sufficient for subjects with foot paresis; however, it can be overpowered by strong, healthy subjects. The hardware components are listed in the Table of Materials.
The use of the foot device builds on the training and testing paradigms developed with earlier hand-grip devices3,4,5,6,7,8,16 and other work11,17,18. At the time of publication, this device was used with chronic stroke subjects with foot-related deficits to study therapy-driven neuroplastic changes via both MR imaging and quantitative performance evaluations.
As described in the protocol below, the subjects undergoing scanning lie supine on the scanner bed, and their heads are immobilized within the scanner&#39;s head coil and positioned at the isocenter of the scanner. The foot device is positioned and locked in place such that the subject&#39;s tested leg is straight, and their foot is strapped into the device&#39;s corresponding pedal. In this manner, bending at the ankle does not cause pushing or pulling against the device, which could shift the head&#39;s position within the coil. A mirror frame is positioned in front of the subject&#39;s eyes, allowing them to view a projection screen that displays instructions and visual cues for the motor task.
During the task, the subject views either a &#34;+&#34; sign during rest periods or a visual metronome during testing, in which one circle moves up and down on the screen (target), and another circle is displayed that moves under the control of the device&#39;s foot pedal position (cursor; Figure 4). Subjects are asked to closely follow the motion of the target. The target speed is determined so that the unenergized viscous reaction force of the device (the viscous forces increase with increasing speed) is low enough for any subject to overcome it, with increased forces applied under computer control.
Robotics are easily deployed, applicable across various motor impairments, have high measurement reliability, and have the capacity to deliver high-intensity training10. This ERF-based device delivers digitally controlled resistance force to the subject, and this device is MR-safe when coupled with non-ferrous/non-magnetic components, as well as MR-compatible due to the use of grounded and shielded electronics12. It has advantages relative to related devices in that it is portable and relatively simple to use, meaning it can be used both in clinical environments and at home, where regular therapy can be performed without the costs related to travel or the clinical facility. The device can produce computer-controlled, time-varying resistance in plantar flexion and dorsiflexion to facilitate the creation of patient-specific rehabilitation routines and, thus, addresses a gap in the field of commercially available rehabilitation devices.
Other research devices do exist but were unsuitable for the present research for various reasons. Some devices are static, measuring forces applied isometrically19 rather than over the subject&#39;s range of motion (RoM). Elastic-based devices apply increasing force with increasing displacement, rather than constant resistance over the RoM, and must be manually adjusted to change the force levels20,21,22. The use of fixed weights and gravitational loading15,23 does not allow for the computerized control of the loads or different loads for plantar flexion and dorsiflexion. Pneumatic devices24,25,26 allow for force variations between tests and a constant force across the RoM; however, the valves would need to be placed at a distance from the scanner, so generally, this device would not be able to switch between plantar flexion and dorsiflexion forces quickly when changing the foot direction and would not have the frequency response capabilities of ERF actuators. Electromagnetic motors can be used27 in the scanner environment but only by extending the mechanism far enough to maintain MR safety and compatibility, which limits the portability and increases the risk of accidents should any of the motor components be brought too close to the bore. Hydraulics28 can be bidirectional at different force levels but have challenges similar to the use of electromagnetic motors in that the compressor/driver (typically not MR-compatible) must be distant from the bore, thus limiting portability and frequency response. Hydraulics have been combined with ERF systems29 so that the system can back-drive the end effector (foot or grip device) and provide isometric resistance; however, this capability was not required for the present research and was added at the cost of using non-MR-compatible hydraulic motors.
The foot device provides a combination of features that enable the following: precise and consistent therapeutic foot-control exercises for extended periods; the measurement of the subject&#39;s current motor performance capability and adjustment of the task difficulty as rehabilitation proceeds; real-time control and independent adjustment of the applied force in both plantar flexion and dorsiflexion; remote control and adjustment of the resistance force without interruptions for manual adjustment; and MR safety and compatibility.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>3T MRI scanner</td>
			<td>Siemens Medical Solutions USA, Inc., Malvern, PA</td>
			<td>Magnetom Skyra</td>
			<td>https://www.siemens-healthineers.com/en-us/magnetic-resonance-imaging/3t-mri-scanner/magnetom-skyra</td>
		</tr>
		<tr>
			<td>Data acquisition unit (DAQ)&#160;</td>
			<td>LabJack Corp., Lakewood, CO</td>
			<td>T4</td>
			<td>https://labjack.com/news/labjack-t4</td>
		</tr>
		<tr>
			<td>High voltage amplifier&#160;</td>
			<td>Trek, Inc., Lockport, NY</td>
			<td>Model 609C-6</td>
			<td>https://www.manualsdir.com/manuals/268654/trek-609e-6-high-voltage-power-amplifier.html?page=2&#38;original=1</td>
		</tr>
		<tr>
			<td>Matlab</td>
			<td>The Mathworks, Ltd., Natick, MA</td>
			<td>n/a</td>
			<td>https://www.mathworks.com/</td>
		</tr>
		<tr>
			<td>USB repeater cable</td>
			<td>Tripp Lite, Chicago, IL</td>
			<td>U026-10M</td>
			<td>https://assets.tripplite.com/product-pdfs/en/u02610m.pdf</td>
		</tr>
	</tbody>
</table>

use of a foot-induced digitally controlled resistance device for functional magnetic resonance imaging evaluation in patients with foot paresis

Neurological deficits from a stroke can result in long-term motor disabilities, including those that affect walking gait. However, extensive rehabilitation following stroke is typically time limited. Establishing predictive biomarkers to identify patients who may meaningfully benefit from additional physical therapy and demonstrate improvement is important to improve the patients&#39; quality of life. Detection of neuroplastic remodeling of the affected region and changes in the activity patterns excited while performing suitable motor tasks could have valuable implications for chronic stroke recovery. This protocol describes the use of a digitally controlled, magnetic resonance-compatible foot-induced robotic device (MR_COFID) to present a personalized foot-motor task involving trajectory following to stroke-affected subjects with gait impairment during functional magnetic resonance imaging (fMRI). In the task, foot flexion is performed against bi-directional resistive forces, which are tuned to the subject&#39;s strength in both the dorsiflexion and plantar flexion directions, while following a visual metronome. fMRI non-invasively uses endogenous deoxyhemoglobin as a contrast agent to detect blood oxygenation level-dependent (BOLD) changes between the active and resting periods during testing. Repeated periodic testing can detect therapy-related changes in excitation patterns during task performance. The use of this technique provides data to identify and measure biomarkers that may indicate the likelihood of an individual benefitting from rehabilitation beyond that which is currently provided to stroke patients.

The results described here relate to the MR compatibility of the foot device, an analysis of typical functional scan results, and notes on the foot device.
The foot device was evaluated for MR safety by the staff of the Athinoula A. Martinos Center and tested for MR compatibility in a 3 T MRI scanner. For phantom tests using a cylinder containing a solution of 1.24 g of NiSO4&#183;6H2O and 2.62 g of NaCl per 1,000 g of H2O, the foot device was attached to the s...

Watch this Scientific Journal Video about Use of a Foot-Induced Digitally Controlled Resistance Device for Functional Magnetic Resonance Imaging Evaluation in Patients with Foot Paresis at JoVE.com

Use of a Foot-Induced Digitally Controlled Resistance Device for Functional Magnetic Resonance Imaging Evaluation in Patients with Foot Paresis

Chronic stroke patients' insured rehabilitation is generally time limited. Imaging-based study of brain activity from walking-related motor tasks can lead to establishing biomarkers to measure improved outcomes and justify extending tailored therapy. A novel, magnetic resonance-compatible, variable-resistance foot motion device and a protocol for use during functional magnetic resonance imaging are presented.