accelerating upper limb rehabilitation in stroke patients

Complete Project: Accelerating Upper Limb Rehabilitation in Stroke Patients by Engaging Synchronous Tongue and Wrist Motion

Co-PIs: Maysam Ghovanloo1, PhD and Andrew Butler2,3, PhD 1Georgia Institute of Technology, 2Georgia State University, 3VA Medical Center

Abstract

In the United States over 900,000 people have a stroke every year and more than half survive. Ninety percent of stroke survivors require therapy due to motor impairments, of which 80% involve upper limbs. There is a critical period, between 1 and 12 months following stroke, when the method of rehabilitation makes a significant difference in the level of functional ability a stroke survivor regains.

We propose to develop a new rehabilitation paradigm for the upper extremity (UE) by engaging the tongue and its major representation in the motor cortex. We propose to enhance the functionality and efficacy of an existing rehabilitation robotic exoskeleton, the Hand Mentor (HM) (Kinetic Muscles Inc., Tempe, AZ) by enabling stroke patients with little to no movement to control their paralyzed UE with their tongue motion, using a wireless, wearable headset, the external Tongue Drive System (eTDS), while enjoying an interactive and game-like graphical user interface (GUI). We hypothesize that stroke patients will be able to perform the rehabilitation tasks easily and repeatedly after a brief training and may additionally receive long-lasting functional benefits over a 12-week period of rehabilitation therapy due to resulting neuroplasticity. We hypothesize that the areas in the brain responsible for motor control of the tongue and the UE will remap intra-cortical pathways after an ischemic injury, establishing a new sensorimotor pathway for the paralyzed UE. In preparation for this study, we have succeeded in developing a prototype interface between the eTDS and HM (TDS-HM). Currently, both systems are connected to a laptop PC, which can be replaced by a smartphone in the future. With the TDS-HM prototype in place, we have divided the proposed research into 3 specific aims:

Aim 1. Development of the TDS-HM sensor signal processing (SSP) algorithm and GUI software: A new SSP algorithm with proportional control capability will be implemented to provide stroke patients with more natural movements of their wrist as they touch their palate with the tip of the tongue, like moving a finger on a touchpad. The position, speed, and direction of the tongue motions will be synchronized with the wrist motions. The GUI will be developed with feedback from Aim-2 to: first, provide subjects with interactive, goal-oriented, and motivating audiovisual biofeedback in an engaging game-like environment. Second, provide the research team with quantitative and intuitive data on the subjects’ performance, rate of improvement, and overall progress towards the designated objectives over the course of the trial.

Aim 2. Clinical trials: We will collect data on the functionality of the TDS-HM in a pilot clinical trial with at least six stroke patients. We will follow the same protocols established in the literature for improving UE function using the HM. We will then compare the results of TDS-HM use with HM use alone.

Hypothesis 2a: In a group of stroke survivors with severe hemiparesis, the TDS-HM therapy intervention will produce significantly greater improvement in wrist motor function from baseline to end of treatment (EOT: 60 hours of therapy) versus therapist-supervised dose-equivalent usual and customary care (DEUCC). Proving Hypothesis 2a: We will utilize clinical outcome measures to note improvement, including: active range of motion (AROM), grip strength, the Wolf Motor Function Test (WMFT), and the upper limb portion of the Fugl-Meyer Motor Assessment Scale (FMA). Meaningful improvements in these measures signify increased functional use of the hand in order to carry out daily tasks and participate in usual activities.

Hypothesis 2b: The TDS-HM therapy intervention will produce significantly greater improvement in hand functional health related quality of life (HRQOL) from baseline to EOT versus therapist-supervised DEUCC. Proving Hypothesis 2b: We will use the 5-item hand function and 9-item mobility subscales of the Stroke Impact Scale (SIS) as HRQOL outcome measures.

Aim 3. Submitting grants for external funding: The pilot data will support a grant application to the NIH-NINDS. This study is one of the first attempts to use a robotic device in severely impaired stroke patients as a physical intervention for recovery of motor function and, to our knowledge, the first effort to specifically use the combined TDS-HM. Should the TDS-HM prove more efficacious than DEUCC, we will propose a randomized clinical trial to determine the clinical effectiveness of TDS-HM training to improve UE motor function and HRQOL for patients with stroke. Results could be used to reduce costs for UE rehabilitation among select stroke patients and reassess how clinical facilities prescribe and deliver therapy targeting the UE.

Ghovanloo and Butler 1

Complete Project: Accelerating Upper Limb Rehabilitation in Stroke Patients by Engaging Synchronous Tongue and Wrist Motion

1. Introduction

In the United States over 900,000 people have a stroke every year and more than half of them survive [1]. Ninety percent of the survivors require therapy for motor impairments due to stroke, whereas the upper limbs are involved for approximately 80% of stroke survivors [2], [3]. The relative incidence of a stroke doubles every ten years for people older than 55. With the percentage of people over 65 years in the U.S. estimated to double by 2050, the number of stroke patients is going to increase by 5,000,000 [4]. Long-term motor rehabilitation is necessary in order to help stroke survivors move their paralyzed extremities again [2]. There is a critical period, between one and twelve months following the stroke, when the rehabilitation method and efficacy can make a significant difference in the level of functional ability a stroke survivor can regain [3]. Intense rehabilitation therapy given multiple times per day over many weeks has been shown to produce positive clinical outcomes. This mode of intense rehabilitation is usually performed in specialized rehabilitation clinics and is often associated with high costs due to the use of expensive therapy equipment and highly trained personnel. One solution to reduce these costs is to use rehabilitation robots [4]-[6]. The robots that are currently used, however, require the patient to have a minimum ability to move the upper limbs to operate the robot [7], which is not possible for patients with complete limb paralysis. There are few therapeutic solutions for those clients that have little or no movement capability following stroke, and there is a need to not only address those patients but also accelerate the rate of improvement in patients who undergo robotic rehabilitation.

The tongue has many inherent capabilities that can be exploited to overcome the above limitations (e.g. the need for voluntary upper limb movement) in the existing rehabilitation robots and even offer secondary benefits to stroke patients. For instance, the cortical area of the motor cortex occupied by the tongue and mouth rivals that of the fingers and the hand, providing the tongue with sophisticated motor control and manipulation capability with many degrees of freedom, evident from its role in speech and ingestion [8]. Furthermore, the tongue can move rapidly and accurately in almost every direction within the oral space. Its motion is intuitive and does not require thinking or concentration. Although speech is often affected by stroke, patients generally maintain their voluntary tongue control. Additionally, the tongue muscle fibers are quite fatigue resistant and can operate over extended exercise periods as long as the tongue can move freely. The position of the tongue is reflexively adjusted with changes in body position, allowing tongue-operated devices to be easily accessed while sitting or lying in bed. Lastly, noninvasive access to tongue motion is readily available [9].

We propose to develop a new rehabilitation paradigm by engaging the tongue and its major representation in the motor cortex. We propose to enhance the functionality and efficacy of an existing rehabilitation robotic exoskeleton, called the Hand Mentor (HM) by Kinetic Muscles Inc. (KMI, Tempe, AZ) [7], by enabling stroke patients with little to no movement to control their paralyzed upper limbs with their tongue motion, using a wireless and wearable headset, called the external Tongue Drive System (eTDS) [10], while enjoying an interactive game-like graphical user interface (GUI). In preparation for this study, we have succeeded in developing a prototype interface between the eTDS and HM, creating the TDS-HM prototype shown in Fig. 1. Currently both systems are connected to a laptop PC, which can be replaced by a smartphone in the future.

Our primary hypothesis for the proposed pilot study is that stroke patients who cannot benefit from robotic rehabilitation due to having little or no movement capability will be able to perform the rehabilitation tasks involving a combination of tongue and wrist movements easily and repeatedly after a brief training (30 min). It is our secondary hypothesis that the areas in the brain responsible for motor control of the tongue and the upper limbs will reorganize and remap intra-cortical pathways after an ischemic injury [11], establishing a new sensorimotor pathway for the paralyzed upper limb. Therefore, stroke patients may receive additional long-lasting functional benefits, over the 12-week period of rehabilitation therapy as a result of neuroplasticity.

Fig. 1. Playing a game on a PC using TDS-HM prototype.


Neuroplasticity refers to the ability of the nervous system to change its structure, function, and connections in response to experience or the environment [12], [13], when they routinely synchronize the activities in two key areas of the motor cortex, here, the tongue and hand. By using the HM robot as the rehabilitation device for paralyzed upper limbs in conjunction with the tongue motion, representations in the primary motor cortex may reorganize to some extent due to the neuroplasticity of the brain [14]. If this rehabilitation paradigm proves to be successful, patients will be able to facilitate similar motor activities without the assistance of either the robot or eTDS by simply engaging their voluntary tongue motions in sync with their desired upper limb movements.

This project will be a collaboration between Co-PI Ghovanloo, PhD, from Georgia Tech (GT) and Co-PI Butler, PhD, MBA, PT, FAHA, from Georgia State University (GSU) and Atlanta VA Medical Center (VAMC). Although not being tested in the current pilot study, the combined TDS-HM device has the potential of being used remotely in telerehabilitation settings. It is not only a novel method to deliver healthcare, but it can lower the healthcare costs and reduce the financial and emotional burden of stroke survivors and their families. Patients with completely paralyzed limbs will be able to use the low cost and portable HM in the comfort of their homes along with the wireless and wearable eTDS headset, based on their prescribed rehabilitation schedule, making the presence of in-person physical therapists unnecessary. Moreover, TDS-HM can accurately record the specific activities conducted during each exercise session and provide the patient, family members, clinicians, and healthcare providers with an objective summary of the patient’s progress over the course of the therapy.

2. Background

The HM is a motor rehabilitation device for upper limbs [6]. It has a handgrip and a computer-controlled pneumatic actuator with soft bladders (Fig. 1), which can sense the wrist position during flexion and extension via a rotary encoder. Clinical trials have shown a statistically significant improvement in the activities of daily living (ADL) for stroke patients using HM due to enhancement of their hand functionality [15]. Co-PI Butler was a clinical advisor to the developing team and has intimate knowledge of its range of applications, benefits, limitations, and impact on stroke patients’ rehabilitation [16].

The TDS was invented by Co-PI Ghovanloo in 2005 as an assistive technology (AT) for individuals with tetraplegia [10]. The TDS has since been continuously enhanced by Ghovanloo’s team [17]-[24]. The external version of the TDS (eTDS) consists of a wireless headset with bilateral extensions that position an array of four 3-axis magnetic sensors near the user’s cheeks, as shown in Fig. 1 [18]. These sensors are used to trace a small magnetic tracer, the size of a lentil (∅3 mm x 1.1 mm), which is glued temporarily near the tip of the user’s tongue. The 12-D magnetic field data measured at the sensors is sent wirelessly to a PC or iPhone where it is translated into commands by a sensor signal processing (SSP) algorithm enabling users to access a PC, smartphone, wheelchair, or other devices in their environment. The usability of the eTDS for high SCI patients has already been demonstrated in two clinical studies at the Shepherd Center in Atlanta [22], [23].

We intend to give stroke patients the ability to independently exercise movements of their paralyzed upper limbs at home, offering them a robotic device for motor rehabilitation that is controllable by their tongue motion. If successful, the proposed device will help stroke patients with unilateral upper limb impairment move their wrist voluntarily. Using the current TDS, as is, stroke patients will be able to flex or extend their wrist with the help of HM at a constant speed and stop the motion when the wrist angle reaches a desired position. While this switch-based control is quite useful, a smoother and more natural exercise would be controlling the wrist angle in a proportional fashion, for example, by sliding the tongue back and forth over the palate along the sagittal plane, while having the robot control the flexion and extension of the wrist in a synchronous fashion at the same proportional angle as the position of the tongue tip over a certain predefined anterior-posterior segment of the palate. We intend to add proportional control capability to the TDS as part of the proposed research and synchronize the HM position with that of the magnetic tracer along a 1-D trajectory.

Fig. 2 shows the block diagram of the proposed TDS-HM system. Depending on their hand movement ability, patients can generate commands either by moving their hands or their tongues. In one possible scenario, when patients reach the extent of their active range of motion, the tongue control engages allowing patients to reach a desired wrist angle by sliding the magnetic tracer over their palate. The changes in the magnetic field are measured by the quad eTDS 3-axis magnetic sensors (LF, LB, RF, and RB) and wirelessly delivered to the PC to be translated into a 1-D proportional command in real time by the SSP algorithm. Similarly, the actual wrist angle is measured by the HM and reported to the PC via the TDS-HM interface. The GUI software, running on the PC, then represents both the tongue position and wrist angle on the PC screen either directly or


embedded within an interactive game-like biofeedback to create a goal-oriented, motivating environment for patients to increase their active wrist range of motion over multiple repetitions, aided by their synchronous tongue movements. The TDS-HM software also controls the HM pneumatic actuators by activating its pump and valves to help patients reach their desired wrist angle, as instructed by the GUI.

3. Specific Aims

Aim-1. Development of the TDS-HM SSP algorithm and GUI software: A new SSP algorithm with proportional control capability will be implemented to provide stroke patients with more natural movements of their wrist as they touch their palate with the tip of the tongue, like moving a finger on a touchpad. The position, speed, and direction of the tongue motions will be synchronized with the wrist motions. Detaching the tongue from the palate will disengage the tongue and stop the robotic arm, similar to lifting the finger from a touchpad. The GUI will be developed, while being informed by feedback from Aim-2, with two key objectives: First, providing subjects with interactive, goal-oriented, and motivating audiovisual biofeedback in an engaging game-like environment. Second, providing the experimenter and research team with quantitative and intuitive data on the subjects’ performance, rate of improvement, and overall progress towards the designated objectives over the course of the trial.

Aim-2. Clinical trial: We will collect data on the functionality of the proposed system in a pilot clinical trial with at least six stroke patients. During this pilot study, we will follow the same protocols that have already been established for improving upper limb function using the HM, as documented in the literature [15], [16]. We will then compare the rehabilitation success of TDS-HM users with those who have only used the HM.

Hypothesis 2a: In a group of stroke survivors with severe hemiparesis, the TDS-HM therapy intervention will produce significantly greater improvement in wrist motor function from baseline to end of treatment (EOT; 60 hours of therapy) when compared with those who received therapist-supervised dose-equivalent usual and customary care (DEUCC). Proving Hypothesis 2a: We will utilize clinical outcome measures to note improvement, including: active range of motion, grip strength, the Wolf Motor Function Test (WMFT), and the upper limb portion of the Fugl-Meyer Motor Assessment Scale (FMMAS). Meaningful improvements in these measures will allow an individual post-stroke to regain functional use of the hand in order to carry out daily tasks and participate in usual activities.

Hypothesis 2b: In a group of stroke survivors with severe hemiparesis, the TDS-HM therapy intervention will produce significantly greater improvement in hand functional health related quality of life (HRQOL) from baseline to end of treatment (EOT; 60 hours of therapy) when compared with those who received therapist-supervised DEUCC. Proving Hypothesis 2b: We will use the five-item hand function subscale and nine-item mobility function subscale of the Stroke Impact Scale (SIS) as HRQOL outcome variable. The HRQOL will benefit from the improvements made in active range of motion, grip strength, and functional tasks by allowing patients to experience a greater level of participation in their usual activities.

Aim 3. Submitting grants for external funding: Our goal is to use the pilot data to support a grant application to the NIH-NINDS. This study represents one of the first attempts to use a robotic device in severely impaired stroke patients as a physical intervention designed to improve recovery of motor function and, to our knowledge, the first effort to use a combined TDS-HM in patients with severe impairment. Should the use of TDS-HM prove more efficacious than DEUCC, a randomized clinical trial would be proposed to systematically determine the clinical effectiveness in TDS-HM training to improve upper extremity motor function and quality of life for patients with stroke. The implications for such a possibility include reduced costs for upper extremity rehabilitation among select patients who have sustained strokes and a reassessment for how clinical facilities prescribe and deliver therapy targeting the upper extremity.

4. Research Methodology

Implementation of the TDS-HM proportional control algorithm and GUI software to merge the functionalities of the robotic hand and TDS in Aim-1 will be conducted at GT by Ghovanloo’s team and input from Co-PI Butler’s

Fig. 2: Block diagram of the proposed TDS-HM with the human user as part of the rehabilitative control loop.


team, who will conduct the clinical study on the TDS-HM at GSU towards Aim-2. Both Co-PIs will be involved in the analysis and interpretation of the acquired data and writing of the subsequent grant(s) and publications.

A1. Development of the TDS-HM SSP algorithm and GUI software: The extension of the SSP algorithm from discrete to 1-D proportional control is the main technical component of this proposal, which we have already started working on and achieved promising results. A flow-chart of this SSP with actual measured data for implementation of the 1-D proportional controller is shown in Fig. 3. The left panel shows the magnetic field strengths in the x, y and z axes of 4 magnetic sensors (LF, LB, RF, and RB) of the eTDS headset (see Fig. 2) when the magnetic tracer is moved along a straight posterior-anterior trajectory. Sensor outputs form a 12-D vector, which is the input to the SSP algorithm. The SSP will first attenuate the earth’s magnetic field (EMF) and then determine whether the tracer is touching the palate (engaged) or not using a support vector machine (SVM) classifier, which will be trained based on the oral anatomy of each patient. If the tongue is engaged, the trajectory of the magnetic tracer on the palate is monitored and converted to a trajectory of the cursor on the screen and HM wrist angle. This conversion is a transformation from the highly nonlinear 12-D magnetic field space onto a linear 1-D space, for which there is no closed-form equation. Therefore, numerical methods are often required to solve the inverse magnetic localization problem [25]. These methods also require the exact sensor locations and calibration of the sensors which are cumbersome.

We are now using a much less computationally expensive method without exact localization of the magnet. In preliminary offline trials we used linear regression method with subsequent temporal averaging to map the tracer location onto a 1-D linear function. The regression curve after averaging is shown in blue on the right panel of Fig. 3, which is very close to a linear function in red, validating this approach. These results are quite promising and we plan to refine this approach and migrate it from MATLAB to C for real-time online testing.

We will develop a training GUI in LabVIEW environment for the 1-D proportional control of the wrist movement. This GUI will be merged with the existing GUI for discrete TDS [19]. Then with input from Aim-2 studies, an interactive GUI will be developed for hand exercise with TDS-HM. The GUI will include multiple steps for objective measurement of the active range of wrist motion interleaved with goal-oriented Flash games to be played with a combination of wrist and tongue movements. It will include various adjustable parameters to allow the experimenter to progressively increase the difficulty of the rehabilitation tasks over the course of TDS-HM therapy, while recording measures such as current wrist angle, maximally reached angles, range of tongue motion, game scores, and timing/accuracy of the issued discrete/proportional control commands.

A2. Study design and methods: At least six adult subjects with a unilateral ischemic or hemorrhagic stroke (within 3 to 12 months post-stroke) exhibiting persistent hemiparesis, as indicated by a score of 1-3 on the motor arm item of the NIH Stroke Scale, will be recruited from the post-stroke population. They must present with less than 10° extension of wrist and fingers and have significant impairment limiting their activities of daily living (ADL). They must be able to read and follow simple directions. They must have no receptive aphasia, as indicated by a score of 0 on the Best Language item of the NIH Stroke Scale. Sixty hours of therapist-supervised DEUCC will be compared with sixty hours of TDS-HM therapy. Clinical outcomes will include: active range of motion, grip strength, the Wolf Motor Function Test, the upper limb portion of the Fugl-Meyer Motor Assessment Scale, and the SIS. Those will be measured at baseline, immediately post-intervention, and two months post-intervention. Change in outcome score will be assessed in a mixed model analysis.

5. Anticipated Results, Timeline, and Possibility of Subsequent Sponsorship

Stroke is one of the most common neurological diseases. Rehabilitative therapy to minimize functional disability and optimize functional motor recovery for individuals with significant loss of voluntary wrist movement after stroke is quite limited. If impairment is severe enough, therapists may focus more on training

Fig. 3: Example 12-D magnetic vector used for preliminary implementation of the 1-D proportional control algorithm using multi-linear regression to map the magnet displacement onto a linear scale.


compensatory functional movements without the use of the involved upper extremity so the patient can perform daily tasks and transition to the home [26]. Therapists may also utilize passive treatment modalities, such as stretching and passive range of motion to limit loss of mobility. However these treatments do not engage the neural pathways necessary for neuro-remodeling and repair [27]. Rehabilitation robotics and telemedicine are two hot topics that are heavily credited as potential solutions for rising healthcare costs. We are building upon our prior multidisciplinary experience by merging two novel technologies, the HM and TDS, both of which are low cost, portable, and usable in the home environment, to answer an important question: Does synchronous tongue motion improve the upper limb function in stroke patients? The strong representation of the tongue in the motor cortex, its agility, dexterity, and resistance to fatigue, along with the existing evidence in neural reconfiguration in different brain areas by establishment of new sensorimotor pathways between them point to a high probability of a positive outcome. We anticipate collecting sufficient pilot data for a subsequent grant to support the idea that synchronization between the rich areas responsible for motor control of the tongue and the upper limbs over long-term repetitive and interactive training can result in reorganization of the primary motor cortex by establishment of intra-cortical pathways between them, leading to improvements in the upper limb function in stroke patients with severe residual impairments. The TDS-HM system will minimize functional disability and optimize functional motor recovery for these individuals. This system can be developed for use in rehabilitation settings, such as inpatient hospital-based rehabilitation or skilled nursing facilities. With continued development, we intend to deploy TDS-HM to patients' homes without losing the ability to observe their progress, thereby extending and enhancing the home-based outpatient therapy they receive post-stroke.

We realize that our hypotheses may not be supported by the outcomes of this study. Should our results show that participants using the TDS-HM do not make improvements greater than those seen with participants receiving DEUCC, we will consider the possibility that the dose of treatment was insufficient, either in frequency, intensity or duration. We will also have to consider that the TDS-HM does not allow for the neuro-remodeling necessary for improvements to be made, either due to the games selected for the rehabilitation protocol or a misjudgment of the potential of the tongue motor cortex to remodel for active control of the hand. Follow-up studies can explore the use of different games with the TDS-HM, increasing the frequency and/or intensity of the intervention, or extending the length of the treatment episode. We can also investigate how other motor areas might remodel to regain voluntary control of the hand.

6. Budget and Justification

Graduate Research Assistant (GRA), TBD (25% FTE for 24 months): The GRA will be supervised by Dr. Ghovanloo and Dr. Butler will serve on his/her committee. GRA will design and develop the SSP algorithms, interfacing hardware, and GUI. The GRA will be stationed at GT-Bionics lab. Salary $2,150/m, Tuition: $1,170/month, health insurance rate: 1.8%. Physical therapist at GSU, TBD (10% FTE for 12 months) will recruit, consent, and run the experimental trials on stroke

patients. Salary $70,000. Funds will be allocated to human subject compensation at GSU at $25/session.

• Co-PI's will apply for matching funds through internal grants at GT and GSU (University Research Grants) • Kinetic Muscles Inc. has donated two HM rehab robots to Co-PI Butler’s lab to be used in this research. • Both Co-PIs’ labs are equipped with all the necessary equipment to carry out the proposed research.

Appendix-1: Project Management and Timeline

This table shows the project timeline on a quarterly basis. The Co-PIs will meet regularly on a biweekly basis during this research and on a weekly basis during clinical trial periods. The GRA (and the physical therapist during the clinical trial periods) will attend all the meetings and have additional meetings with both Co-PI as needed. Development cycle of the proportional SSP algorithm and GUI software will continue over the course of the proposed research, as data from Aim-2 is used for further improvements. The first human subject trial will be conducted during the 2nd half of the first year. The main pilot clinical trial will be conducted during the 2nd half of the 2nd year using the latest TDS-HM technology at the VAMC and GSU simultaneously. During the last quarter of each year, Co-PIs will prepare proposals for subsequent funding and include the results after data analysis. We also anticipate disseminating the results in at least two conferences and two journal papers.

Research Support for 24 months: GRA at Georgia Tech at 25% (TBD) $25,800 Physical therapist at GSU at 10% (TBD) $7,000 Other costs: GRA Tuition (50%) $14,040 GRA Health Insurance (1.8%) $494 Compensation for trial participants $1,200 Interface electronics $1,460 Total $49,994

Aim Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 1 X X X X X X X X 2 X X X X 3 X X


References:

[1] American Heart Association. “Heart Disease and Stroke Statistics -- 2012 Update,” [Online]. Available: http://circ.ahajournals.org/content/early/2011/12/15/CIR.0b013e31823ac046

[2] B. Dobkin, “Principles and Practices of Neurological Rehabilitation,” in W.G. Bradley, R.B. Daroff, G.M. Fenichel, J. Jankovic, Eds. Neuorology in Clinical Practice. 4th ed. Butterworth Heineman, Philadelphia; 2004: pp. 1027-1070.

[3] A.H. Roper, R.J. Brown. Adams and Victor’s Principles of Neurology. McGraw-Hill Medical Publications Division, NY 2005.

[4] C. R. Carignan and H. I. Krebs, "Telerehabilitation robotics: Bright lights, big future?" Journal of Rehabilitation Research & Development, vol. 43, no. 5, pp. 695-710, 2006.

[5] N. Hogan, H. I. Krebs, B. Rohrer, J. J. Palazzolo, L. Dipietro, S. E. Fasoli, J. Stein and R. Hughes, "Motions or muscles? Some behavioral factors underlying robotic assistance of motor recovery," Journal of rehabilitation research and development, vol. 43, no. 5, pp. 605-618, 2006.

[6] E. M. Frick and J. L. Alberts, "Combined use of repetitive task practice and an assistive robotic device in a patient with subacute stroke," Phys Ther., vol. 86, no. 10, pp. 1378-1386, 2006.

[7] Kinetic Muscles Inc., Hand Mentor, [Online]. Available: http://www.kineticmuscles.com/hand-physical-therapy-hand-mentor.html.

[8] E.R. Kandel, J.H. Schwartz, T.M. Jessell, (2000). Principles of Neural Science, 4th ed. McGraw-Hill.

[9] M. Ghovanloo, “Tongue operated assistive technologies,” Proc. IEEE 29th Eng. in Med. and Biol. Conf., pp. 4376-4379, Aug. 2007.

[10] X. Huo, J. Wang and M. Ghovanloo, "A magneto-inductive sensor based wireless tongue-computer interface," IEEE Trans. Neural Systems and Rehabilitation Eng., vol. 16, no. 5, pp. 497-504, 2008.

[11] R. Nudo, "Postinfarct cortical plasticity and behavioral recovery," Stroke, vol. 38, pp. 840-845, 2007.

[12] P.M. Greenwood and R. Parasuraman, “Neuronal and cognitive plasticity: a neurocognitive framework for ameliorating cognitive aging,” Frontiers Aging Neurosci., vol. 2, pp. 2-14, Nov. 2010.

[13] S.C. Cramer, M. Sur, B.H. Dobkin et al. “Harnessing neuroplasticity for clinical applications,” J. Neurology Brain, vol. 134, pp. 1591-1609, Apr. 2011.

[14] M. Hallet, "Neuroplasticity and rehabilitation," J Rehabil Res Dev., vol. 42, no. 2, pp. xvii-xxii, 2005.

[15] N.G. Kutner, R. Zhang, A.J. Butler, S.L. Wolf, J.L. Alberts. “Quality-of-life change associated with robotic-assisted therapy to improve hand motor function in patients with subacute stroke: a randomized clinical trial,” Phys Therapy, vol. 90, pp. 493-504. PMID: 2018561, Apr. 2010.

[16] C. Inman, G.A. James, S. Hamann, J. Rajendra, G. Pagnoni, A.J. Butler, “Altered resting-state effective connectivity of fronto-parietal action guidance systems on the primary motor network following stroke,” Neuroimage, vol. 59, pp. 227-237, PMID: 21839174, 2012.

[17] X. Huo and M. Ghovanloo, “Using unconstrained tongue motion as an alternative control surface for wheeled mobility,” IEEE Trans. on Biomed. Eng, vol. 56, no. 6, pp. 1719-1726, June 2009.

[18] H. Park, J. Kim, X. Huo, I.O. Hwang and M. Ghovanloo, "New ergonomic headset for tongue-drive system with wireless smartphone interface," Proc. IEEE Eng. in Medicine and Biology Society, pp. 7344-7347, 2011.

[19] B. Yousefi, X. Huo, E. Veledar, and M. Ghovanloo, “Quantitative and comparative assessment of learning in a tongue-operated computer input device,” IEEE Trans. Info. Tech. in Biomedicine, vol. 15, no. 5, pp.747-757, Sep. 2011.

[20] B. Yousefi, X. Huo, J. Kim, E. Veledar, and M. Ghovanloo, “Quantitative and comparative assessment of learning in a tongue-operated computer input device – Part II: Navigation tasks,” IEEE Trans. Info. Tech. in Biomedicine, vol. 16, no. 5, pp. 633-643, July 2012.

[21] H. Park, B. Gosselin, M. Kiani, H.-M. Lee, J. Kim, X. Huo, and M. Ghovanloo, “A wireless magnetoresistive sensing system for an intra-oral tongue-computer interface,” Digest of Technical Papers IEEE Intl. Solid-State Circuits Conference (ISSCC), pp. 124-126, 2012.

[22] X. Huo and M. Ghovanloo, "Evaluation of a wireless wearable tongue–computer interface by individuals with high-level spinal cord injuries," Journal of Neural Engineering , vol. 7, no. 2, p. #026008, 2010.

[23] J. Kim, X. Huo, J. Minocha, J. Holbrook, A. Laumann and M. Ghovanloo, “Evaluation of a smartphone platform as a wireless interface between tongue drive system and electric-powered wheelchairs," IEEE Trans. Biomedical Eng., vol. 59, no. 6, pp. 1787-1796, 2012.

[24] E. Sadeghian, X. Huo and M. Ghovanloo, "Command detection and classification in tongue drive assistive technology," Proc. IEEE Eng. in Medicine and Biology Society, pp. 5465-5468, 2011.

[25] C. Chang, X. Huo, and M. Ghovanloo, "Towards a magnetic localization system for 3-D tracking of tongue movements in speech-language therapy," Proc. IEEE Eng. Med Biol. Soc., pp. 563-566, 2009.

[26] Nijland RH, van Wegen EE, Harmeling-van der Wel BC, Kwakkel G, Early Prediction of Functional Outcome After Stroke I. Accuracy of physical therapists' early predictions of upper-limb function in hospital stroke units: The epos study. Physical therapy. 2013;93:460-469.

[27] Platz T, van Kaick S, Mehrholz J, Leidner O, Eickhof C, Pohl M. Best conventional therapy versus modular impairment-oriented training for arm paresis after stroke: A single-blind, multicenter randomized controlled trial. Neurorehabilitation and neural repair. 2009;23:706-716.

Principal Investigator/Program Director (Last, First, Middle): Ghovanloo, Maysam

1

BIOGRAPHICAL SKETCH Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME

Maysam Ghovanloo

POSITION TITLE

Associate Professor

eRA COMMONS USER NAME

ghovanloo22

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION DEGREE

(if applicable) YEAR(s) FIELD OF STUDY

University of Tehran, Tehran, Iran B.S. 1994 Electrical Engineering

Amirkabir University of Technology, Tehran, Iran M.S. 1997 Biomedical Engineering

University of Michigan, Ann Arbor, MI M.S. 2003 Electrical Engineering

University of Michigan, Ann Arbor, MI Ph.D. 2004 Electrical Engineering

A. Personal Statement

In this project, we intend to develop a new rehabilitation paradigm by engaging the tongue and its major

representation in the motor cortex with an existing rehabilitation robotic exoskeleton, called the Hand Mentor

by Kinetic Muscles Inc. to enable stroke patients with little to no upper limb movement to control their paralyzed

limbs with their tongue motion. We will use a wireless and wearable headset, called the Tongue Drive System

(TDS), which I have developed over the past few years. The hypothesis is that the stroke patients will be able

to perform the rehabilitation tasks easily and repeatedly, and may receive additional long-lasting functional

benefits due to the resulting neuroplasticity. I will oversee all the technical aspects of the proposed research

and collaborate with Prof. Butler, who will be responsible for the clinical aspects. I have a long track record in

design and development of novel medical instruments both in industry and academia. Among a wide variety of

medical devices, my specific areas of interest are implantable microelectronic devices, miniaturized devices

that are ultra low power, and assistive technologies. Over the past 7 years, I have led a research effort that

transformed the TDS from a mere concept to a fully functional assistive technology that has been through two

rounds of clinical trials. Over the past 8 years as a faculty, my research activities have been funded by various

federal and non-federal agencies (e.g. NIH, NSF, Army Research Office, and Christopher and Dana Reeve

Foundation), giving me valuable experience in project administration, student supervision, multidisciplinary

collaboration, and dissemination of the results through publications and presentations. In conclusion, I have

demonstrated the expertise, leadership, and motivation necessary to conduct productive research projects

over the years, and I am truly enthusiastic to perform the proposed preliminary research to generate pilot data

for subsequent funding.

B. POSITIONS AND HONORS

PROFESSIONAL EXPERIENCE 1997-2000 Senior R&D Staff Engineer, IDEA Inc., Tehran Iran 1999-2000 Founder and CEO, Sabz Negar Rayaneh Co. Ltd., Tehran, Iran 2000-2004 Research Assistant, University of Michigan, Ann Arbor, MI 2004-2007 Assistant Professor of Electrical and Computer Engineering, NC State University, Raleigh, NC 2004-2007 Affiliated Faculty of Biomedical Engineering, University of North Carolina in Chapel Hill - NC

State University joint department, Raleigh, NC 2007-2011 Assistant Professor of Electrical and Computer Engineering, Georgia Institute of Technology


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2011-present Associate Professor of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA

2011-present Clinical Research Scientist, Shepherd Center, Atlanta, GA 2012-present Adjunct Faculty, Wallace H. Coulter School of Biomedical Engineering, Georgia Institute of

Technology, Atlanta, GA

HONORS AND OTHER SCIENTIFIC ACTIVITIES 1990 Candidate for the Iranian team in the 21st International Physics Olympiad 2003 Neural Interfaces Workshop Student Travel Assistance Program Recipient 2004 41st DAC/ISSCC student design contest 3rd place award in operational category 2004 Rackham Graduate School Distinguished Dissertation Award Nominee from EECS, Michigan 2009 Georgia Tech’s Faculty Communicator of the Year 2010 NSF CAREER Award

PROFESSIONAL AFFILIATIONS 2009- American Association for the Advancement of Science (AAAS) 2000- IEEE Solid-State Circuits Society 2002- IEEE Engineering in Medicine and Biology Society 2004- IEEE Circuits and Systems Society 2003- Member Tau Beta Pi, the Engineering Honor Society 2004- Member Sigma Xi, the Scientific Research Society

PROFESSIONAL ACTIVITIES 2012 Guest Editor, IEEE Journal of Solid-State Circuits, Special issue on ISSCC’11 2011-present Associate Editor, IEEE Trans. on Biomedical Engineering 2010-present Associate Editor, IEEE Trans. on Biomedical Circuits and Systems 2007-present Associate Editor, IEEE Trans. on Circuits and Systems II, Express Briefs 2009 Co-Organizer for two Special Sessions: Neural Microsystems and Wearable Technologies,

IEEE Engineering in Medicine and Biology Conference, Minneapolis, Sep. 2009. 2007 Special Session Organizer, Modern Assistive Technologies, IEEE Engineering in Medicine

and Biology Conference, Lyon, France, August 2007. 2005 National Science Foundation, Review Panelist, Integrative, Hybrid, and Complex Systems 2002-Present Reviewer for Several Journals such as IEEE Trans. on Med. and Biol., Trans. On Neural

Systems and Rehab. Engineering, Journal of Solid-State Circuits, etc. C. SELECTED PEER-REVIEWED PUBLICATIONS (Selected from 100 peer-reviewed publications)

MOST RELEVANT TO THE CURRENT APPLICATION

J. Kim, X. Huo, J. Minocha, J. Holbrook, A. Laumann, and M. Ghovanloo, “Evaluation of a smartphone platform as a wireless interface between Tongue Drive System and electric-powered wheelchairs,” IEEE Trans. Biomed. Eng., vol. 59, no. 6, pp. 1787–1796, June. 2012.

C. Cheng, X. Huo, and M. Ghovanloo, “Towards a magnetic localization system for 3-D tracking of tongue movements in speech-language therapy,” Proc. IEEE 31st Eng. in Med. and Biol. Conf., pp. 563-566, Sep. 2009.

X. Huo and M. Ghovanloo, “Evaluation of a wireless wearable tongue computer interface by individuals with high level spinal cord injuries,” Journal of Neural Engineering, vol. 7, no. 2, pp. 026008, Apr. 2010.

X. Huo, J. Wang, and M. Ghovanloo, “A magneto-inductive sensor based wireless tongue-computer interface,” IEEE Trans. on Neural Sys. Rehab. Eng., vol. 16, no. 5, pp. 497-504, Oct. 2008.

X. Huo and M. Ghovanloo, “Using unconstrained tongue motion as an alternative control surface for wheeled mobility,” IEEE Trans. on Biomed. Eng, vol. 56, no. 6, pp. 1719-1726, June 2009.

ADDITIONAL RECENT PUBLICATIONS OF IMPORTANCE TO THE FIELD (IN CHRONOLOGICAL ORDER)

M. Ghovanloo and K. Najafi, “Fully integrated wide-band high-current rectifiers for wireless biomedical implants,” IEEE Journal of Solid-State Circuits, vol. 39, no. 11, pp. 1976-1984, Nov. 2004.


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M. Ghovanloo and K. Najafi, “A modular 32-site wireless neural stimulation microsystem,” IEEE Journal on Solid-State Circuits, vol. 39, no. 12, pp. 2457-2466, Dec. 2004.

M. Ghovanloo and K. Najafi, “A wideband frequency shift keying wireless link for inductively powered biomedical implants,” IEEE Trans. on Circuits and Systems I, vol. 51, no. 12, pp. 2374-2383, Dec. 2004.

M. Ghovanloo and K. Najafi, “A compact large voltage compliance high output impedance programmable current source for biomedical implantable microstimulators,” IEEE Trans. on Biomed. Eng, vol. 52, no. 1, pp. 97-105, Jan. 2005.

M. Ghovanloo and K. Najafi, “A wireless implantable multichannel microstimulating system-on-a-chip with modular architecture,” IEEE Trans. on Neural Sys. Rehab. Eng., vol. 15, no. 3, pp. 449-457, Sep. 2007.

U. Jow and M. Ghovanloo, “Design and optimization of printed spiral coils for efficient transcutaneous inductive power transmission,” IEEE Trans. on Biomed. Circuits and Systems, vol. 1, no. 3, pp. 193-202, Sep. 2007.

M. Ghovanloo and S. Atluri, “A wideband power-efficient inductive wireless link for implantable microelectronic devices using multiple carriers,” IEEE Trans. Circuits and Systems I, vol. 54, no. 10, pp. 2211-2221, Oct. 2007.

J. Wang, X. Huo, and M. Ghovanloo, “Tracking tongue movements for environment control using particle swarm optimization,” Proc. IEEE Intl. Symp. on Circuits and Systems, pp.1982-1985, May 2008.

G. Bawa and M. Ghovanloo, “Analysis, design and implementation of a high efficiency fullwave rectifier in standard CMOS technology,” Analog Integrated Circuits and Signal Processing, Aug. 2008.

G. Bawa and M. Ghovanloo, “An active high power conversion efficiency rectifier with built–in dual–mode back telemetry in standard CMOS technology,” IEEE Trans. on Biomed. Circuits and Systems, vol. 2, no. 3, pp. 184-192, Sep. 2008.

M. Ghovanloo and S. Atluri, “An Integrated full-wave CMOS rectifier with built-in back telemetry for RFID and implantable biomedical applications,” IEEE Trans. on Circuits and Systems I, vol. 55, no. 10, pp. 3328-3334, Nov. 2008.

U. Jow and M. Ghovanloo, “Modeling and optimization of printed spiral coils in air, saline, and muscle tissue environments,” IEEE Trans. on Biomed. Circuits and Systems, IEEE Trans. on Biomed. Circuits and Systems, vol. 3, no. 5, pp. 339-347, Oct. 2009.

G. Bawa and M. Ghovanloo, “Analysis, design and implementation of a high efficiency fullwave rectifier in standard CMOS technology,” Analog Integrated Circuits and Signal Processing, vol. 60, pp. 71-81, Aug. 2009.

M. Yin and M. Ghovanloo, “Using pulse width modulation for wireless transmission of neural signals in multichannel neural recording systems,” IEEE Trans. on Neural Sys. Rehab. Eng., vol. 17, no. 4, pp. 354-363, Aug. 2009.

RECENT BOOK CHAPTERS AND INVITED REVIEWS

M. Ghovanloo, (July, 2008) “Integrated circuits for neural interfacing: Neural stimulation,” In VLSI Circuits for Biomedical Applications (K. Iniewski, ed.) Norwood, MA: Artech House, Inc.

M. Ghovanloo and G. Lazzi, (April 14, 2006) “Transcutaneous magnetic coupling of power and data,” In Wiley Encyclopedia of Biomedical Engineering (Metin Akay, ed.) Hoboken: John Wiley & Sons, Inc. [Online] http://www.mrw.interscience.wiley.com/ebe/articles/ebs1372/bibliography-fs.html

M. Ghovanloo and K. Najafi, (January 2007) “Towards a button-sized 1024-site wireless cortical microstimulating array,” in Handbook of Neural Engineering, Ed. M. Akay, Ch. 23, Hoboken: John Wiley & Sons, Inc. Wiley. D. RESEARCH SUPPORT

ONGOING RESEARCH SUPPORT

NSF 0953107 Ghovanloo (PI) 9/1/10 – 8/31/14 Brain-Tongue-Computer Interfacing The goal of this project is to explore the human factors associated with the use of tongue motion as a mean for manipulation and control. It will explore the optimal use of brain-tongue interconnect and develop novel technologies that tap into rich inherent capabilities of the human tongue, particularly for those with disabilities.


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Role: PI R01 NS062031-02 Oweiss (PI) 8/1/08 – 7/31/13 A Wireless, Multiscale, Distributed Interface to the Cortex, National Institutes of Health My role in this project involves development of a multi-carrier wireless link and its driving circuitry for a comprehensive scalable wireless neural recording system. Role: Co-Investigator R21 EB009437-01A1 Ghovanloo (PI) 9/1/09 – 8/31/13 EnerCage: A Scalable Array of Intelligent Wireless Sensor Modules to Energize and Track Miniature Inductively-Powered Devices in Small Freely Moving Animals The goal of this project is to develop a smart array of planar inductors that tile the bottom of a cage and wirelessly energize a batteryless headstage that allows wireless neural recording from a freely behaving animal for an unlimited period of time. Role: PI NSF 0824199 Ghovanloo (PI) 9/1/08 – 8/31/13 A Multichannel Wireless Implantable Neural Recording and Stimulating Systems for Hippocampal Electrophysiology Research on Memory The goal of this project is to develop a 32 channel wireless implantable neural recording and stimulating systems for a variety of neuroscience research on behaving animal subjects, performing memory tasks. Role: PI NSF 0828882 Ghovanloo (PI) 1/1/09 – 12/30/12 Wireless Tracking of Tongue Movements for Wheelchair Control and Computer Access The goal of this project is to explore the usability and assess the efficacy of the human tongue motion in accessing computers and controlling powered wheelchairs by able-bodied subjects. Role: PI COMPLETED RESEARCH SUPPORT

Ghovanloo (PI), ARRA: Development and Translational Assessment of A Tongue-Based Assistive Technology (RC1 EB010915-01), 9/30/09 - 8/31/11. This project involved further development of the Tongue Drive System and clinical evaluation of its usability and acceptability among potential end users (high-level SCI patients) in two major rehabilitation hospitals: Shepherd Center in Atlanta and Rehabilitation Institute of Chicago.

Ghovanloo (PI), Use of Tongue Movements as a Substitute for Arm/Hand Functions in Quadriplegics, Christopher and Dana Reeve Foundation, 9/1/07 – 8/31/9. This project involved development of the Tongue Drive system and performing human trials using the TDS prototype, and evaluating its efficacy in substituting arm and hand functions in accessing computers by emulating the mouse functions.

Ghovanloo (PI), Floating Gate Building Blocks for High Performance Operational Amplifier Circuits, GTronix, 7/1/08 – 12/31/08. This project involved using floating gate transistors with a tunable feature on Op-Amps to improve their performance by eliminating offset, increasing the input range, and improve linearity.

Ghovanloo, Tongue Drive: A Tongue Operated Magnetic Sensor Based Assistive Technology for People with Severe Disabilities, National Science Foundation, 8/1/07 – 7/31/08. This project involved design and development of a switched-based tongue-operated wireless assistive technology, called Tongue Drive, including its hardware, signal processing algorithms, and user interface software.

E. CURRENT TRAINEES

Uei-Ming Jow, Seung Bae Lee, Mehdi Kiani, Hyung Min Lee, Jeonghee Kim, Hangue Park, Abner Ayala-Acevedo, Jacob Block, Temiloluwa Olubanjo (Ph.D. Student, Georgia Tech, Atlanta, GA)

BIOGRAPHICAL SKETCH Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME

Butler, Andrew J. POSITION TITLE

Professor of Physical Therapy

eRA COMMONS USER NAME

Abutler01

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION DEGREE

(if applicable) MM/YY FIELD OF STUDY

Loras College, Dubuque, Iowa B.S. 05/87 Biology, Chemistry University of Iowa, Iowa City, Iowa Ph.D. 12/95 Motor Control University of Iowa, Iowa City, Iowa Post-Doc 09/96 Stroke and Aging Texas Woman’s University, Houston, Texas M.S. 12/98 Physical Therapy Heinrich-Heine University, Duesseldorf, Germany Emory University, Atlanta, Georgia

Post-Doc M.B.A.

07/01 05/09

Neuroimaging Bus. Administration

A. Personal Statement Andrew J. Butler, Ph.D.PT will be a Co-PI on this project with Dr. Ghovanloo at Georgia Tech. Dr. Butler is a neuroscientist and physical therapist with a special interest in motor control, neuro-rehabilitation, functional neuroimaging, and transcranial magnetic stimulation. He currently serves as the Director of the Neural Control of Movement laboratory at the Atlanta VA Medical Center (VAMC) and Director of the Clinical Neuroplasticity laboratory at Georgia State University. As such, Dr. Butler has developed an expertise in the modalities required to successfully accomplish the goals of the proposed study and will provide excellent feedback to Dr. Ghovanloo on clinical aspects of the project. As PI or co-investigator on several previous VA, university and NIH funded grants, Dr. Butler has laid the groundwork for the proposed research involving robotic devices for upper limb rehabilitation in stroke survivors. Dr. Butler and Dr. Ghovanloo have been in contact about rehabilitation projects since 2009 as Dr. Butler serves on the DSMB of Dr. Ghovanloo’s NIH clinic trial in which people with spinal cord injury used the TDS to control wheelchairs. Since that point, Dr. Butler and Dr. Ghovanloo have worked together on the development of a TDS controlled-robotic device for stroke rehabilitation. Dr. Butler has demonstrated a record of successful and productive line of research in an area of high relevance to the VA as reflected by his recent VA Industry Innovation Competition funding and NIH R21 awards. B. Positions and Honors Positions and Employment 2012- Professor Department of Physical Therapy, Georgia State University, Atlanta, GA 2002- Senior Research Investigator, Veterans Administration Medical Center (VAMC) 2007-2012 Associate Professor Department of Rehabilitation Medicine, Emory University School of

Medicine, Atlanta, GA. 2001-2007 Assistant Professor Department of Rehabilitation Medicine, Emory University School of

Medicine, Atlanta, GA. Other Experience and Professional Memberships 2000- American Heart Association 1996- American Physical Therapy Association: Neurology and Research Section member 1989-1990 International Brain Research Organization 1988-1989 Sigma Xi, The Scientific Research Honor Society 1999- Organization for Human Brain Mapping 1989- Society for Neuroscience Honors 2011 Woodruff Leadership Academy Fellow. Emory University. 2011. 2007 Appointed as Fellow to the Council of the American Heart and Stroke Association

2003 Outstanding Research Proposal, ERRIS Intensive workshop University of Virginia. 2002 Young Investigator Award, Center on Aging, University of Kansas Medical Center.

C. Selected peer-reviewed publications.

Most relevant to the current application (Selected from 30 peer-reviewed publications)

1. Butler AJ, Cazeaux, J, Fidler, A, Jansen, J, Lefkove, N. Gregg, M, Hall, C, Easley K, Shenvi N. and SL

Wolf. (2012) The Movement Imagery Questionnaire-Revised, Second Edition (MIQ-RS) is a Reliable and Valid Tool for Evaluating Motor Imagery Ability in Stroke Populations. Evidence Based Complementary and Alternative Medicine vol. 2012, doi:10.1155/2012/497289.

2. McGregor, K., Carpenter, H., Kleim, E., Sudhyadhom, A., White, K.D., Butler, A.J., Kleim, J.A., Crosson, B. (2012) Motor Map Reliability and Aging: A TMS/fMRI Study. Experimental Brain Research May;219(1):97-106. PMID: 22466408

3. Niyazov DM, Butler AJ, Kadah YM, Epstein CM, Hu XP. (2005): Functional magnetic resonance imaging and transcranial magnetic stimulation: Effects of motor imagery, movement and coil orientation. Clin Neurophysiol 116(7):1601-10. PMID: 15953559

4. Butler AJ, Wolf SL (2007) Putting the brain on the map: use of transcranial magnetic stimulation to assess and induce cortical plasticity of upper-extremity movement. Physical Therapy Journal. 87(6):719-36. PMID: 17429003

5. Qiu M, Darling WG, Morecraft RJ, Ni CC, Rajendra J, Butler AJ. White matter integrity is a stronger predictor of motor function than BOLD response in patients with stroke. Neurorehabil Neural Repair. 2011 Mar-Apr;25(3):275-84.

6. Darling WG, Wolf SL, Butler AJ. (2006) Variability of motor potentials evoked by transcranial magnetic stimulation depends on muscle activation. Exp Brain Res. 174(2):376-385. PMID: 16636787.

7. Wolf SL, Butler AJ, Campana GI, Parris TA, Struys DM, Weinstein SR. (2004) Intra-subject reliability of parameters contributing to maps generated by transcranial magnetic stimulation in able-bodied adults. Clinical Neurophysiol 115:1740-1747. PMID: 15261852

8. Park, SW, Butler AJ., V. Cavalheiro, and S L. Wolf (2004). Changes in serial optical topography with constraint-induced movement therapy in stroke: a case study. Neurorehabil Neural Repair 18:95-105. PMID: 15228805

9. Butler, AJ, Wolf, SL. Transcranial magnetic stimulation to assess cortical plasticity: A critical perspective for stroke rehabilitation (2003) J Rehabil Med; Suppl. 41:20-26. PMID: 12817653

10. Butler, AJ., Fink, G., Dohle, C, Wunderlich, G., Tellman, L., Seitz, R. J., Zilles, K., and H.-J. Freund (2004) The differential effects of kinesthetic and visual cueing for left and right hemispace on the neural mechanisms of reaching for remembered targets, Human Brain Mapping 21(3):165-177. PMID: 14755836

Additional recent publications of importance to the field (in chronological order)

1. Inman CS, James GA, Hamann S, Rajendra JK, Pagnoni G, Butler AJ. (2012) Altered resting-state effective connectivity of fronto-parietal motor control systems on the primary motor network following stroke. Neuroimage. 59(1):227-37. PMID:21839174

2. Zhang L, Butler AJ, Sun CK, Sahgal V, Wittenberg GF, Yue GH. (2008) Fractal dimension assessment of brain white matter structural complexity post stroke in relation to upper-extremity motor function. Brain Res. 1228:229-40.

3. Corneal SF, Butler AJ, Wolf SL. (2005): Intra- and intersubject reliability of abductor pollicis brevis muscle motor map characteristics with transcranial magnetic stimulation. Arch Phys Med Rehabil 86(8):1670-5. PMID: 16084825

4. Butler AJ, Page SJ. (2006) Mental practice with motor imagery; evidence for motor recovery, and cortical reorganization after stroke. Arch Phys Med Rehabil (12 Suppl 2):S2-11. PMID: 17140874

5. James, GA, Lu, Z-L, VanMeter, J. Sathian, K, Hu, X.P., Butler, A.J. (2009) Changes in resting-state effective connectivity in the motor network following rehabilitation of upper-extremity post-stroke

paresis. Topics in Stroke Rehabilitation. 16(4): 270-281. PMID: 19740732 6. Butler AJ, Kahn SE, Wolf SL, Weiss P. (2005): Finger extensor variability in TMS parameters among

chronic stroke patients. J Neuroengineering Rehabil 2(1):10. PMID: 15927075 7. Alberts J.L., Butler, AJ., S.L. Wolf. (2004) The effects of constraint-induced therapy on precision grip: a

preliminary study. Neurorehabil Neural Repair, 2004. 18(4): p. 250-8. PMID: 15537995

D. Research Support Ongoing Research Support

1I01RX- U.S. Department of Veterans Affairs, Butler (PI) 2/01/13-1/30/15 The aim of this research is to test the hypothesis there will be significant association between the fNIRS effective connectivity maps and the fMRI effective connectivity maps in people who suffered stroke greater than 12 months and in able-bodied controls Role: PI 1 VA Innovation Initiatives (VAi2) Industry Innovation Butler (PI) 10/01/11-9/30/13 The aim of this field test is to quantify the cost, quality and access of using robotic telemedicine to improve function in people who suffered stroke greater than 12 months. Role: PI 1 I01RX000421-01 Butler (PI) 11/01/10-10/31/12 Effects of sympathetic nerve activity on cortical excitability during a hand motor task The aim of the project is to determine predictors and examine the effects of physiologically heightened sympathetic nerve activity on motor cortex intracortical inhibition and facilitation when a hand muscle is relaxed and performing a precision task. Role: PI 1 U01NS056256. Winstein (PI) 9/1/08-8/31/13 Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (I-CARE) for Stroke Initiative The aim of this study is to compare the efficacy of a full-defined, evidence-based and theoretically defensible therapy program (ASAP) and an equivalent dose of usual and customary occupational therapy initiated within the earliest post-acute outpatient interval (1-3 months) for significant gains in the primary outcome of paretic upper extremity function 1 year after treatment. Role: Co-Investigator 1 T32HD055180-01A1. Gregor (PI) 5/1/08-4/30/13 Training Movement Scientists: Focus on Prosthetics and Orthotics This is a training grant to support Ph.D. students in Prosthetics and Orthotics at the Georgia Institute of Technology. Role: Co-Investigator 1 R01 NS059909-01A2 Cramer (PI) 5/1/09-11/30/13 Motor function after stroke This multi-site clinical study will explore the genetic determinants of natural recovery in stroke survivors. Role: Site-PI

Completed Research Support The Georgia Tech/Emory Center (GTEC) for the Engineering of Living Tissues and the Atlanta Clinical and Translational Science Institute (ACTSI). Traynelis (PI) 10/1/09-9/30/10 The Role of NMDA Receptors in Motor Learning in Humans Recovering from Stroke and Brain This study explores the mechanisms of motor learning in stroke survivors using TMS and behavioral testing. Role: Co-Investigator

The Robert W. Woodruff Health Sciences Center Fund. Braun-Wu (PI) 8/1/07-7/31/09 Neural Substrates of Mindfulness Meditation in Cancer Patients Undergoing Stem Cell/Autologous Bone Marrow Transplant The aim of this study is to assess the neural effects of mindfulness meditation in cancer survivors. This study explores the neural mechanisms of mindfulness mediation on cognition using fMRI Role: Co-Investigator

accelerating upper limb rehabilitation in stroke patients

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