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Chronic sensorimotor impairment of the upper extremity is prevalent in more than 6 million stroke survivors in the U.S. (Go, et al., 2013), especially in the distal upper extremity (Trombly, 1989). In our studies of the impairment mechanisms of hand motor control after stroke, e.g., (Cruz, et al., 2005; Kamper, et al., 2006; Triandafilou, et al., 2011), we have been struck by two phenomena which arise following the original brain lesion: i) involuntary hyperexcitability of the motor units in certain muscles and ii) the difficulty in producing and controlling voluntary muscle activation. We propose to directly treat both of these phenomena simultaneously in order to improve motor control of the hand and arm.

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We will reduce motoneuronal hyperexcitability through administration of an anti-serotonergic drug which does not increase weakness, and we will guide the generation of proper muscle activation with a custom device and computer program. We believe that our multimodality treatment approach is innovative in that we combine the use of pharmacological agents with individualized movement therapy in a manner that can be used with patients with poor initial motor control. In separate preliminary studies, we were able to show that a single dose of the agent cyproheptadine could reduce unwanted muscle excitation without decreasing voluntary strength (Seo, et al., 2011) and that active motor training, assisted by an electromyographically (EMG) controlled actuated glove, could lead to statistically significant improvement both in measures of impairment and task performance. In this study, we will combine these approaches to create a novel treatment paradigm for improving motor control of the distal upper extremity after stroke. These techniques are amenable to rapid and widespread integration into the clinic for the arm and hand, and could be applied to the lower extremity as well.

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Over the course of the study, subjects will participate in a therapy regimen involving either active practice of hand and arm movements or passive stretching of the digits, while concurrently receiving either cyproheptadine or placebo. Thus, the study has two experimental factors: Drug (cyproheptadine hydrochloride/placebo) and rehabilitative movement training (active/passive). Subjects will be randomly divided into four groups, stratified by initial FMA score, consisting of the four combinations of Drug and Training:

1. cyproheptadine with active movement training
2. placebo with active movement training
3. cyproheptadine with passive stretching
4. placebo with passive stretching.

The therapists, other research personnel (including the PI), and the subjects will all be blinded as to which agent each subject is taking.  The sensorimotor therapy, consisting of 18 one-hour sessions held over 6 weeks, will focus on the impaired upper extremity, particularly the hand. 

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A Voice and EMG-driven Actuated hand orthosis, the VAEDA glove, will be worn by all subjects during these therapy sessions. The VAEDA glove contains cables (Spectra kite wire) which run across the back of the digits in order to provide extension and resist flexion (Fig 3). Forces are transmitted through the cables from a DC micromotor (1724, Faulhaber, Inc), located remotely, to the digits. The single actuator controls torque or displacement in the cable. Tension in the cable is measured directly with a custom tension sensor; cable displacement is estimated from the motor encoder (IE2-16, Faulhaber, Inc.). The cable travels from the actuator through a Bowden cable to a forearm splint, at which point it is attached to the 5 cables running to the digits. Along the digits, the cables traverse through custom plastic blocks, which serve both to guide the cable and to prevent joint hyperextension. The weight of the glove with the cables and cable guides is 2.2 N and the forearm splint is an additional 1.5 N, thereby making the total weight on the arm less than 4 N.

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The alternate session will consist of directly training muscle activation patterns by playing a computer game. A cursor, or ¡°game piece¡± will be controlled by the patterns recorded from surface EMG electrodes (Bagnoli, Delsys, Inc.) positioned over a subset of the following muscles: FDS, EDC, thenar eminence, hypothenar eminence, first dorsal interosseous, flexor carpi radialis (FCR), and extensor carpi ulnaris (ECU). We will use principal component analysis (PCA) to determine basis vectors which can be used to explore the activation workspace defined by these muscle groups for each subject. Actions on the computer screen are associated with activation of specific principle components (PCs) (Fig. 5). For example, activation levels of the first and second PCs can correspond to the x- and y-coordinates for the user¡¯s game piece. Movement of the game piece can then be used to spell specific words (Fig. 5b), reveal a hidden picture (Fig. 5c), navigate a maze, or play a version of Asteroids. As the user progresses, the PCs controlling the game piece will be periodically cycled, such that the third and fourth PCs control the x- and ycoordinates, for example. Desired PCs can also be explicitly created from the graphical user interface, such as to have the user focus on activating individual muscles. If simultaneous control of 2 PCs proves too difficult, one-dimensional versions of the letter and hidden picture games can be used. Again, half of the subjects in this active training group will be concurrently taking cyproheptadine while the other half will be taking a placebo.

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We recognize that exposure to a novel device such as the VAEDA glove and regular visits to the Coleman Hand Rehabilitation Laboratory could have a placebo effect by focusing attention on the impaired upper extremity. Thus, the comparison group, comprised of the other half of the subjects, will have similar exposure to the laboratory and device, but will not undergo active movement therapy. Instead, they will wear the VAEDA glove while it moves their digits from a flexed posture to full extension and then allows them to return to the flexed resting posture at a rate of roughly 15 cycles per minute. We have found this passive, cyclical stretching to have a transient impact on motor control, although the effects did not seem to carry over from one day to the next in individuals with chronic impairment (Triandafilou, et al., 2014). For each session, subjects will receive two 20-minute stretching sessions, with 10 minutes of rest in between. Half of this group will concurrently be taking cyproheptadine while the other half will be taking a placebo.