Bruce T. Volpe

Robot-aided neurorehabilitation

Our goal is to apply robotics and automation technology to assist, enhance, quantify, and document neurorehabilitation. This paper reviews a clinical trial involving 20 stroke patients with a prototype robot-aided rehabilitation facility developed at the Massachusetts Institute of Technology, Cambridge, (MIT) and tested at Burke Rehabilitation Hospital, White Plains, NY. It also presents our approach to analyze kinematic data collected in the robot-aided assessment procedure. In particular, we present evidence 1) that robot-aided therapy does not have adverse effects, 2) that patients tolerate the procedure, and 3) that peripheral manipulation of the impaired limb may influence brain recovery. These results are based on standard clinical assessment procedures. We also present one approach using kinematic data in a robot-aided assessment procedure.

Robot-Assisted Therapy for Long-Term Upper-Limb Impairment after Stroke

BACKGROUND Effective rehabilitative therapies are needed for patients with long-term deficits after stroke. METHODS In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks. RESULTS At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported. CONCLUSIONS In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)

A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus.

In systemic lupus erythematosus, antibodies against double-stranded DNA are a major contributor to renal disease. We have previously demonstrated that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is a molecular mimic of double-stranded DNA. This sequence is also present in the extracellular domain of murine and human NMDA (N-methyl-d-aspartate) receptor subunits NR2a and NR2b. Here we show that the NR2 receptor is recognized by both murine and human anti-DNA antibodies. Moreover, anti-DNA antibodies with this cross-reactivity mediate apoptotic death of neurons in vivo and in vitro. Finally, we show that the cerebrospinal fluid of a patient with systemic lupus erythematosus contains these antibodies and also mediates neuronal death via an apoptotic pathway. These observations indicate that lupus antibodies cross-react with DNA and NMDA receptors, gain access to cerebrospinal fluid and may mediate non-thrombotic and non-vasculitic abnormalities of the central nervous system.

A novel approach to stroke rehabilitation: robot-aided sensorimotor stimulation.

Objective: In patients with stroke, the authors tested whether additional sensorimotor training of the paralyzed or paretic upper limb delivered by a robotic device enhanced motor outcome. Methods: Fifty-six patients with stroke and hemiparesis or hemiplegia received standard poststroke multidisciplinary rehabilitation, and were randomly assigned either to receive robotic training (at least 25 hours) or exposure to the robotic device without training. Outcomes were assessed by the same masked raters, before treatment began and at the end of treatment, with the upper extremity component of the Fugl-Meyer Motor Assessment, the Motor Status score, the Motor Power score, and Functional Independence Measurement. Result: The robot treatment and control group had comparable clinical characteristics, lesion size, and pretreatment impairment scores. By the end of treatment, the robot-trained group demonstrated improvement in motor outcome for the trained shoulder and elbow (Motor Power score, p < 0.001; Motor Status score, p < 0.01) that did not generalize to untrained wrist and hand. The robot-treated group also demonstrated significantly improved functional outcome (Functional Independence Measurement–Motor, p < 0.01). Conclusion: Robot-delivered quantitative and reproducible sensorimotor training enhanced the motor performance of the exercised shoulder and elbow. The robot-treated group also demonstrated improved functional outcome. When added to standard multidisciplinary rehabilitation, robotics provides novel therapeutic strategies that focus on impairment reduction and improved motor performance.

Rehabilitation Robotics: Performance-Based Progressive Robot-Assisted Therapy

In this paper we describe the novel concept of performance-based progressive robot therapy that uses speed, time, or EMG thresholds to initiate robot assistance. We pioneered the clinical application of robot-assisted therapy focusing on stroke—the largest cause of disability in the US. We have completed several clinical studies involving well over 200 stroke patients. Research to date has shown that repetitive task-specific, goal-directed, robot-assisted therapy is effective in reducing motor impairments in the affected arm after stroke. One research goal is to determine the optimal therapy tailored to each stroke patient that will maximize his/her recovery. A proposed method to achieve this goal is a novel performance-based impedance control algorithm, which is triggered via speed, time, or EMG. While it is too early to determine the effectiveness of the algorithm, therapists have already noted one very strong benefit, a significant reduction in arm tone.

The gut microbiota influences blood-brain barrier permeability in mice

The intestinal microbiota helps to maintain the integrity of the blood-brain barrier in fetal and adult mice. The Gut Microbiota and the Blood-Brain Barrier The blood-brain barrier is an important gateway that controls the passage of molecules and nutrients in and out of the brain. An intact blood-brain barrier is a crucial checkpoint for appropriate development and function of the brain. Braniste et al. now show that germ-free pregnant dams, devoid of maternal microbes, have offspring that show increased permeability of the blood-brain barrier. This elevated permeability was also observed in adult germ-free mice. However, fecal transplants from mice exposed to bacteria into adult germ-free mice reduced blood-brain barrier permeability, possibly through the regulation of tight junction proteins. These findings suggest that crosstalk between the gut microbiota and the brain, initiated during the intrauterine period, is perpetuated throughout life. Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota–BBB communication is initiated during gestation and propagated throughout life.

Robot-Aided Neurorehabilitation: A Robot for Wrist Rehabilitation

In 1991, a novel robot, MIT-MANUS, was introduced to study the potential that robots might assist in and quantify the neuro-rehabilitation of motor function. MIT-MANUS proved an excellent tool for shoulder and elbow rehabilitation in stroke patients, showing in clinical trials a reduction of impairment in movements confined to the exercised joints. This successful proof of principle as to additional targeted and intensive movement treatment prompted a test of robot training examining other limb segments. This paper focuses on a robot for wrist rehabilitation designed to provide three rotational degrees-of-freedom. The first clinical trial of the device will enroll 200 stroke survivors. Ultimately 160 stroke survivors will train with both the proximal shoulder and elbow MIT-MANUS robot, as well as with the novel distal wrist robot, in addition to 40 stroke survivor controls. So far 52 stroke patients have completed the robot training (ongoing protocol). Here, we report on the initial results on 36 of these volunteers. These results demonstrate that further improvement should be expected by adding additional training to other limb segments.

Rehabilitation robotics: pilot trial of a spatial extension for MIT-Manus

BackgroundPrevious results with the planar robot MIT-MANUS demonstrated positive benefits in trials with over 250 stroke patients. Consistent with motor learning, the positive effects did not generalize to other muscle groups or limb segments. Therefore we are designing a new class of robots to exercise other muscle groups or limb segments. This paper presents basic engineering aspects of a novel robotic module that extends our approach to anti-gravity movements out of the horizontal plane and a pilot study with 10 outpatients. Patients were trained during the initial six-weeks with the planar module (i.e., performance-based training limited to horizontal movements with gravity compensation). This training was followed by six-weeks of robotic therapy that focused on performing vertical arm movements against gravity. The 12-week protocol includes three one-hour robot therapy sessions per week (total 36 robot treatment sessions).ResultsPilot study demonstrated that the protocol was safe and well tolerated with no patient presenting any adverse effect. Consistent with our past experience with persons with chronic strokes, there was a statistically significant reduction in tone measurement from admission to discharge of performance-based planar robot therapy and we have not observed increases in muscle tone or spasticity during the anti-gravity training protocol. Pilot results showed also a reduction in shoulder-elbow impairment following planar horizontal training. Furthermore, it suggested an additional reduction in shoulder-elbow impairment following the anti-gravity training.ConclusionOur clinical experiments have focused on a fundamental question of whether task specific robotic training influences brain recovery. To date several studies demonstrate that in mature and damaged nervous systems, nurture indeed has an effect on nature. The improved recovery is most pronounced in the trained limb segments. We have now embarked on experiments that test whether we can continue to influence recovery, long after the acute insult, with a novel class of spatial robotic devices. This pilot results support the pursuit of further clinical trials to test efficacy and the pursuit of optimal therapy following brain injury.

Motions or muscles? Some behavioral factors underlying robotic assistance of motor recovery

Robotics and related technologies have begun to realize their promise to improve the delivery of rehabilitation therapy. However, the mechanism by which they enhance recovery remains unclear. Ultimately, recovery depends on biology, yet the details of the recovery process remain largely unknown; a deeper understanding is important to accelerate refinements of robotic therapy or suggest new approaches. Fortunately, robots provide an excellent instrument platform from which to study recovery at the behavioral level. This article reviews some initial insights about the process of upper-limb behavioral recovery that have emerged from our work. Evidence to date suggests that the form of therapy may be more important than its intensity: muscle strengthening offers no advantage over movement training. Passive movement is insufficient; active participation is required. Progressive training based on measures of movement coordination yields substantially improved outcomes. Together these results indicate that movement coordination rather than muscle activation may be the most appropriate focus for robotic therapy.

Robot training enhanced motor outcome in patients with stroke maintained over 3 years

Article abstract In an attempt to improve motor recovery of the upper limb after stroke, we added a robot (MIT-Manus) experience that provided additional goal-directed sensorimotor activity to standard rehabilitation treatments. The first trial produced a significant decrease in motor impairment in the upper limb for the treated group. In re-evaluating 12 of those 20 patients, nearly 3 years later, robot-trained patients showed further significant decreases in impairment measures of the affected limb. The groups were comparable at the start of the study.