News Article | October 26, 2016
The prosthetic exoskeleton sits bolt upright in a chair, looking as if a robot has stood up, walked away and left part of itself behind. Roughly three minutes later Kevin Oldt is strapped into the metal frame and ready to stand. He closes his eyes and takes a deep breath, stretching his arms away from his body like a high diver about to take a plunge. Except Oldt holds a crutch in each hand, and when it’s go time he pushes upward with his powerful arms. The exoskeleton’s four electric motors kick in with a low whir, straightening Oldt’s lower body as he steadies himself with the crutches. Once Oldt is standing, a physical therapist checks the exoskeleton’s settings on a digital screen connected to its back support, and gives him the okay. Oldt takes a few steps, looks up and says, “I’m learning how to walk all over again.” When a 49-year-old man says that, one assumes he has been through something terrible. For Oldt that was a snowmobile accident more than 14 years ago that injured his spine and left him in a wheelchair. After more than a decade of physical therapy and hard work he is back on his feet several times a week, with the help of a robotic medical exoskeleton. The device offers Oldt the support his legs no longer provide. “It almost feels like I am walking, with a little bit of help from the motors,” he says as he strides across the room, the exoskeleton clicking and purring. His steps are surprisingly fluid, given that they are a combination of the machine’s programming and the remaining strength in his legs. The exoskeleton’s software calibrates how much assistance Oldt needs by sensing how much force he generates as he lifts his foot off the ground and pushes forward. “I’m always trying to use my mind to initiate my leg to go forward,” he says, his forehead moist from the effort it takes to work with the device. “I look down because I can’t feel my feet, but I can at least see where they’re going.” That, he says, helps reconstruct the missing connection between his mind and his body. Mechanical exoskeletons have been in development for decades, but for most of that time the focus was on creating hydraulic-powered suits that soldiers could wear to carry heavy loads. These exist mostly in the form of prototypes as the U.S. government’s Defense Advanced Research Projects Agency (DARPA) and contractors try to figure out how to make them practical for military operations, in terms of cost and logistics. But Oldt’s exoskeleton—the Ekso GT, made by Ekso Bionics—and a variety of similar products from other companies have had much more impact in recent years on medical rehabilitation for spinal cord injury patients. In April the GT became the first exoskeleton approved by the U.S. Food and Drug Administration for use with stroke patients as well as patients suffering injuries as far up the spine as the cervical region (just below the neck), thanks to the device’s tall back plate. In March the FDA granted Parker Hannifin Corp. approval to sell its Indego robotic exoskeletons both to hospitals and directly to patients. Argo Medical Technologies—makers of the ReWalk exoskeleton—is reportedly the only other company that can sell directly to patients. In December 2015 the U.S. Department of Veterans Affairs began covering the cost of the ReWalk exoskeleton for eligible paralyzed veterans. Standard care is very hands-on—two or three physical therapists often support and guide each step a patient takes. Often one of those therapists must manipulate the patient’s legs if the patient does not have the strength to move. That technique can be effective over time in helping patients regain some strength and mobility in their lower bodies, but measuring a patient’s progress is difficult and the work is very strenuous for therapists and patients alike. Another recent option has been assistive standing devices such as Hocoma’s Lokomat, which places a patient in an exoskeleton suspended by cables over a treadmill. Patients walk on the treadmill with the Lokomat exoskeleton’s help but do not have the untethered freedom that freestanding exoskeletons provide. Exoskeletons such as the one Oldt uses require a single therapist. They can be tuned to provide varying levels of support to meet different patients’ needs, and they measure a patient’s progress more precisely. This leads to more effective therapy sessions, says Tom Looby, Ekso Bionics’ president and CEO. During a patient’s first rehabilitation session a team of physical therapists working without an exoskeleton can normally get that person to take eight “quality” steps, meaning the patient is not trying to contort his or her body to compensate for a lack of strength or balance, Looby says. He claims the same patient in an Ekso GT can take 400 quality steps during that first session. Robotic “gait trainer” exoskeletons like these have become increasingly popular as a rehabilitation option, says Liza McHugh, a physical therapist at Kennedy Krieger Institute in Baltimore. The GT enables individuals with paralysis to have long therapy sessions during which they are able step in a way that “we believe is good for restoring the nervous system after spinal cord injury,” McHugh says, adding that Kennedy Krieger has treated dozens of patients with the device since it arrived in August 2015. The latest exoskeletons allow therapists to measure and document statistics including the length and number of steps, how much power the suit’s motors are using to assist a patient, and how the patients shift their weight as they step. This allows therapists to measure progress more precisely than in the past, McHugh says, explaining that physical therapists have traditionally judged progress based largely on subjective observations. But exoskeletons still have several drawbacks. In addition to being expensive—one can cost $70,000 to $150,000—and requiring a lot of special training for therapists, they are designed to be used only on surfaces that are solid, dry and level, McHugh says. A patient’s ability to walk in the clinic might not translate to wet, sandy or uneven terrain. The Ekso GT is adjustable for heights only between 1.5 and 1.8 meters, so “we are unable to use it with our pediatric population,” she adds. There is also a lack of concrete evidence that exoskeletons are more successful than conventional physical therapy at rehabilitating patients. Ekso is sponsoring a study that compares the progress of 160 spinal cord injury patients undergoing rehabilitation with the GT, with hands-on therapy and with no therapy, over 12 weeks. In August the company enrolled its first patient in its WISE, or “walking improvement for spinal cord injury with exoskeletons,” clinical trial. “Generally, all things being equal, those using exoskeletons are able to get more therapy—do more work—in a shorter amount of time,” says Dylan Edwards, WISE’s lead investigator and director of the Burke Medical Research Institute’s Laboratory for Non-Invasive Brain Stimulation and Human Motor Control in White Plains, N.Y. Edwards and his colleagues plan to evaluate whether robotic gait training can improve a patient’s walking speed—progress that would indicate that the brain, spinal cord, peripheral nerves and muscles are beginning to work together more effectively. The researchers will also evaluate patient pain and muscle spasticity, as well as economic factors such as number of physical therapists and staff required during training. “I’m trying to build an argument that we should embrace this technology in the physical therapy profession,” Edwards says. Kevin Oldt is perhaps the best endorsement for exoskeletons thus far. He has been helping promote its technology for the past several years through demonstrations for the press and public. He says he relishes the relative freedom that wearing the Ekso GT gives him, even for a brief amount of time. And he claims that consistent use of the exoskeleton three days per week for the past few years has helped him regain some strength and motor control in his legs. Oldt acknowledges that the technology needed to help him walk again with minimal or no exoskeleton help is years away. Still, his experience has given him hope. “Sixteen years ago there was nothing,” he says. “This was just a comic book design—reading about Iron Man. Now it’s reality.”
Kamikawa Y.F.,Burke Medical Research Institute |
Kamikawa Y.F.,New York Medical College |
Donohoe M.E.,Burke Medical Research Institute |
Donohoe M.E.,New York Medical College
Epigenetics | Year: 2014
Jmjd3 is required for cellular differentiation and senescence, and inhibits the induction of pluripotent stem cells by demethylating histone 3 lysine 27 trimethylation (H3K27me3). Although recent studies reveal crucial biological roles for Jmjd3, it is unclear how its demethylase activity is controlled. Here, we show that nuclear localization of Jmjd3 is required for effective demethylation of H3K27me3. Our subcellular localization analysis of Jmjd3 shows that the N-terminal region of the protein is responsible for its nuclear placement, whereas the C-terminal region harboring the catalytic Jumonji C (JmjC) domain cannot situate into the nucleus. We identify two classical nuclear localization signals (cNLSs) in the N-terminal domain of Jmjd3. Forced nuclear emplacement of the catalytic domain of Jmjd3 by fusion with a heterologous cNLS significantly enhances its H3K27me3 demethylation activity. A dynamic nucleocytoplasmic shuttling of endogenous Jmjd3 occurs in mouse embryonic fibroblasts. Jmjd3 is localized both into the cytoplasm and the nucleus, and its nuclear export is dependent on Exportin-1, as treatment with leptomycin B triggers nuclear accumulation of Jmjd3. These results suggest that the subcellular localization of Jmjd3 is dynamically regulated and has pivotal roles for H3K27me3 status. © 2014 Landes Bioscience.
Hollis E.R.,Burke Medical Research Institute |
Hollis E.R.,New York Medical College
Neurotherapeutics | Year: 2016
…once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably.Santiago Ramón y Cajal Cajal’s neurotropic theory postulates that the complexity of the nervous system arises from the collaboration of neurotropic signals from neuronal and non-neuronal cells and that once development has ended, a paucity of neurotropic signals means that the pathways of the central nervous system are “fixed, ended, immutable”. While the capacity for regeneration and plasticity of the central nervous system may not be quite as paltry as Cajal proposed, regeneration is severely limited in scope as there is no spontaneous regeneration of long-distance projections in mammals and therefore limited opportunity for functional recovery following spinal cord injury. It is not a far stretch from Cajal to hypothesize that reappropriation of the neurotropic programs of development may be an appropriate strategy for reconstitution of injured circuits. It has become clear, however, that a significant number of the molecular cues governing circuit development become re-active after injury and many assume roles that paradoxically obstruct the functional re-wiring of severed neural connections. Therefore, the problem to address is how individual neural circuits respond to specific molecular cues following injury, and what strategies will be necessary for instigating functional repair or remodeling of the injured spinal cord. © 2015, The American Society for Experimental NeuroTherapeutics, Inc.
Goldfine A.M.,Burke Medical Research Institute |
Goldfine A.M.,New York Medical College |
Schiff N.D.,New York Medical College
Current Opinion in Neurology | Year: 2011
Purpose of Review: Standard neurorehabilitation approaches have limited impact on motor recovery in patients with severe brain injuries. Consideration of the contributions of impaired arousal offers a novel approach to understand and enhance recovery. Recent Findings: Animal and human neuroimaging studies are elucidating the neuroanatomical bases of arousal and of arousal regulation, the process by which the cerebrum mobilizes resources. Studies of patients with disorders of consciousness have revealed that recovery of these processes is associated with marked improvements in motor performance. Recent studies have also demonstrated that patients with less severe brain injuries also have impaired arousal, manifesting as diminished sustained attention, fatigue, and apathy. In these less severely injured patients, it is difficult to connect disorders of arousal with motor recovery because of a lack of measures of arousal that are independent of motor function. Summary: Arousal impairment is common after brain injury and likely plays a significant role in recovery of motor function. A more detailed understanding of this connection will help to develop new therapeutic strategies applicable for a wide range of patients. This requires new tools that continuously and objectively measure arousal in patients with brain injury, to correlate with detailed measures of motor performance and recovery. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Zhong J.,Burke Medical Research Institute |
Zhong J.,Cornell University |
Zou H.,Mount Sinai School of Medicine
Current Opinion in Neurobiology | Year: 2014
Neuronal competence to re-extend axons and a permissive environment that allows growth cone navigation are two major determinants for successful axon regeneration. Here, we review the roles of bone morphogenetic protein (BMP) signaling in mediating both neuronal and glial injury responses after CNS injury. BMPs can activate a pro-regenerative transcription program in neurons through Smad-mediated canonical pathway, or act locally on cytoskeleton assembly at distal axons via non-canonical pathways. Emerging evidence implicates retrograde BMP signalosomes in connecting the cytoskeletal and nuclear responses. In addition, BMP/Smad signaling modulates neurotrophin-mediated axonal outgrowth, and interacts with the epigenetic machinery to initiate epigenetic reprogramming for axon regeneration. Besides their influences on neurons, BMPs also regulate astrogliosis, inflammatory processes, and neural progenitor cell differentiation at the injury site, all of which can either positively or negatively modify the injury microenvironment. Lastly, an increasing number of BMP signaling partners, sensitizers, and downstream effectors collectively fine-tune the signaling intensity and spatiotemporal dynamics of BMP activity in an integrated signaling network during axon regeneration. © 2014 Elsevier Ltd.
Magrane J.,Cornell University |
Sahawneh M.A.,Burke Medical Research Institute |
Przedborski S.,Columbia University |
Estevez A.G.,University of Central Florida |
Manfredi G.,Cornell University
Journal of Neuroscience | Year: 2012
Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease. MutantSOD1has pleiotropic toxic effects on motor neurons,amongwhich mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise. Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired mitochondrial dynamics in motor neurons may be involved in pathogenesis.Weaddressed this hypothesis by live imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing mutant or wild-type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential. Furthermore, mislocalization of mitochondria at synapses among motor neurons, in vitro, correlates with abnormal synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron mitochondria, since they are absent in wild-type SOD1 motor neurons, they do not involve other organelles, and they are not found in cortical neurons. Together, these results suggest that impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS. ©2012 the authors.
Karuppagounder S.S.,Burke Medical Research Institute |
Karuppagounder S.S.,Cornell College |
Ratan R.R.,Burke Medical Research Institute |
Ratan R.R.,Cornell College
Journal of Cerebral Blood Flow and Metabolism | Year: 2012
A major challenge in developing stroke therapeutics that augment adaptive pathways to stress has been to identify targets that can activate compensatory programs without inducing or adding to the stress of injury. In this regard, hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) are central gatekeepers of posttranscriptional and transcriptional adaptation to hypoxia, oxidative stress, and excitotoxicity. Indeed, some of the known salutary effects of putative antioxidant iron chelators in ischemic and hemorrhagic stroke may derive from their abilities to inhibit this family of iron, 2-oxoglutarate, and oxygen-dependent enzymes. Evidence from a number of laboratories supports the notion that HIF PHD inhibition can improve histological and functional outcomes in ischemic and hemorrhagic stroke models. In this review, we discuss this evidence and highlight important gaps in our understanding that render HIF PHD inhibition a promising but not yet preclinically validated target for protection and repair after stroke. © 2012 ISCBFM All rights reserved.
Cave J.W.,Cornell College |
Cave J.W.,Burke Medical Research Institute
Developmental Biology | Year: 2011
The Notch signaling pathway regulates metazoan development, in part, by directly controlling the transcription of target genes. For a given cellular context, however, only subsets of the known target genes are transcribed when the pathway is activated. Thus, there are context-dependent mechanisms that selectively maintain repression of target gene transcription when the Notch pathway is activated. This review focuses on molecular mechanisms that have been recently reported to mediate selective repression of Notch pathway target gene transcription. These mechanisms are essential for generating the complex spatial and temporal expression patterns of Notch target genes during development. © 2011 Elsevier Inc.
Butler K.V.,University of Illinois at Chicago |
Kalin J.,University of Illinois at Chicago |
Brochier C.,Burke Medical Research Institute |
Vistoli G.,University of Milan |
And 2 more authors.
Journal of the American Chemical Society | Year: 2010
Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the HDAC6 isozyme compared to other inhibitors. These inhibitors can be assembled in a few synthetic steps, and thus are readily scaled up for in vivo studies. An optimized compound from this series, designated Tubastatin A, was tested in primary cortical neuron cultures in which it was found to induce elevated levels of acetylated α-tubulin, but not histone, consistent with its HDAC6 selectivity. Tubastatin A also conferred dose-dependent protection in primary cortical neuron cultures against glutathione depletion-induced oxidative stress. Importantly, when given alone at all concentrations tested, this hydroxamate-containing HDAC6-selective compound displayed no neuronal toxicity, thus, forecasting the potential application of this agent and its analogues to neurodegenerative conditions. © 2010 American Chemical Society.
News Article | March 16, 2016
Elite ski jumpers rely on extreme balance and power to descend the steep slopes that allow them to reach up to 100 kilometres per hour. But the US Ski and Snowboard Association (USSA) is seeking to give its elite athletes an edge by training a different muscle: the mind. Working with Halo Neuroscience in San Francisco, California, the sports group is testing whether stimulating the brain with electricity can improve the performance of ski jumpers by making it easier for them to hone their skills. Other research suggests that targeted brain stimulation can reduce an athlete’s ability to perceive fatigue1. Such technologies could aid recovery from injury or let athletes try 'brain doping' to gain a competitive advantage. Yet many scientists question whether brain stimulation is as effective as its proponents claim, pointing out that studies have looked at only small groups of people. “They’re cool findings, but who knows what they mean,” says cognitive psychologist Jared Horvath at the University of Melbourne in Australia. The USSA is working with Halo to judge the efficacy of a device that delivers electricity to the motor cortex, an area of the brain that controls physical skills. The company claims that the stimulation helps the brain to build new connections as it learns a skill. It tested its device in an unpublished study of seven elite Nordic ski jumpers, including Olympic athletes. Four times per week, for two weeks, the skiers practised jumping onto an unstable platform. Four athletes received transcranial direct-current stimulation (tDCS) as they trained; the other three received a sham procedure. The stimulation ultimately improved the athletes' jumping force by 70% and their coordination by 80%, compared with the sham group, Halo announced in February. Troy Taylor, high-performance director for the USSA, is encouraged by the results — but concedes that they are preliminary. Another study, presented on 7 March at the Biomedical Basis of Elite Performance meeting in Nottingham, UK, suggests that tDCS may reduce the perception of fatigue. Sports scientist Lex Mauger of the University of Kent in Canterbury, UK, and his colleagues found that stimulating the motor-cortex region that controls leg function allows cyclists to pedal longer without feeling tired. The researchers stimulated the brains of 12 untrained volunteers before directing the athletes to pedal stationary bicycles until they were exhausted. Every minute, they asked the cyclists to rate their level of effort. Volunteers who received tDCS were able to pedal two minutes longer, on average, than were those who were given a sham treatment. They also rated themselves as less tired. But there was no difference in heart rate or the lactate level in the muscles between the treatment and control groups. This suggests that changes in brain perception, rather than muscle pain or other body feedback, drove the improved performance. Alexandre Okano, a biological engineer at Federal University of Rio Grande do Norte in Brazil, found similar increases in cyclists’ performance when he stimulated the brain’s temporal cortex, which is involved in body awareness and in automatic functions such as breathing2. This suggests that the temporal and motor cortices are connected in ways that are not understood, or that tDCS does not target locations in the brain precisely, Okano says. These results support the notion that the brain manages exertion by collating feedback from the body and then slowing muscles to prevent fatigue, says Dylan Edwards, a neurophysiologist at Burke Medical Research Institute in White Plains, New York3. “Even when you think you’re exercising as hard as you can, there is always some reserve of ability,” he says. But Horvath cautions that little is known about the long-term effects of stimulating the brain. And others are sceptical of the technique’s potential to increase performance. Vincent Walsh, a neuroscientist at University College London, notes that the methods used in tDCS studies often differ between research groups — and might not always be optimized. For instance, the fairly intense amount of electricity that Mauger's team used has been shown to sometimes have complex and unintended effects on the brain's activity4. Replicating such experiments is difficult because of variations in how people respond to brain stimulation. Some people do not respond at all; others might respond only when stimulated in a certain way. And even an individual’s response can differ from day to day. Edwards says that it is important to map these differences if tDCS is to be used therapeutically or for other purposes. “We’re moving toward customized prescription of brain stimulation,” he says. Nonetheless, the use of tDCS in sports is only likely to increase. Stimulating the motor cortex, for instance, seems to increase dexterity, so videogamers have been quick to take up the technique. And it is increasingly easy to acquire stimulation devices; Halo has begun to market its equipment for the express purpose of increasing athletic performance. Taylor compares the use of brain stimulation by athletes to eating carbohydrates ahead of an athletic event, in the hopes of boosting endurance. “It piggybacks on the ability to learn,” he says. “It's not introducing something artificial into the body.” But Edwards worries that the availability of tDCS devices will tempt athletes to try “brain doping”, in part because there is no way to detect its use. “If this is real,” he says, “then absolutely the Olympics should be concerned about it.”