The present prognosis for the recovery of voluntary control of movement in patients diagnosed as motor complete is generally poor. Herein we introduce a novel and noninvasive stimulation strategy of painless transcutaneous electrical enabling motor control and a pharmacological enabling motor control strategy to neuromodulate the physiological state of the spinal cord. This neuromodulation enabled the spinal locomotor networks of individuals with motor complete paralysis for 2-6 years American Spinal Cord Injury Association Impairment Scale (AIS) to be re-engaged and trained. We showed that locomotor-like stepping could be induced without voluntary effort within a single test session using electrical stimulation and training. We also observed significant facilitation of voluntary influence on the stepping movements in the presence of stimulation over a 4-week period in each subject. Using these strategies we transformed brain-spinal neuronal networks from a dormant to a functional state sufficiently to enable recovery of voluntary movement in five out of five subjects. Pharmacological intervention combined with stimulation and training resulted in further improvement in voluntary motor control of stepping-like movements in all subjects. We also observed on-command selective activation of the gastrocnemius and soleus muscles when attempting to plantarflex. At the end of 18 weeks of weekly interventions the mean changes in the amplitude of voluntarily controlled movement without stimulation was as high as occurred when combined with electrical stimulation. Additionally, spinally evoked motor potentials were readily modulated in the presence of voluntary effort, providing electrophysiological evidence of the re-establishment of functional connectivity among neural networks between the brain and the spinal cord.

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The spinal cord of vertebrate animals is comprised of intrinsic circuits that are capable of sensing the environment and generating complex motor behaviors. There are two major perspectives for understanding the biology of this complicated structure. The first approaches the spinal cord from the point of view of function and is based on classic and ongoing research in electrophysiology, adult behavior, and spinal cord injury. The second view considers the spinal cord from a developmental perspective and is founded mostly on gene expression and gain-of-function and loss-of-function genetic experiments. Together these studies have uncovered functional classes of neurons and their lineage relationships. In this review, we summarize our knowledge of developmental classes, with an eye toward understanding the functional roles of each group.

The amyloid beta-protein precursor gives rise to the amyloid beta-protein, the principal constituent of senile plaques and a cytotoxic fragment involved in the pathogenesis of Alzheimer disease. Here we show that amyloid beta-protein precursor was proteolytically cleaved by caspases in the C terminus to generate a second unrelated peptide, called C31. The resultant C31 peptide was a potent inducer of apoptosis. Both caspase-cleaved amyloid beta-protein precursor and activated caspase-9 were present in brains of Alzheimer disease patients but not in control brains. These findings indicate the possibility that caspase cleavage of amyloid beta-protein precursor with the generation of C31 may be involved in the neuronal death associated with Alzheimer disease.

We asked whether coordinated voluntary movement of the lower limbs could be regained in an individual having been completely paralyzed (>4 year) and completely absent of vision (>15 year) using two novel strategies—transcutaneous electrical spinal cord stimulation at selected sites over the spine as well as pharmacological neuromodulation by buspirone. We also asked whether these neuromodulatory strategies could facilitate stepping assisted by an exoskeleton (EKSO, EKSO Bionics, CA) that is designed so that the subject can voluntarily complement the work being performed by the exoskeleton. We found that spinal cord stimulation and drug enhanced the level of effort that the subject could generate while stepping in the exoskeleton. In addition, stimulation improved the coordination patterns of the lower limb muscles resulting in a more continuous, smooth stepping motion in the exoskeleton along with changes in autonomic functions including cardiovascular and thermoregulation. Based on these data from this case study it appears that there is considerable potential for positive synergistic effects after complete paralysis by combining the over-ground step training in an exoskeleton, combined with transcutaneous electrical spinal cord stimulation either without or with pharmacological modulation.

Amyloid β-peptide (Aβ) is postulated to play a central role in the pathogenesis of Alzheimer's disease. We recently proposed a pathway of Aβ-induced toxicity that is APP dependent and involves the facilitation of APP complex formation by Aβ. The APP-dependent component requires cleavage of APP at position 664 in the cytoplasmic domain, presumably by caspases or caspase-like proteases, with release of a potentially cytotoxic C31 peptide. In this study we show that Aβ interacted directly and specifically with membrane-bound APP to facilitate APP homo-oligomerization. Using chimeric APP molecules, this interaction was shown to take place between Aβ and its homologous sequence on APP. Consistent with this finding, we demonstrated that Aβ also facilitated the oligomerization of β-secretase cleaved APP C-terminal fragment (C99). We found that the YENPTY domain in the APP cytoplasmic tail and contained within C31 is critical for this cell death pathway. Deletion or alanine-scanning mutagenesis through this domain significantly attenuated cell death apparently without affecting either APP dimerization or cleavage at position 664. This indicated that sequences within C31 are required after its release from APP. As the YENPTY domain has been shown to interact with a number of cytosolic adaptor molecules, it is possible that the interaction of APP, especially dimeric forms of APP, with these molecules contribute to cell death. Keywords C31; YENPTY region; APP homo-oligomerizationThe accumulation and deposition of amyloid β-protein (Aβ) within senile plaques in brain is one of the histopathological hallmarks of Alzheimer's disease (AD). Aβ is derived by sequential proteolysis from the amyloid precursor protein (APP). Substantial data suggest that Aβ plays a critical role in initiating the cascade of events that results in AD (reviewed in ref 1). In addition to senile plaques and neurofibrillary tangles, synapse loss and neuronal death are consistently observed, and these latter changes have been hypothesized to be due to the increased levels of Aβ in brain (2). Although the traditional view suggests that Aβ assembled into insoluble and fibrillar forms is cytotoxic, increasing evidence indicates that soluble prefibrillar oligomeric Aβ species are equally, if not more, detrimental to neuronal function in vitro and in vivo (2-6). Many varied mechanisms have been proposed for Aβ-induced toxicity, but no consensus has emerged to account for its deleterious effects (7).APP is a type I membrane protein whose function has not been clearly defined. It belongs to a gene family that includes its mammalian paralogs APLP1 and APLP2 (amyloid precursor- NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript like proteins 1, 2) (8-10). APLP1 and APLP2 are also type I membrane proteins and share sequence similarity with APP in the N and C termini, but do not contain the Aβ domain.APP may function as a cell surface receptor and mediate the transduction of extracellular signals into the cell, although a definitive ...

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Background Paralysis of the upper-limbs from spinal cord injury results in an enormous loss of independence in an individual’s daily life. Meaningful improvement in hand function is rare after one year of tetraparesis. Therapeutic developments that result in even modest gains in hand volitional function will significantly impact the quality of life for patients afflicted with high cervical injury. The ability to neuromodulate the lumbosacral spinal circuitry via epidural stimulation in regaining postural function and volitional control of the legs has been recently shown. A key question is whether a similar neuromodulatory strategy can be used to improve volitional motor control of the upper-limbs, i.e., performance of motor tasks considered to be less “automatic” than posture and locomotion. In this study, the effects of cervical epidural stimulation on hand function are characterized in subjects with chronic cervical cord injury. Objective Herein we show that epidural stimulation can be applied to the chronic injured human cervical spinal cord to promote volitional hand function. Methods and results Two subjects implanted with an cervical epidural electrode array demonstrated improved hand strength (approximately three-fold) and volitional hand control in the presence of epidural stimulation. Conclusions The present data are sufficient to suggest that hand motor function in individuals with chronic tetraplegia can be improved with cervical cord neuromodulation and thus should be comprehensively explored as a possible clinical intervention.