Dataset Information

Noninvasive Reactivation of Motor Descending Control after Paralysis.

ABSTRACT: 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.

SUBMITTER: Gerasimenko YP

PROVIDER: S-EPMC4677519 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Noninvasive Reactivation of Motor Descending Control after Paralysis.

Gerasimenko Yury P YP Lu Daniel C DC Modaber Morteza M Zdunowski Sharon S Gad Parag P Sayenko Dimitry G DG Morikawa Erika E Haakana Piia P Ferguson Adam R AR Roy Roland R RR Edgerton V Reggie VR

Journal of neurotrauma 20150820 24

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 S ...[more]

PMID: 26077679

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Project description:The formation of mature spinal motor circuits is dependent on both activity-dependent and independent mechanisms during postnatal development. During this time, reorganization and refinement of spinal sensorimotor circuits occurs as supraspinal projections are integrated. However, specific features of postnatal spinal circuit development remain poorly understood. This study provides the first detailed characterization of rat spinal sensorimotor circuit development in the presence and absence of descending systems. We show that the development of proprioceptive afferent input to motoneurons (MNs) and Renshaw cells (RCs) is disrupted by thoracic spinal cord transection at postnatal day 5 (P5TX). P5TX also led to malformation of GABApre neuron axo-axonic contacts on Ia afferents and of the recurrent inhibitory circuit between MNs and RCs. Using a novel in situ perfused preparation for studying motor control, we show that malformation of these spinal circuits leads to hyperexcitability of the monosynaptic reflex. Our results demonstrate that removing descending input severely disrupts the development of spinal circuits and identifies key mechanisms contributing to motor dysfunction in conditions such as cerebral palsy and spinal cord injury.SIGNIFICANCE STATEMENT Acquisition of mature behavior during postnatal development correlates with the arrival and maturation of supraspinal projections to the spinal cord. However, we know little about the role that descending systems play in the maturation of spinal circuits. Here, we characterize postnatal development of key spinal microcircuits in the presence and absence of descending systems. We show that formation of these circuits is abnormal after early (postnatal day 5) removal of descending systems, inducing hyperexcitability of the monosynaptic reflex. The study is a detailed characterization of spinal circuit development elucidating how these mechanisms contribute to motor dysfunction in conditions such as cerebral palsy and spinal cord injury. Understanding these circuits is crucial to developing new therapeutics and improving existing ones in such conditions.

Project description:Layer 5 extratelencephalic (ET) neurons are a main class of neocortical projection neurons that predominate in the motor cortex and send their axon to multiple proximal and distal targets including the thalamus, pons, medulla and spinal cord1-6. Precise connectivity of ET neurons is critical for fine motor control; they are central to loss of function upon spinal cord injury and specifically degenerate in amyotrophic lateral sclerosis7-10. ET neurons consist of several subtypes of cells with distinct laminar and areal locations, molecular identities, connectivities, and functions11,12. Two cardinal subtypes of ET neurons have been identified: neurons that express Nprs1 or Hpgd and project proximally to the pons and thalamus (ETprox), and neurons that express Slco2a1 and project more distally to the pons, medulla and spinal cord (ETdist)11. Despite their critical function, how these neuronal subtypes emerge during development and acquire their area-specific distributions remains unaddressed. Here, using combinations of anatomical labeling, MAPseq mapping13, and single- nucleus transcriptomics across developing cortical areas, we reveal that these two subtypes of ET neurons are present at birth along opposite antero-posterior cortical gradients. We first characterize area-specific developmental axonal dynamics of ETprox and ETdist neurons and find that the former can emerge by pruning of subsets of ETdist neurons. We next identify area- and ET neuron subtype-specific developmental transcriptional programs to identify key target genes in vivo and predict their gene regulatory networks. Finally, we reprogram ET neuron subtype- specific connectivity from motor to visual-like, by generating more proximal connections through postnatal in vivo knockdown of three subtype-specific transcription factors. Together, these findings delineate the functional transcriptional programs controlling ET neuron diversity across cortical areas and provide a molecular blueprint to investigate and direct the developmental emergence of corticospinal motor function.

Dataset Information

Noninvasive Reactivation of Motor Descending Control after Paralysis.

Publications

Noninvasive Reactivation of Motor Descending Control after Paralysis.

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