Learning to promote recovery after spinal cord injury

Grau, James W.; Baine, Rachel E; Bean, Paris; Davis, Jacob A.; Fauss, Gizelle N. K.; Henwood, Melissa K.; Hudson, Kelsey; Johnston, David T.; Tarbet, Megan M.; Strain, Misty M.

doi:10.1016/j.expneurol.2020.113334

Cited by 25 publications

(27 citation statements)

References 162 publications

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“…However, the immunoexpression of KCC2 in the GT-ES group was higher compared to the intact animals. This observation corresponds to the view that activity-based therapies and an increase in neurotrophic factors expression modulate KCC2 plasticity resulting in a decrease in nociceptive and spasticity circuits in the lumbar spinal cord [58,59]. The pattern of Hsp27 and KCC2 may be indicated on the regeneration processes in the spinal cord in treated pigs.…”

Section: Discussionsupporting

confidence: 81%

Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

Islamov

Bashirov

Fadeev

et al. 2020

IJMS

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The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.

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Section: Discussionsupporting

confidence: 81%

Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

Islamov

Bashirov

Fadeev

et al. 2020

IJMS

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“…When the latter component becomes too large, learning is degraded and eventually destroyed at any given learning rate. This effect of sensorimotor noise on learning may partly explain why learning may sometimes be impaired in populations with sensorimotor deficits [44][45][46][47][48] .…”

Section: Effect Of Adding Asymmetric Leg Massmentioning

confidence: 99%

Exploration-based learning of a step to step controller predicts locomotor adaptation

Seethapathi

Clark

Srinivasan

2021

Preprint

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Humans are able to adapt their locomotion to a variety of novel circumstances, for instance, walking on diverse terrain and walking with new footwear. During locomotor adaptation, humans have been shown to exhibit stereotypical changes in their movement patterns. Here, we provide a theoretical account of such locomotor adaptation, positing that the nervous system prioritizes stability in the short timescale and improves energy expenditure over a longer timescale. The resulting mathematical model has two processes: a stabilizing controller which is gradually changed by a reinforcement learner that exploits local gradients to lower energy expenditure, estimating gradients indirectly via intentional exploratory noise. We consider this model walking and adapting under three novel circumstances: walking on a split-belt treadmill (walking with each foot on a different belt, each belt at different speeds), walking with an exoskeleton, and walking with an asymmetric leg mass. This model predicts the short and long timescale changes observed in walking symmetry on the split-belt treadmill and while walking with the asymmetric mass. The model exhibits energy reductions with exoskeletal assistance, as well as entrainment to time-periodic assistance. We show that such exploration-based learning is degraded in the presence of large sensorimotor noise, providing a potential account for some impairments in learning.

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“…The findings encourage a new perspective regarding learning within the spinal cord, shifting the focus to the regulation of physiological circuits. We have shown that uncontrollable/ unpredictable stimulation can disable the capacity to learn, an effect we have related to an impairment in relational processing (Grau et al, 1998(Grau et al, , 2006(Grau et al, , 2020Crown et al, 2002b;Ferguson et al, 2012a,b;Grau, 2014). Conversely, prior exposure to controllable/predictable stimulation can counter this effect and foster relational learning (Crown and Grau, 2001;Grau et al, 2012;Huie et al, 2012b).…”

Section: Revising Our Model Of Learningmentioning

confidence: 62%

Evidence That the Central Nervous System Can Induce a Modification at the Neuromuscular Junction That Contributes to the Maintenance of a Behavioral Response

et al. 2020

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Neurons within the spinal cord are sensitive to environmental relations and can bring about a behavioral modification without input from the brain. For example, rats that have undergone a thoracic (T2) transection can learn to maintain a hind leg in a flexed position to minimize exposure to a noxious electrical stimulation (shock). Inactivating neurons within the spinal cord with lidocaine, or cutting communication between the spinal cord and the periphery (sciatic transection), eliminates the capacity to learn, which implies that it depends on spinal neurons. Here we show that these manipulations have no effect on the maintenance of the learned response, which implicates a peripheral process. EMG showed that learning augments the muscular response evoked by motoneuron output and that this effect survives a sciatic transection. Quantitative fluorescent imaging revealed that training brings about an increase in the area and intensity of ACh receptor labeling at the neuromuscular junction (NMJ). It is hypothesized that efferent motoneuron output, in conjunction with electrical stimulation of the tibialis anterior muscle, strengthens the connection at the NMJ in a Hebbian manner. Supporting this, paired stimulation of the efferent nerve and tibialis anterior generated an increase in flexion duration and augmented the evoked electrical response without input from the spinal cord. Evidence is presented that glutamatergic signaling contributes to plasticity at the NMJ. Labeling for vesicular glutamate transporter is evident at the motor endplate. Intramuscular application of an NMDAR antagonist blocked the acquisition/maintenance of the learned response and the strengthening of the evoked electrical response.

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Learning to promote recovery after spinal cord injury

Cited by 25 publications

References 162 publications

Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

Exploration-based learning of a step to step controller predicts locomotor adaptation

Evidence That the Central Nervous System Can Induce a Modification at the Neuromuscular Junction That Contributes to the Maintenance of a Behavioral Response

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