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Motor cortex electrical stimulation augments sprouting of the corticospinal tract and promotes recovery of motor function.

Carmel JB, Martin JH - Front Integr Neurosci (2014)

Bottom Line: Reversible inactivation of the stimulated motor cortex reinstated the impairment demonstrating the importance of the stimulated system to recovery.Motor cortex electrical stimulation is an effective approach to promote spouting of spared CST axons.By optimizing activity-dependent sprouting in animals, we could have an approach that can be translated to the human for evaluation with minimal delay.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Weill Cornell Medical College New York, NY, USA ; Department of Pediatrics, Weill Cornell Medical College New York, NY, USA ; Brain and Mind Research Institute, Weill Cornell Medical College New York, NY, USA ; Burke Medical Research Institute White Plains, NY, USA.

ABSTRACT
The corticospinal system-with its direct spinal pathway, the corticospinal tract (CST) - is the primary system for controlling voluntary movement. Our approach to CST repair after injury in mature animals was informed by our finding that activity drives establishment of connections with spinal cord circuits during postnatal development. After incomplete injury in maturity, spared CST circuits sprout, and partially restore lost function. Our approach harnesses activity to augment this injury-dependent CST sprouting and to promote function. Lesion of the medullary pyramid unilaterally eliminates all CST axons from one hemisphere and allows examination of CST sprouting from the unaffected hemisphere. We discovered that 10 days of electrical stimulation of either the spared CST or motor cortex induces CST axon sprouting that partially reconstructs the lost CST. Stimulation also leads to sprouting of the cortical projection to the magnocellular red nucleus, where the rubrospinal tract originates. Coordinated outgrowth of the CST and cortical projections to the red nucleus could support partial re-establishment of motor systems connections to the denervated spinal motor circuits. Stimulation restores skilled motor function in our animal model. Lesioned animals have a persistent forelimb deficit contralateral to pyramidotomy in the horizontal ladder task. Rats that received motor cortex stimulation either after acute or chronic injury showed a significant functional improvement that brought error rate to pre-lesion control levels. Reversible inactivation of the stimulated motor cortex reinstated the impairment demonstrating the importance of the stimulated system to recovery. Motor cortex electrical stimulation is an effective approach to promote spouting of spared CST axons. By optimizing activity-dependent sprouting in animals, we could have an approach that can be translated to the human for evaluation with minimal delay.

No MeSH data available.


Related in: MedlinePlus

Effects of stimulation, injury and their combination on the ipsilateral corticospinal tract. (A) Changes in the strength of ipsilateral corticospinal tract axons are assayed by the ratio of the thresholds to evoke an ipsilateral response and a contralateral response in each animal. Stimulation (Stim) and injury alone both show enhanced capacity to evoke ipsilateral motor responses, which is augmented further in the combined condition (Inj + stim). (B) The regional density of corticospinal tract axons within the ipsilateral spinal cord is displayed as heatmaps for each condition. Each heat map is an average of 4–6 animals per group. The color scales are the same for all animals. Calibrations: 500 μm; Color scale: 0–5.7 μm axon/μm2 area. (C) Stimulation (Stim) and injury alone and in combination augment total ipsilateral CS termination axon length. Total average ipsilateral axon length in the controls, stimulation alone, injury alone, and combined injury and stimulation. Stimulation (p < 0.011) and injury (p < 0.003) alone each augmented total axon length significantly compared with control. Combined, there was a larger increase (p < 0.002). p Values were calculated from t test with Bonferroni/Dunn correction. (A–C) were modified from Brus-Ramer et al. (2007).
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Figure 2: Effects of stimulation, injury and their combination on the ipsilateral corticospinal tract. (A) Changes in the strength of ipsilateral corticospinal tract axons are assayed by the ratio of the thresholds to evoke an ipsilateral response and a contralateral response in each animal. Stimulation (Stim) and injury alone both show enhanced capacity to evoke ipsilateral motor responses, which is augmented further in the combined condition (Inj + stim). (B) The regional density of corticospinal tract axons within the ipsilateral spinal cord is displayed as heatmaps for each condition. Each heat map is an average of 4–6 animals per group. The color scales are the same for all animals. Calibrations: 500 μm; Color scale: 0–5.7 μm axon/μm2 area. (C) Stimulation (Stim) and injury alone and in combination augment total ipsilateral CS termination axon length. Total average ipsilateral axon length in the controls, stimulation alone, injury alone, and combined injury and stimulation. Stimulation (p < 0.011) and injury (p < 0.003) alone each augmented total axon length significantly compared with control. Combined, there was a larger increase (p < 0.002). p Values were calculated from t test with Bonferroni/Dunn correction. (A–C) were modified from Brus-Ramer et al. (2007).

Mentions: Using pyramidotomy, electrical stimulation, and their combination, we compared four groups of animals: naive rats, injury only, stimulation only, or stimulation after injury. To assess CST connection strength we electrically stimulated the pyramidal tract and recorded evoked responses in a forelimb nerve bilaterally. As a physiological assay, pyramidal tract stimulation is more selective for the CST than motor cortex stimulation; corticobulbar and corticorubral projections may be recruited with motor cortex stimulation. Furthermore, the difference between the contralateral and ipsilateral current thresholds is greater in the pyramid than motor cortex and can thus provide a more sensitive measure of ipsilateral connection strength. The current threshold for producing an evoked motor nerve potential in naïve rats is roughly 5 times the current amplitude than the threshold for eliciting a contralateral response. With stimulation alone, there is a strong augmentation of the ipsilateral response to stimulation (Figure 2A). This activity-dependent plasticity is similar in magnitude to the effects of injury-dependent plasticity in rats with injury only (Figure 2A; compare Stim and Injured bars). Stimulating the spared CST in injured animals (Figure 2A; Inj + Stim) augments the ipsilateral response more than either intact or injured-alone animals; the effects are additive. This shows the injury-dependent augmentation of CST spinal connections can be further enhanced by activity.


Motor cortex electrical stimulation augments sprouting of the corticospinal tract and promotes recovery of motor function.

Carmel JB, Martin JH - Front Integr Neurosci (2014)

Effects of stimulation, injury and their combination on the ipsilateral corticospinal tract. (A) Changes in the strength of ipsilateral corticospinal tract axons are assayed by the ratio of the thresholds to evoke an ipsilateral response and a contralateral response in each animal. Stimulation (Stim) and injury alone both show enhanced capacity to evoke ipsilateral motor responses, which is augmented further in the combined condition (Inj + stim). (B) The regional density of corticospinal tract axons within the ipsilateral spinal cord is displayed as heatmaps for each condition. Each heat map is an average of 4–6 animals per group. The color scales are the same for all animals. Calibrations: 500 μm; Color scale: 0–5.7 μm axon/μm2 area. (C) Stimulation (Stim) and injury alone and in combination augment total ipsilateral CS termination axon length. Total average ipsilateral axon length in the controls, stimulation alone, injury alone, and combined injury and stimulation. Stimulation (p < 0.011) and injury (p < 0.003) alone each augmented total axon length significantly compared with control. Combined, there was a larger increase (p < 0.002). p Values were calculated from t test with Bonferroni/Dunn correction. (A–C) were modified from Brus-Ramer et al. (2007).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 2: Effects of stimulation, injury and their combination on the ipsilateral corticospinal tract. (A) Changes in the strength of ipsilateral corticospinal tract axons are assayed by the ratio of the thresholds to evoke an ipsilateral response and a contralateral response in each animal. Stimulation (Stim) and injury alone both show enhanced capacity to evoke ipsilateral motor responses, which is augmented further in the combined condition (Inj + stim). (B) The regional density of corticospinal tract axons within the ipsilateral spinal cord is displayed as heatmaps for each condition. Each heat map is an average of 4–6 animals per group. The color scales are the same for all animals. Calibrations: 500 μm; Color scale: 0–5.7 μm axon/μm2 area. (C) Stimulation (Stim) and injury alone and in combination augment total ipsilateral CS termination axon length. Total average ipsilateral axon length in the controls, stimulation alone, injury alone, and combined injury and stimulation. Stimulation (p < 0.011) and injury (p < 0.003) alone each augmented total axon length significantly compared with control. Combined, there was a larger increase (p < 0.002). p Values were calculated from t test with Bonferroni/Dunn correction. (A–C) were modified from Brus-Ramer et al. (2007).
Mentions: Using pyramidotomy, electrical stimulation, and their combination, we compared four groups of animals: naive rats, injury only, stimulation only, or stimulation after injury. To assess CST connection strength we electrically stimulated the pyramidal tract and recorded evoked responses in a forelimb nerve bilaterally. As a physiological assay, pyramidal tract stimulation is more selective for the CST than motor cortex stimulation; corticobulbar and corticorubral projections may be recruited with motor cortex stimulation. Furthermore, the difference between the contralateral and ipsilateral current thresholds is greater in the pyramid than motor cortex and can thus provide a more sensitive measure of ipsilateral connection strength. The current threshold for producing an evoked motor nerve potential in naïve rats is roughly 5 times the current amplitude than the threshold for eliciting a contralateral response. With stimulation alone, there is a strong augmentation of the ipsilateral response to stimulation (Figure 2A). This activity-dependent plasticity is similar in magnitude to the effects of injury-dependent plasticity in rats with injury only (Figure 2A; compare Stim and Injured bars). Stimulating the spared CST in injured animals (Figure 2A; Inj + Stim) augments the ipsilateral response more than either intact or injured-alone animals; the effects are additive. This shows the injury-dependent augmentation of CST spinal connections can be further enhanced by activity.

Bottom Line: Reversible inactivation of the stimulated motor cortex reinstated the impairment demonstrating the importance of the stimulated system to recovery.Motor cortex electrical stimulation is an effective approach to promote spouting of spared CST axons.By optimizing activity-dependent sprouting in animals, we could have an approach that can be translated to the human for evaluation with minimal delay.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Weill Cornell Medical College New York, NY, USA ; Department of Pediatrics, Weill Cornell Medical College New York, NY, USA ; Brain and Mind Research Institute, Weill Cornell Medical College New York, NY, USA ; Burke Medical Research Institute White Plains, NY, USA.

ABSTRACT
The corticospinal system-with its direct spinal pathway, the corticospinal tract (CST) - is the primary system for controlling voluntary movement. Our approach to CST repair after injury in mature animals was informed by our finding that activity drives establishment of connections with spinal cord circuits during postnatal development. After incomplete injury in maturity, spared CST circuits sprout, and partially restore lost function. Our approach harnesses activity to augment this injury-dependent CST sprouting and to promote function. Lesion of the medullary pyramid unilaterally eliminates all CST axons from one hemisphere and allows examination of CST sprouting from the unaffected hemisphere. We discovered that 10 days of electrical stimulation of either the spared CST or motor cortex induces CST axon sprouting that partially reconstructs the lost CST. Stimulation also leads to sprouting of the cortical projection to the magnocellular red nucleus, where the rubrospinal tract originates. Coordinated outgrowth of the CST and cortical projections to the red nucleus could support partial re-establishment of motor systems connections to the denervated spinal motor circuits. Stimulation restores skilled motor function in our animal model. Lesioned animals have a persistent forelimb deficit contralateral to pyramidotomy in the horizontal ladder task. Rats that received motor cortex stimulation either after acute or chronic injury showed a significant functional improvement that brought error rate to pre-lesion control levels. Reversible inactivation of the stimulated motor cortex reinstated the impairment demonstrating the importance of the stimulated system to recovery. Motor cortex electrical stimulation is an effective approach to promote spouting of spared CST axons. By optimizing activity-dependent sprouting in animals, we could have an approach that can be translated to the human for evaluation with minimal delay.

No MeSH data available.


Related in: MedlinePlus