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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

The stimulated motor cortex mediates motor recovery after injury. Rats were trained to cross a horizontal ladder with irregularly spaced rungs until they achieved a baseline error rate below 20%. (A) Effect of motor cortex stimulation beginning the day after injury. The error rates increased in the affected forelimb to a similar degree in rats with injury only (blue) and rats with injury and stimulation (red). Modified from Carmel et al. (2010). (B) Effect of motor cortex stimulation after chronic injury. Until the start of stimulation (weeks 1–7) the error rates in the two groups were not different. After the start of stimulation (weeks 8–11) the groups differed significantly (repeated measures ANOVA, with Bonferroni post hoc correction, asterisk, p = 0.03). (C) After stimulation, motor cortex inactivation reinstates the motor impairment. After completion of motor cortex stimulation, performance on the horizontal ladder was measured before and during inactivation. In the rats with injury only, inactivation did not change the error rate in the impaired forelimb (blue bars are not different). In contrast, in rats with injury and stimulation (red bars) inactivation of the stimulated motor cortex reinstated their initial deficit in the ipsilateral forelimb (paired t-test, p = 0.01). (B,C) were modified from Carmel et al. (2014).
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Figure 5: The stimulated motor cortex mediates motor recovery after injury. Rats were trained to cross a horizontal ladder with irregularly spaced rungs until they achieved a baseline error rate below 20%. (A) Effect of motor cortex stimulation beginning the day after injury. The error rates increased in the affected forelimb to a similar degree in rats with injury only (blue) and rats with injury and stimulation (red). Modified from Carmel et al. (2010). (B) Effect of motor cortex stimulation after chronic injury. Until the start of stimulation (weeks 1–7) the error rates in the two groups were not different. After the start of stimulation (weeks 8–11) the groups differed significantly (repeated measures ANOVA, with Bonferroni post hoc correction, asterisk, p = 0.03). (C) After stimulation, motor cortex inactivation reinstates the motor impairment. After completion of motor cortex stimulation, performance on the horizontal ladder was measured before and during inactivation. In the rats with injury only, inactivation did not change the error rate in the impaired forelimb (blue bars are not different). In contrast, in rats with injury and stimulation (red bars) inactivation of the stimulated motor cortex reinstated their initial deficit in the ipsilateral forelimb (paired t-test, p = 0.01). (B,C) were modified from Carmel et al. (2014).

Mentions: Having demonstrated that CST electrical stimulation can strengthen connections with spinal motor circuits and promote axon outgrowth, we next determined if the injured animals showed improved motor recovery after stimulation. We tested CST function using a horizontal ladder with irregularly spaced rungs. To perform the task correctly, the rat needs to integrate sensory information about the position of the next rung (visual, vibrissal, and somatosensory) and alter the trajectory of the step to place the paw accurately on the rung. This sensory-motor transformation is a key attribute of the corticospinal system (Porter and Lemon, 1993). After training to a criterion error rate, rats had a pyramidotomy and the next day began 10 days of electrical stimulation using the protocol described above. We measured task performance every 5 days for 30 days (Figure 5A). Rats with injury only had a persistent deficit in the forelimb contralateral to pyramidotomy. By contrast, rats with injury and motor cortex stimulation had a significant reduction in forelimb errors (Carmel et al., 2010). At end of testing, the performance of stimulated animals was not different from uninjured rats. Interestingly, in each of the six animals examined there was transient improvement on day 15 that was followed by a worsening of performance on the next examination day. The improvement may be due to early injury-dependent sprouting (Brus-Ramer et al., 2007) that is not maintained without motor cortex stimulation (Carmel et al., 2010). The types of errors that the rats made (understep of the rung, overstep, or miss) were not different from baseline, suggesting recovery of neurological function rather than behavioral compensation (Krakauer et al., 2012). Importantly, we never observed maladaptive effects of stimulation. There was consistent improvement on the affected side, ipsilateral to stimulation and performance on the unaffected side remained stable (Carmel et al., 2010).


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

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

The stimulated motor cortex mediates motor recovery after injury. Rats were trained to cross a horizontal ladder with irregularly spaced rungs until they achieved a baseline error rate below 20%. (A) Effect of motor cortex stimulation beginning the day after injury. The error rates increased in the affected forelimb to a similar degree in rats with injury only (blue) and rats with injury and stimulation (red). Modified from Carmel et al. (2010). (B) Effect of motor cortex stimulation after chronic injury. Until the start of stimulation (weeks 1–7) the error rates in the two groups were not different. After the start of stimulation (weeks 8–11) the groups differed significantly (repeated measures ANOVA, with Bonferroni post hoc correction, asterisk, p = 0.03). (C) After stimulation, motor cortex inactivation reinstates the motor impairment. After completion of motor cortex stimulation, performance on the horizontal ladder was measured before and during inactivation. In the rats with injury only, inactivation did not change the error rate in the impaired forelimb (blue bars are not different). In contrast, in rats with injury and stimulation (red bars) inactivation of the stimulated motor cortex reinstated their initial deficit in the ipsilateral forelimb (paired t-test, p = 0.01). (B,C) were modified from Carmel et al. (2014).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 5: The stimulated motor cortex mediates motor recovery after injury. Rats were trained to cross a horizontal ladder with irregularly spaced rungs until they achieved a baseline error rate below 20%. (A) Effect of motor cortex stimulation beginning the day after injury. The error rates increased in the affected forelimb to a similar degree in rats with injury only (blue) and rats with injury and stimulation (red). Modified from Carmel et al. (2010). (B) Effect of motor cortex stimulation after chronic injury. Until the start of stimulation (weeks 1–7) the error rates in the two groups were not different. After the start of stimulation (weeks 8–11) the groups differed significantly (repeated measures ANOVA, with Bonferroni post hoc correction, asterisk, p = 0.03). (C) After stimulation, motor cortex inactivation reinstates the motor impairment. After completion of motor cortex stimulation, performance on the horizontal ladder was measured before and during inactivation. In the rats with injury only, inactivation did not change the error rate in the impaired forelimb (blue bars are not different). In contrast, in rats with injury and stimulation (red bars) inactivation of the stimulated motor cortex reinstated their initial deficit in the ipsilateral forelimb (paired t-test, p = 0.01). (B,C) were modified from Carmel et al. (2014).
Mentions: Having demonstrated that CST electrical stimulation can strengthen connections with spinal motor circuits and promote axon outgrowth, we next determined if the injured animals showed improved motor recovery after stimulation. We tested CST function using a horizontal ladder with irregularly spaced rungs. To perform the task correctly, the rat needs to integrate sensory information about the position of the next rung (visual, vibrissal, and somatosensory) and alter the trajectory of the step to place the paw accurately on the rung. This sensory-motor transformation is a key attribute of the corticospinal system (Porter and Lemon, 1993). After training to a criterion error rate, rats had a pyramidotomy and the next day began 10 days of electrical stimulation using the protocol described above. We measured task performance every 5 days for 30 days (Figure 5A). Rats with injury only had a persistent deficit in the forelimb contralateral to pyramidotomy. By contrast, rats with injury and motor cortex stimulation had a significant reduction in forelimb errors (Carmel et al., 2010). At end of testing, the performance of stimulated animals was not different from uninjured rats. Interestingly, in each of the six animals examined there was transient improvement on day 15 that was followed by a worsening of performance on the next examination day. The improvement may be due to early injury-dependent sprouting (Brus-Ramer et al., 2007) that is not maintained without motor cortex stimulation (Carmel et al., 2010). The types of errors that the rats made (understep of the rung, overstep, or miss) were not different from baseline, suggesting recovery of neurological function rather than behavioral compensation (Krakauer et al., 2012). Importantly, we never observed maladaptive effects of stimulation. There was consistent improvement on the affected side, ipsilateral to stimulation and performance on the unaffected side remained stable (Carmel et al., 2010).

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