Our overall goal is to take advantage of the extraordinary activity-dependent plasticity of the mature motor systems, to achieve significant repair of the damaged corticospinal tract (CST) after brain or spinal cord injury.
We aim to promote the motor functions of the CST spared after an incomplete injury. These spared connections are sparse and weak;by themselves, they cannot exert significant motor control. Our rat studies use a unilateral pyramidal tract lesion (PTX) that eliminates all CST axons from one motor cortex (M1). This lesion eliminates most of the CST on the affected contralateral spinal cord, with only sparse ipsilateral CST axons remaining. PTX produces significant sprouting from the spared ipsilateral CST, which we hypothesize is adaptive because M1 electrical stimulation after injury promotes this sprouting, leading to motor recovery. PTX also produces proprioceptive afferent sprouting and spinal neuron changes that we hypothesize are maladaptive, because they can lead to spasticity and weakness.
Aim 1 will determine the activity dependence of spinal reactive changes after unilateral CST lesion. We hypothesize that activity loss, not just the physical loss of connections, is an important trigger for reactive changes after injury. We will unilaterally inactivate M1 to determine the activity dependence of CST changes (Aim 1A) and impairments in spinal interneuron and motoneuron function (Aim 1B). We will determine the effects of optogenetic activation of spinal interneurons on reactive spinal changes produced by M1 inactivation (Aim 1C).
In Aim 2 we will determine the role of spinal cord activation in abrogating maladaptive segmental changes after injury and in promoting the motor functions of the spared CST. We hypothesize that stimulating spinal circuits after injury will increase their response to signals from spared CST axons.
Aim 2 A directly tests this hypothesis using the optogenetic approach to activate spinal interneurons with temporal precision, and trans-spinal direct current stimulation (tsDC), an activation approach with translational potential. Spinal stimulation provides segmental activation after CST loss.
In Aim 2 B we will determine if tsDC promotes sprouting of spared CST connections, abrogates maladaptive spinal changes and, together, strengthens the M1-to-muscle pathway.
In Aim 2 C we will determine if tsDC promotes behavioral recovery after PTX.
Aim 3 will harness short-term functional M1 plasticity and spinal activation in combination, to strengthen CST connections, enhance CST outgrowth, and promote motor function after injury. We combine """"""""top down"""""""" M1 activation with """"""""bottom up"""""""" spinal activation to achieve novel therapeutic insights. We hypothesize that potent short-term plasticity, produced by high-frequency patterned M1electrical stimulation, strengthens and produces sprouting of spared CST axons. Augmented CST signals will now be amplified by spinal activation.
In Aim 3 A we study the acute effects of patterned M1 stimulation, alone and combined with tsDC, on CST transmission and M1 intracortical circuits.
Aim 3 B will determine if CST sprouting, connection strength, and locomotor recovery are promoted by chronic patterned M1 stimulation, and if tsDC affects the response.
Aim 3 C combines cortical and spinal stimulation to restore distal forelimb motor function in a clinically relevant cortical lesion model.

Public Health Relevance

The overall goal of our experiments is to promote motor function after spinal cord or brain injury. We focus on the corticospinal tract, the principal moto control pathway in humans. Using a rat model, we increase neural activity of the motor cortex and/or spinal cord after injury, by electrical stimulation and other means, to restore lost connections to spinal cord motor control centers.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1)
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Jakeman, Lyn B
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City College of New York
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New York
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Zareen, Neela; Dodson, Shahid; Armada, Kristine et al. (2018) Stimulation-dependent remodeling of the corticospinal tract requires reactivation of growth-promoting developmental signaling pathways. Exp Neurol 307:133-144
Jiang, Yu-Qiu; Sarkar, Adrish; Amer, Alzahraa et al. (2018) Transneuronal Downregulation of the Premotor Cholinergic System After Corticospinal Tract Loss. J Neurosci 38:8329-8344
Song, Weiguo; Martin, John H (2017) Spinal cord direct current stimulation differentially modulates neuronal activity in the dorsal and ventral spinal cord. J Neurophysiol 117:1143-1155
Williams, Preston T J A; Jiang, Yu-Qiu; Martin, John H (2017) Motor system plasticity after unilateral injury in the developing brain. Dev Med Child Neurol 59:1224-1229
Zareen, N; Shinozaki, M; Ryan, D et al. (2017) Motor cortex and spinal cord neuromodulation promote corticospinal tract axonal outgrowth and motor recovery after cervical contusion spinal cord injury. Exp Neurol 297:179-189
Song, Weiguo; Amer, Alzahraa; Ryan, Daniel et al. (2016) Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury. Exp Neurol 277:46-57
Martin, John H (2016) Harnessing neural activity to promote repair of the damaged corticospinal system after spinal cord injury. Neural Regen Res 11:1389-1391
Jiang, Yu-Qiu; Zaaimi, Boubker; Martin, John H (2016) Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits. J Neurosci 36:193-203
Song, Weiguo; Truong, Dennis Q; Bikson, Marom et al. (2015) Transspinal direct current stimulation immediately modifies motor cortex sensorimotor maps. J Neurophysiol 113:2801-11
Lemmon, Vance P; Ferguson, Adam R; Popovich, Phillip G et al. (2014) Minimum information about a spinal cord injury experiment: a proposed reporting standard for spinal cord injury experiments. J Neurotrauma 31:1354-61

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