Functional Electrical Stimulation and the Modulation of the Axon Regeneration Program

Abstract

Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation.

Analysis of the Differential Gene and Protein Expression Profiles of Corneal Epithelial Cells Stimulated with Alternating Current Electric Fields

“…Likewise, we also observed activation of PI3K/AKT and MAPK signaling pathways, along with other interconnected pathways, including T cell receptor signaling, Toll-like receptor signaling, TNF signaling, IL-17 signaling, FoxO signaling, and focal adhesion pathways, upon stimulation of corneal epithelial cells with oscillating EFs. In addition, electric stimulation upregulates expression of RAGs, increases neurotrophin signaling, accelerates axon guidance and outgrowth during peripheral nerve regeneration [ 25 , 54 , 55 , 56 , 57 ], and is also known to activate axon guidance, along with various metabolic and signaling pathways that play crucial interconnecting roles during axon regeneration [ 17 , 57 , 58 , 59 ]. Accordingly, our gene array data analysis also showed activation of similar pathways during AC EF stimulation of corneal epithelial cells.…”

Neuroregenerative Effects of Intraspinal Microstimulation (ISMS) Following Spinal Cord Injury (SCI)

“…The specific cellular mechanism behind this is still being studied, but it has been theorized that a lesion in the central nervous system transiently increases the level of secondary messenger cyclic adenosine monophosphate (cAMP). Increasing cAMP can further catalyze the upregulation of protein kinase A (PKA), cAMP response element-binding protein (CREB), and arginase 1 (ARG1), which are implicated to support the intrinsic regeneration of neurons (Cai et al, 2001;Jara et al, 2020). Importantly, these mechanisms only facilitate a limited recovery following neural injury.…”

“…Importantly, these mechanisms only facilitate a limited recovery following neural injury. However, a recent breakthrough in neuroscience discovered that central nervous system circuitry can be strengthened with continuous activation of the neural connections (Jara et al, 2020). In effect, introducing electrical stimulation to activate the desired circuitry may strengthen neurological recovery, or in some cases, cause axonal growth.…”

Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets

“…Apart from the regenerative potential of both peripheral and central axons, researchers are now working to understand the molecular pathways that activate the regenerative program for axonal regeneration in mammalian PNS and CNS [ 9 ]. Identification and modulation of these pathways may give therapeutic approaches to improve neuronal functional recovery after axonal damage.…”