Spinal Cord Injury and Loss of Cortical Inhibition

Abstract

After spinal cord injury (SCI), the destruction of spinal parenchyma causes permanent deficits in motor functions, which correlates with the severity and location of the lesion. Despite being disconnected from their targets, most cortical motor neurons survive the acute phase of SCI, and these neurons can therefore be a resource for functional recovery, provided that they are properly reconnected and retuned to a physiological state. However, inappropriate re-integration of cortical neurons or aberrant activity of corticospinal networks may worsen the long-term outcomes of SCI. In this review, we revisit recent studies addressing the relation between cortical disinhibition and functional recovery after SCI. Evidence suggests that cortical disinhibition can be either beneficial or detrimental in a context-dependent manner. A careful examination of clinical data helps to resolve apparent paradoxes and explain the heterogeneity of treatment outcomes. Additionally, evidence gained from SCI animal models indicates probable mechanisms mediating cortical disinhibition. Understanding the mechanisms and dynamics of cortical disinhibition is a prerequisite to improve current interventions through targeted pharmacological and/or rehabilitative interventions following SCI.

Keywords: TMS; cortical inhibition; disinhibition; interneuron; neocortex; spinal cord injury; transcranial magnetic stimulation.

Figure 1

TMS enables measurement of cortical and subcortical excitability and inhibition after SCI. (A) TMS-evoked activity reveals the direct and indirect trans-synaptic activation of corticospinal neurons evident as D- and I-waves in descending volleys from the spinal cord. Changes in I-waves reflect altered cortical inhibition after SCI. Similarly, changes in motor evoked potentials (MEP) and cortical silent period (CSP), evoked by TMS pulses and recorded with electromyography, reflect altered integrity of the corticospinal tract after SCI. (B) The physiological balance (blue) between excitation and inhibition in cortical and corticospinal networks is perturbed (yellow) by SCI. On one hand, altered inhibition supports rewiring and motor recovery and appears as an exploitable condition in therapeutic treatments. On the other hand, altered inhibition contributes to detrimental aspects, such as exacerbated pain, spasticity and poor motor coordination. (C) Altered balance between excitability and inhibition of cortical and corticospinal areas is long-lasting and can endure for decades after SCI. However, alterations vary qualitatively between patients, and therefore, inhibition may be decreased [2,34,57,58,59,60,61,62] or increased [50,63,64] as a consequence of SCI. Moreover, there may be phases of decreased excitability, weeks and years after SCI, interspersed with transiently decreased inhibition months after SCI [65]. Such transient events can contribute to fluctuation in the balance of excitation and inhibition over time during the recovery process. Better resolution of the pathophysiological mechanisms of altered inhibition can allow the determination of relevant factors for the occurrence, duration, heterogeneity and alternation of such phases. This figure was created with biorender.com. Adapted from “Ascending and Descending Spinal Pathways”, by biorender.com. Retrieved from https://app.biorender.com/biorender-templates (accessed on 29 March 2022).

Figure 2

Possible causes for loss of inhibition. Multiple mechanisms contribute to network plasticity and altered inhibition in cortical and subcortical areas after SCI. These include metabolic stress, which can be exacerbated by inflammation and by decreased blood flow, as well as altered astrocytic metabolism. Furthermore, increased excitability of principal (excitatory) neurons may be exacerbated by altered neuromodulation, contributing to increased output volume in corticospinal circuits. Moreover, disinhibition is associated with decreased GABAergic tone that contributes to plasticity during network rewiring. Additionally, remodeling of perineuronal nets, which involves atrophy of interneurons, can contribute to complex patterns of altered inhibition in the central nervous system after SCI. Thus, multiple mechanisms, some of which are yet to be identified (represented by empty octagons) may coexist and combine heterogeneously amongst each other and/or to other pathophysiological components, increasing inter-patient variability. This figure was created with biorender.com.