Nonpharmacological modulation of cortical spreading depolarization

Abstract

Aims: Cortical spreading depolarization (CSD) is a wave of pathologic neuronal dysfunction that spreads through cerebral gray matter, causing neurologic disturbance in migraine and promoting lesion development in acute brain injury. Pharmacologic interventions have been found to be effective in migraine with aura, but their efficacy in acutely injured brains may be limited. This necessitates the assessment of possible adjunctive treatments, such as nonpharmacologic methods. This review aims to summarize currently available nonpharmacological techniques for modulating CSDs, present their mechanisms of action, and provide insight and future directions for CSD treatment.

Main methods: A systematic literature review was performed, generating 22 articles across 3 decades. Relevant data is broken down according to method of treatment.

Key findings: Both pharmacologic and nonpharmacologic interventions can mitigate the pathological impact of CSDs via shared molecular mechanisms, including modulating K⁺/Ca²⁺/Na⁺/Cl^- ion channels and NMDA, GABA_A, serotonin, and CGRP ligand-based receptors and decreasing microglial activation. Preclinical evidence suggests that nonpharmacologic interventions, including neuromodulation, physical exercise, therapeutic hypothermia, and lifestyle changes can also target unique mechanisms, such as increasing adrenergic tone and myelination and modulating membrane fluidity, which may lend broader modulatory effects. Collectively, these mechanisms increase the electrical initiation threshold, increase CSD latency, slow CSD velocity, and decrease CSD amplitude and duration.

Significance: Given the harmful consequences of CSDs, limitations of current pharmacological interventions to inhibit CSDs in acutely injured brains, and translational potentials of nonpharmacologic interventions to modulate CSDs, further assessment of nonpharmacologic modalities and their mechanisms to mitigate CSD-related neurologic dysfunction is warranted.

Keywords: Acute brain injury; Cortical spreading depolarization; Migraine; Neuromodulation; Peri-infarct depolarization; Spreading depression.