Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

Considerable experimental evidence suggests that serotonin (5-HT) at sensory neuron-->motor neuron (SN-->MN) synapses, as well as other neuronal sites, contributes importantly to simple forms of learning such as sensitization and classical conditioning in Aplysia. However, the actual release of 5-HT in the CNS induced by sensitizing stimuli such as tail shock has not been directly demonstrated. In this study, we addressed this question by (1) immunohistochemically labeling central 5-HT processes and (2) directly measuring with chronoamperometry the release of 5-HT induced by pedal tail nerve (P9) shock onto tail SNs in the pleural ganglion and their synapses onto tail MNs in the pedal ganglion. We found that numerous 5-HT-immunoreactive fibers surround both the SN cell bodies in the pleural ganglion and SN axons in the pedal ganglion. Chronoamperometric detection of 5-HT performed with carbon fiber electrodes implanted in the vicinity of tail SN somata and synapses revealed an electrochemical 5-HT signal lasting approximately 40 sec after a brief shock of P9. 5-HT release was restricted to discrete subregions (modulatory fields) of the CNS, including the vicinity of tail SN soma and synapses ipsilateral to the stimulation. Increasing P9 shock frequency augmented the amplitude of the 5-HT signal and, in parallel, increased SN excitability and SN synaptic transmission onto tail MNs. However, the relationship between the amount of 5-HT release and the two forms of SN plasticity was not uniform: SN excitability increased in a graded manner with increased 5-HT release, whereas synaptic facilitation exhibited a highly nonlinear relationship. The development of chronoamperometric techniques in Aplysia now paves the way for a more complete understanding of the contribution of the serotonergic modulatory pathway to memory processing in this system.

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