Characterization and modulation of spreading depolarizations (SDs) as occurring after traumatic brain injury, using soft neural interfaces.

Spreading depolarizations (SDs) are massive waves of depolarization of neurons and astrocytes, which are characterized by a massive reduction of local cortical activity that can last up to several minutes. Restoration of the homeostasis following this brain phenomenon is extremely energy-consuming, therefore it can be delayed or completely absent in already energy-deprived tissues, leading to deleterious consequences. Although related to the pathophysiology of a broad number of diseases, including hemorrhage, migraine and stroke, SDs play a particular harmful role in the context of traumatic brain injury (TBI), as they are linked to the development of secondary injury. This further evolution of already detrimental damages often results in poor clinical outcome, which strongly affects patients' quality of life, diminishing their functional independence. The prevention of secondary injury is an additional focus of neurointensive care management of TBI and SDs represent a therapeutic challenge due to the current lack in clinical protocols aimed at preventing their generation and propagation. Patients with severe TBI often require a decompressive craniectomy to release the intracranial pressure, and a few large trauma centers have recently started to exploit this surgical procedure to place a subdural implant and continuously monitor the brain activity, revealing the presence of SDs. This approach hints at the possibility of combining the monitoring of spreading depolarizations with their electrical modulation in a closed-loop manner, automatically triggering the stimulation when they are detected. Therefore, this work aimed at investigating the impact of subdural electrical stimulation on SDs elicited in a rat animal model, establishing an experimental protocol to assess the stimulation effectiveness. The SDs were KCl-induced, following a widely used protocol that mimics the accumulation of extracellular potassium responsible for their development under pathological conditions. For this new application, we propose the use of a novel soft electrode technology that favors a reduction in mechanical mismatch with the tissue, promoting a better contact, and allows for customizable designs. In order to target the small rat brain, and to allow for spatial resolution, the electrodes dimensions were designed to be smaller compared to standard clinical ones. Our preliminary analysis, aimed at assessing any difference in the signal recorded due to the electrodes size, showed that the use of smaller electrodes has a positive impact on the quality of the signal, resulting in improved capability of monitoring SDs. Our work resulted in the modulation of the majority of the SDs, which was achieved in terms of reduction of the area under one of the characteristic peaks of the wave, meaning both in amplitude and duration. Also, our results suggest a possible slowing down effect of stimulation on SDs, which goes in the right direction of eventually being able to stop them. Despite the relatively modest effect of the modulation achieved, we successfully demonstrated the feasibility of this approach, suggesting a possible stimulation protocol that can be further developed and improved in order to have a bigger impact on propagating SDs. This research represents the first preclinical study on the closed-loop electrical modulation of spreading depolarizations, and our findings shed light on a possible additional line of defence against their deleterious consequences in the context of traumatic brain injury.