Intranasal Orexin After Cardiac Arrest Leads to Increased Electroencephalographic Gamma Activity and Enhanced Neurologic Recovery in Rats

Abstract

Objectives: Prolonged cardiac arrest is known to cause global ischemic brain injury and functional impairment. Upon resuscitation, electroencephalographic recordings of brain activity begin to resume and can potentially be used to monitor neurologic recovery. We have previously shown that intrathecal orexin shows promise as a restorative drug and arousal agent in rodents. Our goal is to determine the electrophysiology effects of orexin in a rodent model of asphyxial cardiac arrest, focusing on the electroencephalographic activity in the gamma and super-gamma bands (indicative of return of higher brain function). Design: Experimental animal study. Setting: University-based animal research laboratory. Subjects: Adult male Wistar rats. Interventions: In an established model of asphyxial cardiac arrest (n = 24), we treated half of Wistar rats with orexin administered intranasally by atomizer 30 minutes post return of spontaneous circulation in one of two dose levels (10 and 50 µM); the rest were treated with saline as control. Continuous electroencephalographic recording was obtained and quantitatively analyzed for the gamma fraction. Gamma and high-frequency super-gamma band measures were compared against clinical recovery according to Neuro-Deficit Score. Measurements and Main Results: Compared with the control cohort, the high-dose orexin cohort showed significantly better Neuro-Deficit Score 4 hours after return of spontaneous circulation (55.17 vs 47.58; p < 0.02) and significantly higher mean gamma fraction (0.251 vs 0.177; p < 0.02) in cerebral regions surveyed by rostral electrodes for the first 170 minutes after administration of orexin. Conclusions: Our findings support early and continuous monitoring of electroencephalography-based gamma activity as a marker of better functional recovery after intranasal administration of orexin as measured by Neuro-Deficit Score in an established animal model of asphyxial cardiac arrest.

Hyperacute autonomic and cortical function recovery following cardiac arrest resuscitation in a rodent model

“…The detrended standard deviation of the downsampled EEG was calculated to determine approximate bin thresholding for the calculation of Shannon entropy. The downsampled EEG was divided into nonoverlapping eight‐second windows and decomposed into frequency bands using a one‐dimensional, five‐level dyadic, symlet9 wavelet decomposition, which after coefficient‐based reconstruction provides six signals representing the target ranges of super‐gamma as 61.5–122 Hz, gamma as 30.75–61.5 Hz, beta as 15.375–30.75 Hz, alpha as 7.688–15.375 Hz, theta as 3.844–7.688 Hz, and delta as 1.922–3.844 Hz 30 . The spectral power of each range was calculated from the wavelet coefficients using the Parseval equivalence identity.…”

“…Entropy has been used to quantify the randomness of EEG signals to reflect their complexity and is defined as 31,32 where is the probability that the signal belongs to a considered amplitude interval with partitions and with the understanding that (a) with and (b) if . These methods used in quantitative EEG analysis were validated in our previous research 30,33–35 …”

“…The downsampled EEG was divided into nonoverlapping eight-second windows and decomposed into frequency bands using a onedimensional, five-level dyadic, symlet9 wavelet decomposition, which after coefficient-based reconstruction provides six signals representing the target ranges of supergamma as 61.5-122 Hz, gamma as 30.75-61.5 Hz, beta as 15.375-30.75 Hz, alpha as 7.688-15.375 Hz, theta as 3.844-7.688 Hz, and delta as 1.922-3.844 Hz. 30 The spectral power of each range was calculated from the wavelet coefficients using the Parseval equivalence identity. The total spectral power of all ranges was used as the denominator in calculating the power fraction.…”

“…These methods used in quantitative EEG analysis were validated in our previous research. 30,[33][34][35] For this study, post-resuscitation recording was up to 90 min, and isoflurane was not applied to the CAsubjected animals during this recording period, and the animals were allowed to recover spontaneously. In our prior work, animals subjected to 7-min CA remained comatose status over the first 2-3 h after resuscitation.…”