Sleep dysfunction following neonatal ischemic seizures are differential by neonatal age of insult as determined by qEEG in a mouse model.

Neonatal seizures associated with hypoxic-ischemic encephalopathy (HIE) pose a challenge in their acute clinical management and are often followed by long-term neurological consequences. We used a newly characterized CD-1 mouse model of neonatal ischemic seizures associated with age-dependent (P7 vs. P10) seizure severity and phenobarbital efficacy (i.e.; PB-resistant vs. PB-efficacious respectively) following unilateral carotid ligation. The long-term consequences following untreated neonatal seizures in P7 vs. P10 ligated pups were investigated using neurobehavioral testing, 24 h v- quantitative EEG -EMG (qEEG, qEMG), and western blot analyses in adult mice. Significant hyperactivity emerged in a small sub-set of mice in both age-groups associated with a failure to habituate during open-field (OF) testing. 24 h continuous qEEGs detected significantly altered sleep architecture due to long-wake cycles in both age-groups. Delta power (0.5-4 Hz) quantification during slow-wave-sleep (SWS) revealed significant SWS compensation in P10 ligates following periods of increased sleep pressure which the P7 ligate group failed to show. Theta/beta ratios deemed as negative correlation markers of attentional control were significantly higher only in the P10 ligates. These results indicate that neonatal age-dependent differences in the characteristics of ischemic neonatal seizures in CD-1 pups differentially modulate long-term outcomes, when evaluated with v-qEEG/EMG as adults.

Rescue of PB-resistant neonatal seizures with single-dose of small-molecule TrkB antagonist show long-term benefits.

A recently characterized CD-1 mouse model of phenobarbital (PB)-resistant neonatal ischemic-seizures (i.e.; unilateral carotid ligation) was shown to be associated with age-dependent (P7 vs. P10) acute seizure severity and PB-efficacy (i.e.; PB-resistant vs. PB-responsive). ANA12, a novel small-molecule TrkB antagonist, rescued the PB-resistance at P7 in a dose-dependent manner and prevented the post-ischemic downregulation of KCC2, the chief Cl- extruder in neurons. The long-term consequences of this novel rescue-intervention with ANA12 + PB in P7 and P10 ligated pups was investigated and compared to the standard first-line protocol of PB-alone loading dose. The mice underwent neurobehavioral testing, 24 h video-EEG-EMG monitoring, and immunohistochemistry in ipsi- and contralateral cortices as adults following the neonatal interventions. ANA12 + PB rescued the emergence of hyperactivity in post-ischemic P7, but not in P10 pups as adults. ANA12 + PB administration at neither P7 nor P10 significantly altered 24 h macro-sleep architecture in adults when compared to PB-alone. Behavioral state-dependent gamma (35-50 Hz) power homeostasis showed the most significant between-group differences that were age-dependent. ANA12 + PB treatment, but not PB-alone, rescued the loss of gamma power homeostasis present in P7 ligate-control but absent in P10 ligate group, highlighting the age-dependence. In contrast, PB-alone treatment, but not ANA12+PB, significantly reduced the elevated delta-AUC observed in P10 ligate-controls, when PB is efficacious by itself. These results indicate that the rescue of acute PB-resistant neonatal seizures using a novel intervention positively modulates the long-term outcomes at P7 when the seizures are refractory.

Reduced Jet Velocity in Venous Flow after CSF Drainage: Assessing Hemodynamic Causes of Pulsatile Tinnitus.

BACKGROUND AND PURPOSE: Idiopathic intracranial hypertension is commonly associated with transverse sinus stenosis, a venous cause of pulsatile tinnitus. In patients with idiopathic intracranial hypertension, CSF drainage via lumbar puncture decreases intracranial pressure, which relieves the stenosis, and may provide at least temporary cessation of pulsatile tinnitus. The objective of this study was to evaluate changes in venous blood flow caused by lowered intracranial pressure in patients with pulsatile tinnitus to help identify the cause of pulsatile tinnitus. MATERIALS AND METHODS: Ten patients with suspected transverse sinus stenosis as a venous etiology for pulsatile tinnitus symptoms underwent MR imaging before and after lumbar puncture in the same session. The protocol included flow assessment and rating of pulsatile tinnitus intensity before and after lumbar puncture and MR venography before lumbar puncture. Post-lumbar puncture MR venography was performed in 1 subject. RESULTS: There was a lumbar puncture-induced reduction in venous peak velocity that correlated with the opening pressure (r = -0.72, P = .019) without a concomitant reduction in flow rate. Patients with flow jets had their peak velocity reduced by 0.30 ± 0.18 m/s (P = .002), correlating with a reduction in CSF pressure (r = 0.82, P = .024) and the reduction in subjectively scored pulsatile tinnitus intensity (r = 0.78, P = .023). The post-lumbar puncture MR venography demonstrated alleviation of the stenosis. CONCLUSIONS: Our results show a lumbar puncture-induced reduction in venous peak velocity without a concomitant reduction in flow rate. We hypothesize that the reduction is caused by the expansion of the stenosis after lumbar puncture. Our results further show a correlation between the peak velocity and pulsatile tinnitus intensity, suggesting the flow jet to be instrumental in the development of sound.

Circadian cycle-dependent EEG biomarkers of pathogenicity in adult mice following prenatal exposure to in utero inflammation.

Intrauterine infection or inflammation in preterm neonates is a known risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. Our previous data suggest that there is acute fetal brain inflammation in a mouse model of intrauterine exposure to lipopolysaccharides (LPS). We hypothesized that the in utero inflammation induced by LPS produces long-term electroencephalogram (EEG) biomarkers of neurodegeneration in the exposed mice that could be determined by using continuous quantitative video/EEG/electromyogram (EMG) analyses. A single LPS injection at E17 was performed in pregnant CD1 dams. Control dams were injected with same volumes of saline (LPS n=10, Control n=8). At postnatal age of P90-100, 24-h synchronous video/EEG/EMG recordings were done using a tethered recording system and implanted subdural electrodes. Behavioral state scoring was performed blind to treatment group, on each 10s EEG epoch using synchronous video, EMG and EEG trace signatures to generate individual hypnograms. Automated EEG power spectrums were analyzed for delta and theta-beta power ratios during wake vs. sleep cycles. Both control and LPS hypnograms showed an ultradian wake/sleep cycling. Since rodents are nocturnal animals, control mice showed the expected diurnal variation with significantly longer time spent in wake states during the dark cycle phase. In contrast, the LPS-treated mice lost this circadian rhythm. Sleep microstructure also showed significant alteration in the LPS mice specifically during the dark cycle, caused by significantly longer average non-rapid eye movement (NREM) cycle durations. No significance was found between treatment groups for the delta power data; however, significant activity-dependent changes in theta-beta power ratios seen in controls were absent in the LPS-exposed mice. In conclusion, exposure to in utero inflammation in CD1 mice resulted in significantly altered sleep architecture as adults that were circadian cycle and activity state dependent.