Hypothermic preconditioning attenuates hypobaric hypoxia induced spatial memory impairment in rats.

Hypobaric Hypoxia (HH) is known to cause oxidative stress in the brain that leads to spatial memory deficit and neurodegeneration. For decades therapeutic hypothermia is used to treat global and focal ischemia in preserving brain functions that proved to be beneficial in humans and rodents. Considering these previous reports, the present study was designed to establish the therapeutic potential of hypothermia preconditioning on HH induced spatial memory, biochemical and morphological changes in adult rats. Male Sprague Dawley rats were exposed to HH (7620 m, ~ 282 mmHg) for 1, 3 and 7 days with and without hypothermic preconditioning. Spatial learning memory was assessed by Morris water maze (MWM) test along with evaluation of hippocampal pyramidal neuron damage by histological study. Oxidative stress was measured by studying the levels of nitric oxide (NO), reactive oxygen species (ROS), lipid peroxidation (LPO), oxidized and reduced glutathione (GSSG and GSH). Results of MWM test indicated prolonged path length and latency to reach the platform in HH groups that regained to normal in cold pre-treated groups. A likely neurodegeneration was evident in HH groups that lessen in the cold pre-treated groups. Hypothermic preconditioning prevented spatial memory impairment and neurodegeneration in animals subjected to HH via decreasing the NO, ROS and LPO compared to control animals. The GSH level and GSH/GSSG ratio was found to be higher in preconditioned animals as compared to respective HH exposed animals, indicative of redox scavenging and restoration of hippocampal neuronal structure as well as spatial memory. Therefore, hypothermic preconditioning improves spatial memory deficit by reducing HH induced oxidative stress and hippocampal neurodegeneration, hence can be used as a multi-target prophylactic measure to combat HH induced neurodegeneration.

Rapid and persistent decrease in brain tissue oxygenation in ovine gram-negative sepsis.

The changes in brain perfusion and oxygenation in critical illness, which are thought to contribute to brain dysfunction, are unclear due to the lack of methods to measure these variables. We have developed a technique to chronically measure cerebral tissue perfusion and oxygen tension in unanesthetized sheep. Using this technique, we have determined the changes in cerebral perfusion and Po2 during the development of ovine sepsis. In adult Merino ewes, fiber-optic probes were implanted in the brain, renal cortex, and renal medulla to measure tissue perfusion, oxygen tension (Po2), and temperature, and flow probes were implanted on the pulmonary and renal arteries. Conscious sheep were infused with live Escherichia coli for 24 h, which induced hyperdynamic sepsis; mean arterial pressure decreased (from 85.2 ± 5.6 to 71.5 ± 8.7 mmHg), while cardiac output (from 4.12 ± 0.70 to 6.15 ± 1.26 L/min) and total peripheral conductance (from 48.9 ± 8.5 to 86.8 ± 11.5 mL/min/mmHg) increased (n = 8, all P < 0.001) and arterial Po2 decreased (from 104 ± 8 to 83 ± 10 mmHg; P < 0.01). Cerebral perfusion tended to decrease acutely, although this did not reach significance, but there was a significant and sustained decrease in cerebral tissue Po2 (from 32.2 ± 10.1 to 18.8 ± 11.7 mmHg) after 3 h and to 22.8 ± 5.2 mmHg after 24 h of sepsis (P < 0.02). Sepsis induced large reductions in both renal medullary perfusion and Po2 but had no effect in the renal cortex. In ovine sepsis, there is an early decrease in cerebral Po2 that is maintained for 24 h despite minimal changes in cerebral perfusion. Cerebral hypoxia may be one of the factors causing sepsis-induced malaise and lethargy.

EEG patterns and their correlations with short- and long-term mortality in patients with hypoxic encephalopathy.

OBJECTIVE: To analyze the association between electroencephalographic (EEG) patterns and overall, short- and long-term mortality in patients with hypoxic encephalopathy (HE). METHODS: Retrospective, mono-center analysis of 199 patients using univariate log-rank tests (LR) and multivariate cox regression (MCR). RESULTS: Short-term mortality, defined as death within 30-days post-discharge was 54.8%. Long-term mortality rates were 69.8%, 71.9%, and 72.9%, at 12-, 24-, and 36-months post-HE, respectively. LR revealed a significant association between EEG suppression (SUP) and short-term mortality, and identified low voltage EEG (LV), burst suppression (BSP), periodic discharges (PD) and post-hypoxic status epilepticus (PSE) as well as missing (aBA) or non-reactive background activity (nrBA) as predictors for overall, short- and long-term mortality. MCR indicated SUP, LV, BSP, PD, aBA and nrBA as significantly associated with overall and short-term mortality to varying extents. LV and BSP were significant predictors for long-term mortality in short-term survivors. Rhythmic delta activity, stimulus induced rhythmic, periodic or ictal discharges and sharp waves were not significantly associated with a higher mortality. CONCLUSION: The presence of several specific EEG patterns can help to predict overall, short- and long-term mortality in HE patients. SIGNIFICANCE: The present findings may help to improve the challenging prognosis estimation in HE patients.

Tubular calcium, magnesium, and phosphate excretion during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy: A prospective study.

OBJECTIVES: Hypocalcemia, hypomagnesemia, and hyperphosphatemia are common electrolyte disturbances in perinatal asphyxia (PA). Different reasons have been proposed for these electrolyte disturbances. This study investigated the effect of the urinary excretion of calcium (Ca), magnesium (Mg), and phosphorus (P) on the serum levels of these substances in babies who were treated using therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) caused by PA. This study sheds light on the pathophysiology that may cause changes in the serum values of these electrolytes. METHODS: This study included 21 healthy newborns (control group) and 38 patients (HIE group) who had undergone therapeutic hypothermia due to HIE. Only infants with a gestational age of 36 weeks and above and a birth weight of 2000 g and above were evaluated. The urine and serum Ca, Mg, P, and creatinine levels of all infants were evaluated at 24, 48, and 72 h. RESULTS: The lower serum Ca value and the higher serum P value of the HIE group were found to be statistically significant compared to the control group (p<0.05). There was no significant difference in serum Mg values between the groups. However, hypomagnesemia was detected in five patients from the HIE group. The urine excretion of FeCa and FeMg at 24 h, and FeP excretion at 48 and 72 h were found to be significantly higher in the HIE group compared to the control group. CONCLUSIONS: This study determined that the urinary excretion of Ca, Mg, and P has an effect on the serum Ca, Mg, and P levels of infants with HIE.

Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia.

Many genetic and environmental factors increase susceptibility to cognitive impairment (CI), and the gut microbiome is increasingly implicated. However, the identity of gut microbes associated with CI risk, their effects on CI, and their mechanisms remain unclear. Here, we show that a carbohydrate-restricted (ketogenic) diet potentiates CI induced by intermittent hypoxia in mice and alters the gut microbiota. Depleting the microbiome reduces CI, whereas transplantation of the risk-associated microbiome or monocolonization with Bilophila wadsworthia confers CI in mice fed a standard diet. B. wadsworthia and the risk-associated microbiome disrupt hippocampal synaptic plasticity, neurogenesis, and gene expression. The CI is associated with microbiome-dependent increases in intestinal interferon-gamma (IFNg)-producing Th1 cells. Inhibiting Th1 cell development abrogates the adverse effects of both B. wadsworthia and environmental risk factors on CI. Together, these findings identify select gut bacteria that contribute to environmental risk for CI in mice by promoting inflammation and hippocampal dysfunction.

EEG functional connectivity contributes to outcome prediction of postanoxic coma.

OBJECTIVE: To investigate the additional value of EEG functional connectivity features, in addition to non-coupling EEG features, for outcome prediction of comatose patients after cardiac arrest. METHODS: Prospective, multicenter cohort study. Coherence, phase locking value, and mutual information were calculated in 19-channel EEGs at 12 h, 24 h and 48 h after cardiac arrest. Three sets of machine learning classification models were trained and validated with functional connectivity, EEG non-coupling features, and a combination of these. Neurological outcome was assessed at six months and categorized as "good" (Cerebral Performance Category [CPC] 1-2) or "poor" (CPC 3-5). RESULTS: We included 594 patients (46% good outcome). A sensitivity of 51% (95% CI: 34-56%) at 100% specificity in predicting poor outcome was achieved by the best functional connectivity-based classifier at 12 h after cardiac arrest, while the best non-coupling-based model reached a sensitivity of 32% (0-54%) at 100% specificity using data at 12 h and 48 h. Combination of both sets of features achieved a sensitivity of 73% (50-77%) at 100% specificity. CONCLUSION: Functional connectivity measures improve EEG based prediction models for poor outcome of postanoxic coma. SIGNIFICANCE: Functional connectivity features derived from early EEG hold potential to improve outcome prediction of coma after cardiac arrest.

Cerebral oxygen saturation and autoregulation during hypotension in extremely preterm infants.

BACKGROUND: The impact of the permissive hypotension approach in clinically well infants on regional cerebral oxygen saturation (rScO2) and autoregulatory capacity (CAR) remains unknown. METHODS: Prospective cohort study of blinded rScO2 measurements within a randomized controlled trial of management of hypotension (HIP trial) in extremely preterm infants. rScO2, mean arterial blood pressure, duration of cerebral hypoxia, and transfer function (TF) gain inversely proportional to CAR, were compared between hypotensive infants randomized to receive dopamine or placebo and between hypotensive and non-hypotensive infants, and related to early intraventricular hemorrhage or death. RESULTS: In 89 potentially eligible HIP trial patients with rScO2 measurements, the duration of cerebral hypoxia was significantly higher in 36 hypotensive compared to 53 non-hypotensive infants. In 29/36 hypotensive infants (mean GA 25 weeks, 69% males) receiving the study drug, no significant difference in rScO2 was observed after dopamine (n = 13) compared to placebo (n = 16). Duration of cerebral hypoxia was associated with early intraventricular hemorrhage or death.  Calculated TF gain (n = 49/89) was significantly higher reflecting decreased CAR in 16 hypotensive compared to 33 non-hypotensive infants. CONCLUSIONS: Dopamine had no effect on rScO2 compared to placebo in hypotensive infants. Hypotension and cerebral hypoxia are associated with early intraventricular hemorrhage or death. IMPACT: Treatment of hypotension with dopamine in extremely preterm infants increases mean arterial blood pressure, but does not improve cerebral oxygenation. Hypotensive extremely preterm infants have increased duration of cerebral hypoxia and reduced cerebral autoregulatory capacity compared to non-hypotensive infants. Duration of cerebral hypoxia and hypotension are associated with early intraventricular hemorrhage or death in extremely preterm infants. Since systematic treatment of hypotension may not be associated with better outcomes, the diagnosis of cerebral hypoxia in hypotensive extremely preterm infants might guide treatment.

Cerebral Oxygenation and Perfusion when Positioning Preterm Infants: Clinical Implications.

OBJECTIVES: To evaluate cerebral tissue oxygenation (cTOI) and cerebral perfusion in preterm infants in supine vs prone positions. STUDY DESIGN: Sixty preterm infants, born before 32 weeks of gestation, were enrolled; 30 had bronchopulmonary dysplasia (BPD, defined as the need for respiratory support and/or supplemental oxygen at 36 weeks of postmenstrual age). Cerebral perfusion, cTOI, and polysomnography were measured in both the supine and prone position with the initial position being randomized. Infants with a major intraventricular hemorrhage or major congenital abnormality were excluded. RESULTS: Cerebral perfusion was unaffected by position or BPD status. In the BPD group, the mean cTOI was higher in the prone position compared with the supine position by a difference of 3.27% (P = .03; 95% CI 6.28-0.25) with no difference seen in the no-BPD group. For the BPD group, the burden of cerebral hypoxemia (cumulative time spent with cTOI <55%) was significantly lower in the prone position (23%) compared with the supine position (29%) (P < .001). In those without BPD, position had no effect on cTOI. CONCLUSIONS: In preterm infants with BPD, the prone position improved cerebral oxygenation and reduced cerebral hypoxemia. These findings may have implications for positioning practices. Further research will establish the impact of position on short- and long-term developmental outcomes.

Impact of neonatal anoxia and hypothermic treatment on development and memory of rats.

Therapeutic hypothermia (TH) is well established as a standard treatment for term and near-term infants. However, therapeutic effects of hypothermia following neonatal anoxia in very premature babies remains inconclusive. The present rodent model of preterm neonatal anoxia has been shown to alter developmental milestones and hippocampal neurogenesis, and to disrupt spatial learning and memory in adulthood. These effects seem to be reduced by post-insult hypothermia. Epigenetic-related mechanisms have been postulated as valuable tools for developing new therapies. Dentate gyrus neurogenesis is regulated by epigenetic factors. This study evaluated whether TH effects in a rodent model of preterm oxygen deprivation are based on epigenetic alterations. The effects of TH on both developmental features (somatic growth, maturation of physical characteristics and early neurological reflexes) and performance of behavioral tasks at adulthood (spatial reference and working memory, and fear conditioning) were investigated in association with the possible involvement of the epigenetic operator Enhancer of zeste homolog 2 (Ezh2), possibly related to long-lasting effects on hippocampal neurogenesis. Results showed that TH reduced both anoxia-induced hippocampal neurodegeneration and anoxia-induced impairments on risk assessment behavior, acquisition of spatial memory, and extinction of auditory and contextual fear conditioning. In contrast, TH did not prevent developmental alterations caused by neonatal anoxia and did not restore hippocampal neurogenesis or cause changes in EZH2 levels. In conclusion, despite the beneficial effects of TH in hippocampal neurodegeneration and in reversing disruption of performance of behavioral tasks following oxygen deprivation in prematurity, these effects seem not related to developmental alterations and hippocampal neurogenesis and, apparently, is not caused by Ezh2-mediated epigenetic alteration.

Recovery of Hypoxic Regions in a Rat Model of Microembolism.

OBJECTIVES: Endovascular treatment (EVT) has become the standard of care for acute ischemic stroke. Despite successful recanalization, a limited subset of patients benefits from the new treatment. Human MRI studies have shown that during removal of the thrombus, a shower of microclots is released from the initial thrombus, possibly causing new ischemic lesions. The aim of the current study is to quantify tissue damage following microembolism. MATERIALS AND METHODS: In a rat model, microembolism was generated by injection of a mixture of polystyrene fluorescent microspheres (15, 25 and 50 µm in diameter). The animals were killed at three time-points: day 1, 3 or 7. AMIRA and IMARIS software was used for 3D reconstruction of brain structure and damage, respectively. CONCLUSIONS: Microembolism induces ischemia, hypoxia and infarction. Infarcted areas persist, but hypoxic regions recover over time suggesting that repair processes in the brain rescue the regions at risk.

Cerebral Hypoxia: Its Role in Age-Related Chronic and Acute Cognitive Dysfunction.

Postoperative cognitive dysfunction (POCD) has been reported with widely varying frequency but appears to be strongly associated with aging. Outside of the surgical arena, chronic and acute cerebral hypoxia may exist as a result of respiratory, cardiovascular, or anemic conditions. Hypoxia has been extensively implicated in cognitive impairment. Furthermore, disease states associated with hypoxia both accompany and progress with aging. Perioperative cerebral hypoxia is likely underdiagnosed, and its contribution to POCD is underappreciated. Herein, we discuss the various disease processes and forms in which hypoxia may contribute to POCD. Furthermore, we outline hypoxia-related mechanisms, such as hypoxia-inducible factor activation, cerebral ischemia, cerebrovascular reserve, excitotoxicity, and neuroinflammation, which may contribute to cognitive impairment and how these mechanisms interact with aging. Finally, we discuss opportunities to prevent and manage POCD related to hypoxia.

Surveillance Study of Acute Neurological Manifestations among 439 Egyptian Patients with COVID-19 in Assiut and Aswan University Hospitals.

BACKGROUND: COVID-19 can be accompanied by acute neurological complications of both central and peripheral nervous systems (CNS and PNS). In this study, we estimate the frequency of such complications among hospital inpatients with COVID-19 in Assiut and Aswan university hospitals. MATERIALS AND METHODS: We screened all patients with suspected COVID-19 admitted from 1 June to 10 August 2020 to the university hospitals of Assiut and Aswan in Upper Egypt. Clinical and laboratory tests, CT/MRI of the chest and brain, and neurophysiology study were performed for each patient if indicated. RESULTS: 439 patients had confirmed/probable COVID-19; neurological manifestations occurred in 222. Of these, 117 had acute neurological disease and the remainder had nonspecific neuropsychiatric symptoms such as headache, vertigo, and depression. The CNS was affected in 75 patients: 55 had stroke and the others had convulsions (5), encephalitis (6), hypoxic encephalopathy (4), cord myelopathy (2), relapse of multiple sclerosis (2), and meningoencephalitis (1). The PNS was affected in 42 patients: the majority had anosmia and ageusia (31) and the others had Guillain-Barré syndrome (4), peripheral neuropathy (3), myasthenia gravis (MG, 2), or myositis (2). Fever, respiratory symptoms, and headache were the most common general symptoms. Hypertension, diabetes mellitus, and ischemic heart disease were the most common comorbidities in patients with CNS affection. CONCLUSION: In COVID-19, both the CNS and PNS are affected. Stroke was the most common complication for CNS, and anosmia and/or ageusia were common for PNS diseases. However, there were 6 cases of encephalitis, 2 cases of spinal cord myelopathy, 2 cases of MG, and 2 cases of myositis.

Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce 'Brain Fog' and Results in Behavioral Changes that Favor Viral Survival.

Alterations in brain functioning, especially in regions associated with cognition, can result from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and are predicted to result in various psychiatric diseases. Recent studies have shown that SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) can directly or indirectly affect the central nervous system (CNS). Therefore, diseases associated with sequelae of COVID-19, or 'long COVID', also include serious long-term mental and cognitive changes, including the condition recently termed 'brain fog'. Hypoxia in the microenvironment of select brain areas may benefit the reproductive capacity of the virus. It is possible that in areas of cerebral hypoxia, neuronal cell energy metabolism may become compromised after integration of the viral genome, resulting in mitochondrial dysfunction. Because of their need for constant high metabolism, cerebral tissues require an immediate and constant supply of oxygen. In hypoxic conditions, neurons with the highest oxygen demand become dysfunctional. The resulting cognitive impairment benefits viral spread, as infected individuals exhibit behaviors that reduce protection against infection. The effects of compromised mitochondrial function may also be an evolutionary advantage for SARS-CoV-2 in terms of host interaction. A high viral load in patients with COVID-19 that involves the CNS results in the compromise of neurons with high-level energy metabolism. Therefore, we propose that selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce 'brain fog' and results in behavioral changes that favor viral propagation. Cognitive changes associated with COVID-19 will have increasing significance for patient diagnosis, prognosis, and long-term care.

Relationship between Brain Tissue Oxygen Tension and Transcranial Doppler Ultrasonography.

BACKGROUND: Multimodal monitoring of intracranial pressure and brain tissue oxygen tension (PbtO2) have been increasingly used to detect delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. At our center, patients who cannot be easily assessed clinically will undergo intracranial pressure and PbtO2 monitoring via a NEUROVENT-PTO bolt. We aimed to determine whether the Lindegaard ratios (LRs) computed from transcranial Doppler ultrasonography (TCDU) would correlate with, or can predict, the simultaneously recorded PbtO2 value. METHODS: Patients with aneurysmal subarachnoid hemorrhage, PbtO2 recordings from the middle cerebral artery territory, and simultaneous TCDU scans available from the ipsilateral middle cerebral artery and internal carotid artery from August 2018 to 2019 were included in the present study. The index test result was vasospasm (LR of ≥3) found on TCDU. The reference standard was the presence of regional hypoxia (PbtO2 <20 mm Hg). The PbtO2 results were compared with those from computed tomography angiography as a radiological standard. The predictive values were calculated using a contingency table and receiver operating characteristic curve. RESULTS: A total of 28 patients (6 men and 22 women; age, 59.04 ± 13.75 years) were identified with simultaneous brain tissue oxygen and TCDU recordings available. Of the 28 patients, 7 had cerebral hypoxia (PbtO2 <20 mm Hg). We found no correlation between the PbtO2 measurements and simultaneously recorded LRs (r2 = 0.048; P = 0.26). A LR of ≥3 had high specificity (95.24%) for hypoxia but relatively low sensitivity (42.86%; P = 0.037). CONCLUSION: We find TCDU to be specific for predicting cerebral hypoxia (measured via an intraparenchymal probe). Therefore, it could be a useful and noninvasive tool in the context of preventative DCI monitoring. However, given the low sensitivity, the lack of vasospasm on TCDU should not preclude the possibility of the presence of evolving DCI.

Clinical Correlates of Frontal Intermittent Rhythmic Delta Activity Without Structural Brain Lesion.

Frontal intermittent rhythmic delta activity (FIRDA), rhythmic slow wave pattern lasting several seconds over the anterior leads of electroencephalography (EEG), has been reported in a wide variety of clinical conditions. We investigated the clinical significance of FIRDA without structural brain lesions. We reviewed 7689 EEGs between October 2017 and September 2019 at a university hospital. Patients (age >18 years) who were confirmed to have "nonsignificant neuroimaging" were examined. Clinical data were retrospectively collected, and the estimated cause was carefully decided. We found 83 FIRDA among 7689 EEGs (1.08%). After patients with any structural lesion identified on neuroimaging were excluded, 37 FIRDAs were reviewed. There were 20 (51.35%) patients of metabolic encephalopathy. Six patients showed FIRDA due to neurodegenerative disease (16.21%). In addition, we found 6 (16.21%) of neurodegenerative disease and 5 (13.51%) of hypoxic encephalopathy (cardiac arrest). Four (16.21%) patients were related to systemic infection (10.81%), whereas 2 were related to encephalitis (5.40%). We demonstrated several potential etiologies, including metabolic encephalopathy, neurodegenerative disease, hypoxic encephalopathy, and infections, which should be considered in the case of FIRDA without structural brain lesions.

Influence of exertional hypoxemia on cerebral oxygenation in fibrotic interstitial lung disease.

It is unknown whether hypoxemia, a hallmark of fibrotic interstitial lung disease (f-ILD), may impair cerebral oxygenation during exercise in these patients. Twenty-seven patients [23 males, 72 ± 8 years, lung diffusing capacity for carbon monoxide (DLCO) = 44 ± 11 % predicted] and 12 controls performed an incremental bicycle test. Prefrontal oxygenation [tissue saturation index (TSI)] was assessed by near-infrared spectroscopy. Patients showed lower arterial O2 saturation (SpO2) and larger fall in cerebral TSI during exercise vs controls (p < 0.05). However, changes (Δ) from rest to peak-exercise in SpO2 (-2.2 % to -26.9 %) and TSI (1.4 % to -16.6 %) varied substantially among patients. In the 16 patients showing significant cerebral deoxygenation (Δ TSI ≥ 4% based on controls), SpO2 decreased more (-12.6 ± 6.7 % vs -5.7 ± 2.8 %, p = 0.001) and peak O2 uptake was lower (68.3 ± 19.2 % vs 87.8 ± 24.8 % predicted, p = 0.03) vs their 11 counterparts. In association with DLCO and forced vital capacity, Δ cerebral TSI independently predicted peak O2 uptake on multivariable regression analysis (R2 = 0.54). Exertional hypoxemia impairs cerebral oxygenation in a dose-dependent fashion in f-ILD. Future studies are warranted to investigate whether this potentially reversible abnormality play a contributory role in limiting exercise tolerance in these patients.

Occlusion of activity dependent synaptic plasticity by late hypoxic long term potentiation after neonatal intermittent hypoxia.

To elucidate the mechanisms of memory impairment after chronic neonatal intermittent hypoxia (IH), we employed a mice model of severe IH administered at postnatal days 3 to 7. Since prior studies in this model did not demonstrate increased cell death, our primary hypothesis was that IH causes a functional disruption of synaptic plasticity in hippocampal neurons. In vivo recordings of Schaffer collateral stimulation-induced synaptic responses during and after IH in the CA1 region of the hippocampus revealed pathological late phase hypoxic long term potentiation (hLTP) (154%) that lasted more than four hours and could be reversed by depotentiation with low frequency stimulation (LFS), or abolished by NMDA and PKA inhibitors (MK-801 and CMIQ). Furthermore, late phase hLTP partially occluded normal physiological LTP (pLTP) four hours after IH. Early and late hLTP phases were induced by neuronal depolarization and Ca2+ influx, determined with manganese enhanced fMRI, and had increased both AMPA and NMDA - mediated currents. This was consistent with mechanisms of pLTP in neonates and also consistent with mechanisms of ischemic LTP described in vitro with OGD in adults. A decrease of pLTP was also recorded on hippocampal slices obtained 2 days after IH. This decrease was ameliorated by MK-801 injections prior to each IH session and restored by LFS depotentiation. Occlusion of pLTP and the observed decreased proportion of NMDA-only silent synapses after neonatal hLTP may explain long term memory, behavioral deficits and abnormal synaptogenesis and pruning following neonatal IH.