scholarly journals Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia

2017 ◽  
Vol 39 (1-4) ◽  
pp. 156-170 ◽  
Author(s):  
Mojgan Ezzati ◽  
Go Kawano ◽  
Eridan Rocha-Ferreira ◽  
Daniel Alonso-Alconada ◽  
Jane K. Hassell ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Hypothermia ◽  
Perinatal Asphyxia ◽  
White Male ◽  
Brain Regions ◽  
Resonance Spectroscopy ◽  
Large White ◽  
Whole Brain ◽  
Effective Adjunct ◽  
Fentanyl Group

The selective α2-adrenoreceptor agonist dexmedetomidine has shown neuroprotective, analgesic, anti-inflammatory, and sympatholytic properties that may be beneficial in neonatal encephalopathy (NE). As therapeutic hypothermia is only partially effective, adjunct therapies are needed to optimize outcomes. The aim was to assess whether hypothermia + dexmedetomidine treatment augments neuroprotection compared to routine treatment (hypothermia + fentanyl sedation) in a piglet model of NE using magnetic resonance spectroscopy (MRS) biomarkers, which predict outcomes in babies with NE, and immunohistochemistry. After hypoxia-ischaemia (HI), 20 large White male piglets were randomized to: (i) hypothermia + fentanyl with cooling to 33.5°C from 2 to 26 h, or (ii) hypothermia + dexmedetomidine (a loading dose of 2 μg/kg at 10 min followed by 0.028 μg/kg/h for 48 h). Whole-brain phosphorus-31 and regional proton MRS biomarkers were assessed at baseline, 24, and 48 h after HI. At 48 h, cell death was evaluated over 7 brain regions by means of transferase-mediated d-UTP nick end labeling (TUNEL). Dexmedetomidine plasma levels were mainly within the target sedative range of 1 μg/L. In the hypothermia + dexmedetomidine group, there were 6 cardiac arrests (3 fatal) versus 2 (non-fatal) in the hypothermia + fentanyl group. The hypothermia + dexmedetomidine group required more saline (p = 0.005) to maintain blood pressure. Thalamic and white-matter lactate/N-acetylaspartate did not differ between groups (p = 0.66 and p = 0.21, respectively); the whole-brain nucleotide triphosphate/exchangeable phosphate pool was similar (p = 0.73) over 48 h. Cell death (TUNEL-positive cells/mm2) was higher in the hypothermia + dexmedetomidine group than in the hypothermia + fentanyl group (mean 5.1 vs. 2.3, difference 2.8 [95% CI 0.6-4.9], p = 0.036). Hypothermia + dexmedetomidine treatment was associated with adverse cardiovascular events, even within the recommended clinical sedative plasma level; these may have been exacerbated by an interaction with either isoflurane or low body temperature. Hypothermia + dexmedetomidine treatment was neurotoxic following HI in our piglet NE model, suggesting that caution is vital if dexmedetomidine is combined with cooling following NE.

scholarly journals Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia

2020 ◽  
Author(s):  
Raymand Pang ◽  
Adnan Avdic-Belltheus ◽  
Christopher Meehan ◽  
Kathryn Martinello ◽  
Tatenda Mutshiya ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Triple Therapy ◽  
Sensorimotor Cortex ◽  
Perinatal Asphyxia ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Resonance Spectroscopy ◽  
Periventricular White Matter ◽  
Deoxyuridine Triphosphate ◽  
Hypoxia Ischemia ◽  
Effective Adjunct

Abstract As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-hour hypothermia (double therapies) and hypothermia + melatonin + erythropoietin (triple therapy) leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (<48 hours old) were randomized to: (i) hypothermia + vehicle (n = 12), (ii) hypothermia + melatonin (20 mg/kg over 2 hours) (n = 12), (iii) hypothermia + erythropoietin (3000 U/kg bolus) (n = 13) or (iv) triple therapy (n = 12). Melatonin, erythropoietin or vehicle were given at 1, 24 and 48 hours after hypoxia-ischemia. Hypoxia-ischemia severity was similar across groups. Therapeutic levels were achieved 3 hours after hypoxia-ischemia for melatonin (15-30mg/L) and within 30 minutes of erythropoietin administration (maximum concentration 10,000 mU/mL). Compared to hypothermia + vehicle, we observed faster amplitude integrated EEG recovery from 25-30 hours with hypothermia + melatonin (p = 0.02) and hypothermia + erythropoietin (p = 0.033) and from 55-60 hours with triple therapy (p = 0.042). Magnetic Resonance Spectroscopy Lactate/N-acetyl aspartate peak ratio was lower at 66 hours in hypothermia + melatonin (p = 0.012) and triple therapy (p = 0.032). With hypothermia + melatonin, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells were reduced in sensorimotor cortex (p = 0.017) and oligodendrocyte transcription factor 2 labelled-positive counts increased in hippocampus (p = 0.014) and periventricular white matter (p = 0.039). There was no reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells with hypothermia + erythropoietin, but increased oligodendrocyte transcription factor 2 labelled-positive cells in 5 of 8 brain regions (p < 0.05). Overall, melatonin and erythropoietin were safe and effective adjunct therapies to hypothermia. Hypothermia + melatonin double therapy led to faster amplitude integrated EEG recovery, amelioration of Lactate/N-acetyl aspartate rise and reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells in the sensorimotor cortex. Hypothermia + erythropoietin double therapy was association with EEG recovery and was most effective in promoting oligodendrocyte survival. Triple therapy provided no added benefit over the double therapies in this 72-hour study. Melatonin and erythropoietin influenced cell death and oligodendrocyte survival differently, reflecting distinct neuroprotective mechanisms which may become more visible with longer term studies. Staggering the administration of therapies with early melatonin and later erythropoietin (after hypothermia) may provide better protection; each therapy has complementary actions which may be time critical during the neurotoxic cascade after hypoxia-ischemia.

scholarly journals The effects of therapeutic hypothermia on cerebral metabolism in neonates with hypoxic-ischemic encephalopathy: An in vivo 1H-MR spectroscopy study

2015 ◽  
Vol 36 (6) ◽  
pp. 1075-1086 ◽  
Author(s):  
Jessica L Wisnowski ◽  
Tai-Wei Wu ◽  
Aaron J Reitman ◽  
Claire McLean ◽  
Philippe Friedlich ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
Energy Demand ◽  
Cerebral Metabolism ◽  
Brain Regions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Cerebral White Matter ◽  
Similar Degree ◽  
Resonance Spectroscopy ◽  
Ischemic Encephalopathy

Therapeutic hypothermia has emerged as the first empirically supported therapy for neuroprotection in neonates with hypoxic-ischemic encephalopathy (HIE). We used magnetic resonance spectroscopy (1H-MRS) to characterize the effects of hypothermia on energy metabolites, neurotransmitters, and antioxidants. Thirty-one neonates with HIE were studied during hypothermia and after rewarming. Metabolite concentrations (mmol/kg) were determined from the thalamus, basal ganglia, cortical grey matter, and cerebral white matter. In the thalamus, phosphocreatine concentrations were increased by 20% during hypothermia when compared to after rewarming (3.49 ± 0.88 vs. 2.90 ± 0.65, p < 0.001) while free creatine concentrations were reduced to a similar degree (3.00 ± 0.50 vs. 3.74 ± 0.85, p < 0.001). Glutamate (5.33 ± 0.82 vs. 6.32 ± 1.12, p < 0.001), aspartate (3.39 ± 0.66 vs. 3.87 ± 1.19, p < 0.05), and GABA (0.92 ± 0.36 vs. 1.19 ± 0.41, p < 0.05) were also reduced, while taurine (1.39 ± 0.52 vs. 0.79 ± 0.61, p < 0.001) and glutathione (2.23 ± 0.41 vs. 2.09 ± 0.33, p < 0.05) were increased. Similar patterns were observed in other brain regions. These findings support that hypothermia improves energy homeostasis by decreasing the availability of excitatory neurotransmitters, and thereby, cellular energy demand.

scholarly journals Whole-Brain High-Resolution Metabolite Mapping with 3D Compressed-Sensing-SENSE-LowRank 1H FID-MRSI

2020 ◽  
Author(s):  
Antoine Klauser ◽  
Paul Klauser ◽  
Frédéric Grouiller ◽  
Sebastien Courvoisier ◽  
Francois Lazeyras
Keyword(s):  
High Resolution ◽  
Brain Regions ◽  
Low Rank ◽  
Acquisition Time ◽  
Resonance Spectroscopy ◽  
Brain Anatomy ◽  
Reconstruction Technique ◽  
Whole Brain ◽  
Isotropic Resolution

There is a growing interest of the neuroscience community to map the distribution of brain metabolites in vivo. Magnetic resonance spectroscopy imaging (MRSI) is often limited by either a poor spatial resolution and/or a long acquisition time which severely limits its applications for clinical or research purposes. We developed a novel acquisition-reconstruction technique combining fast 1H-FID-MRSI sequence accelerated by random k-space undersampling and a low-rank and total-generalized variation (TGV) constrained model. This framework was applied to the brain of four healthy volunteers. Following 20 min acquisition, reconstruction and quantification, the resulting metabolic maps with a 5 mm isotropic resolution reflected the detailed neurochemical composition of all brain regions and revealed part of the underlying brain anatomy. Contrasts and features from the 3D metabolite distributions were in agreement with the literature and consistent across the four subjects. The successful combination of the 3D 1H-FID-MRSI with a constrained reconstruction enables the detailed mapping of metabolite concentrations at high-resolution in the whole brain and with an acquisition time that is compatible with clinical or research settings.

Conceptual disorganization and redistribution of resting state cortical hubs in untreated first episode psychosis: A 7T MRI study

2020 ◽  
Author(s):  
Avyarthana Dey ◽  
Kara Dempster ◽  
Michael Mackinley ◽  
Peter Jeon ◽  
Tushar Das ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Superior Temporal Gyrus ◽  
Brain Regions ◽  
First Episode Psychosis ◽  
Cortical Reorganization ◽  
First Episode ◽  
Formal Thought Disorder ◽  
Whole Brain ◽  
Episode Psychosis ◽  
Positive And Negative Symptoms

Background:Network level dysconnectivity has been studied in positive and negative symptoms of schizophrenia. Conceptual disorganization (CD) is a symptom subtype which predicts impaired real-world functioning in psychosis. Systematic reviews have reported aberrant connectivity in formal thought disorder, a construct related to CD. However, no studies have investigated whole-brain functional correlates of CD in psychosis. We sought to investigate brain regions explaining the severity of CD in patients with first-episode psychosis (FEPs) compared with healthy controls (HCs).Methods:We computed whole-brain binarized degree centrality maps of 31 FEPs, 25 HCs and characterized the patterns of network connectivity in the two groups. In FEPs, we related these findings to the severity of CD. We also studied the effect of positive and negative symptoms on altered network connectivity.Results:Compared to HCs, reduced hubness of a right superior temporal gyrus (rSTG) cluster was observed in the FEPs. In patients exhibiting high CD, increased hubness of a medial superior parietal (mSPL) cluster was observed, compared to patients exhibiting low CD. These two regions were strongly correlated with CD scores but not with other symptom scores.Discussion:Our observations are congruent with previous findings of reduced but not increased hubness. We observed increased hubness of mSPL suggesting that cortical reorganization occurs to provide alternate routes for information transfer.Conclusion:These findings provide insight into the underlying neural processes mediating the presentation of symptoms in untreated FEP. A longitudinal tracking of the symptom course will be useful to assess the mechanisms underlying these compensatory changes.

scholarly journals Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats

2021 ◽  
Vol 22 (6) ◽  
pp. 3275
Author(s):  
Andrea Tapia-Bustos ◽  
Carolyne Lespay-Rebolledo ◽  
Valentina Vío ◽  
Ronald Pérez-Lobos ◽  
Emmanuel Casanova-Ortiz ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Perinatal Asphyxia ◽  
Mrna Levels ◽  
Protein Levels ◽  
Delayed Cell Death ◽  
External Capsule ◽  
Stem Cell Treatment ◽  
Main Effects

The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 μL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.

scholarly journals Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jason L. He ◽  
Georg Oeltzschner ◽  
Mark Mikkelsen ◽  
Alyssa Deronda ◽  
Ashley D. Harris ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Strong Support ◽  
Empirical Support ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Resonance Spectroscopy ◽  
Primary Sensorimotor Cortex ◽  
Spectrum Disorders ◽  
Inhibitory Signaling

AbstractIndividuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

Prediction of encephalopathy in perinatal asphyxia score: reaching the unreached

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Srinivasa Murthy Doreswamy ◽  
Amulya Ramakrishnegowda
Keyword(s):  
Therapeutic Hypothermia ◽  
Sensitivity And Specificity ◽  
Perinatal Asphyxia ◽  
High Specificity ◽  
Test Sample ◽  
Therapeutic Benefit ◽  
Primary Outcome Measure ◽  
Primary Objective ◽  
Post Test ◽  
Test Probability

Abstract Objectives Neonates who develop moderate to severe encephalopathy following perinatal asphyxia will benefit from therapeutic hypothermia. Current National Institute of Child Health and Human Development (NICHD) criteria for identifying encephalopathic neonates needing therapeutic hypothermia has high specificity. This results in correctly identifying neonates who have already developed moderate to severe encephalopathy but miss out many potential beneficiaries who progress to develop moderate to severe encephalopathy later. The need is therefore not just to diagnose encephalopathy, but to predict development of encephalopathy and extend the therapeutic benefit for all eligible neonates. The primary objective of the study was to develop and validate the statistical model for prediction of moderate to severe encephalopathy following perinatal asphyxia and compare with current NICHD criteria. Methods The study was designed as prospective observational study. It was carried out in a single center Level 3 perinatal unit in India. Neonates>35 weeks of gestation and requiring resuscitation at birth were included. Levels of resuscitation and blood gas lactate were used to determine the pre-test probability, Thompson score between 3 and 5 h of life was used to determine post-test probability of developing encephalopathy. Primary outcome measure: Validation of Prediction of Encephalopathy in Perinatal Asphyxia (PEPA) score by Holdout method. Results A total of 55 babies were included in the study. The PEPA score was validated by Holdout method where the fitted receiver-operating characteristic (ROC) area for the training and test sample were comparable (p=0.758). The sensitivity and specificity of various PEPA scores for prediction of encephalopathy ranged between 74 and 100% in contrast to NICHD criteria which was 42%. PEPA score of 30 had a best combination of sensitivity and specificity of 95 and 89% respectively. Conclusions PEPA score has a higher sensitivity than NICHD criteria for prediction of Encephalopathy in asphyxiated neonates.

scholarly journals Focal changes in brain energy and phospholipid metabolism in first-episode schizophrenia

2004 ◽  
Vol 184 (5) ◽  
pp. 409-415 ◽  
Author(s):  
J. Eric Jensen ◽  
Jodi Miller ◽  
Peter C. Williamson ◽  
Richard W J. Neufeld ◽  
Ravi S. Menon ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Imaging Techniques ◽  
High Energy ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Membrane Breakdown ◽  
First Episode Schizophrenia

BackgroundMembrane phospholipid and high-energy abnormalities measured with phosphorus magnetic resonance spectroscopy (31P-MRS) have been reported in patients with schizophrenia in several brain regions.AimsUsing improved imaging techniques, previously inaccessible brain regions were examined in patients with first-episode schizophrenia and healthy volunteers with 4.0 T 31P-MRS.MethodBrain spectra were collected in vivo from 15 patients with first-episode schizophrenia and 15 healthy volunteers from 15 cm3 effective voxels in the thalamus, cerebellum, hippocampus, anterior/posterior cingulate, prefrontal cortex and parieto-occipital cortex.ResultsPeople with first-episode schizophrenia showed increased levels of glycerophosphocholine in the anterior cingulate. Inorganic phosphate, phosphocreatine and adenosine triphosphate concentrations were also increased in the anterior cingulate in this group.ConclusionsThe increased phosphodiester and high-energy phosphate levels in the anterior cingulate of brains of people with first-episode schizophrenia may indicate neural overactivity in this region during the early stages of the illness, resulting in increased excitotoxic neural membrane breakdown.

scholarly journals Cerebrovascular responses of the rat brain to noxious stimuli as examined by functional near-infrared whole brain imaging

2012 ◽  
Vol 107 (10) ◽  
pp. 2853-2865 ◽  
Author(s):  
Ji-Wei He ◽  
Fenghua Tian ◽  
Hanli Liu ◽  
Yuan Bo Peng
Keyword(s):  
Brain Imaging ◽  
Near Infrared ◽  
Small Animal ◽  
Nir Spectroscopy ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Hemodynamic Changes ◽  
Whole Brain ◽  
Brain Hemodynamics

While near-infrared (NIR) spectroscopy has been increasingly used to detect stimulated brain activities with an advantage of dissociating regional oxy- and deoxyhemoglobin concentrations simultaneously, it has not been utilized much in pain research. Here, we investigated and demonstrated the feasibility of using this technique to obtain whole brain hemodynamics in rats and speculated on the functional relevance of the NIR-based hemodynamic signals during pain processing. NIR signals were emitted and collected using a 26-optodes array on rat's dorsal skull surface after the removal of skin. Following the subcutaneous injection of formalin (50 μl, 3%) into a hindpaw, several isolable brain regions showed hemodynamic changes, including the anterior cingulate cortex, primary/secondary somatosensory cortexes, thalamus, and periaqueductal gray ( n = 6). Time courses of hemodynamic changes in respective regions matched with the well-documented biphasic excitatory response. Surprisingly, an atypical pattern (i.e., a decrease in oxyhemoglobin concentration with a concomitant increase in deoxyhemoglobin concentration) was seen in phase II. In a separate group of rats with innocuous brush and noxious pinch of the same area ( n = 11), results confirmed that the atypical pattern occurred more likely in the presence of nociception than nonpainful stimulation, suggesting it as a physiological substrate when the brain processes pain. In conclusion, the NIR whole brain imaging provides a useful alternative to study pain in vivo using small-animal models. Our results support the notion that neurovascular response patterns depend on stimuli, bringing attention to the interpretation of vascular-based neuroimaging data in studies of pain.

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