Marianne Thoresen

• Glass, Hannah C.; Wood, Thomas R.; Comstock, Bryan A.; Numis, Adam L.; Bonifacio, Sonia L. & Cornet, Marie-Coralie [Show all 18 contributors for this article] (2024). Predictors of Death or Severe Impairment in Neonates With Hypoxic-Ischemic Encephalopathy. JAMA Network Open. 7(12), p. e2449188–e2449188. doi: 10.1001/jamanetworkopen.2024.49188. Full text in Research Archive Show summary

  Importance Outcomes after hypoxic-ischemic encephalopathy (HIE) are variable. Predicting death or severe neurodevelopmental impairment (NDI) in affected neonates is crucial for guiding management and parent communication. Objective To predict death or severe NDI in neonates who receive hypothermia for HIE. Design, Setting, and Participants This prognostic study included participants enrolled in a large US clinical trial conducted in US neonatal intensive care units who were born between January 2017 and October 2019 and followed up to age 2 years. Eligible participants were neonates with moderate-severe HIE born at 36 weeks or more gestation and with 2-year outcome data. Data were analyzed June 2023. External validation was performed with a UK cohort. Exposure Clinical, electroencephalography (EEG), and magnetic resonance imaging (MRI) variables were curated and examined at 24 hours and following cooling. Main Outcome and Measures Death or severe NDI at age 2 years. Severe NDI was defined as Bayley Scales of Infant Toddler Development cognitive score below 70, Gross Motor Function Classification System score of 3 or higher, or quadriparesis. Model performance metrics were derived from training, internal, and external validation datasets. Results Among 424 neonates (mean [SD] gestational age, 39.1 [1.4] weeks; 192 female [45.3%]; 28 Asian [6.6%], 50 Black [11.8%], 311 White [73.3%]), 105 (24.7%) had severe encephalopathy at enrollment. Overall, 59 (13.9%) died and 46 (10.8%) had severe NDI. In the 24-hour model, the combined presence of 3 clinical characteristics—(1) severely abnormal EEG, (2) pH level of 7.11 or below, and (3) 5-minute Apgar score of 0—had a specificity of 99.6% (95% CI, 97.5%-100%) and a positive predictive value (PPV) of 95.2% (95% CI, 73.2%-99.3%). Validation model metrics were 97.9% (95% CI, 92.7%-99.8%) for internal specificity, with a PPV of 77.8% (95% CI, 43.4%-94.1%), and 97.6% (95% CI, 95.1%-99.0%) for external specificity, with a PPV of 46.2% (95% CI, 23.3%-70.8%). In the postcooling model, specificity for T1, T2, or diffusion-weighted imaging (DWI) abnormality in at least 2 of 3 deep gray regions (ie, thalamus, caudate, putamen and/or globus pallidus) plus a severely abnormal EEG within the first 24 hours was 99.1% (95% CI, 96.8%-99.9%), with a PPV of 91.7% (95% CI, 72.8%-97.8%). Internal specificity in this model was 98.9% (95% CI, 94.1%-100%), with a PPV of 92.9% (95% CI, 64.2%-99.0%); external specificity was 98.6% (95% CI, 96.5%-99.6%), with a PPV of 83.3% (95% CI, 64.1%-93.4%). Conclusions and Relevance In this prognostic study of neonates with moderate or severe HIE who were treated with therapeutic hypothermia, simple models using readily available clinical, EEG, and MRI results during the hospital admission had high specificity and PPV for death or severe NDI at age 2 years.

• Bakke, Laura Anne Wortinger; Stavrum, Anne-Kristin Støbakk; Shadrin, Alexey; Szabo, Attila; Rukke, Sondre Høeg & Nerland, Stener [Show all 17 contributors for this article] (2024). Divergent epigenetic responses to perinatal asphyxia in severe mental disorders. Translational Psychiatry. 14. doi: 10.1038/s41398-023-02709-7. Full text in Research Archive Show summary

  Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced perinatal asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of perinatal asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of perinatal asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with perinatal asphyxia. We found an interaction between methylation and exposure to perinatal asphyxia on case–control status, wherein having a history of perinatal asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to perinatal asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.

• Gundersen, Julia Kristine; Chakkarapani, Ela; Menassa, David; Walløe, Lars & Thoresen, Marianne (2024). The effects of anaesthesia on cell death in a porcine model of neonatal hypoxic-ischaemic brain injury. BJA Open. 10. doi: 10.1016/j.bjao.2024.100283. Full text in Research Archive Show summary

  Background Hypothermia is neuroprotective after neonatal hypoxic-ischaemic brain injury. However, systemic cooling to hypothermic temperatures is a stressor and may reduce neuroprotection in awake pigs. We compared two experiments of global hypoxic-ischaemic injury in newborn pigs, in which one group received propofol–remifentanil and the other remained awake during post-insult hypothermia treatment. Methods In both studies, newborn pigs were anaesthetised using halothane during a 45-min global hypoxic-ischaemic insult induced by reducing Fio2 and graded hypotension until a low-voltage <7 μV electroencephalogram was achieved. On reoxygenation, the pigs were randomly allocated to receive 24 h of normothermia or hypothermia. In the first study (n=18) anaesthesia was discontinued and the pigs' tracheas were extubated. In the second study (n=14) anaesthesia was continued using propofol and remifentanil. Brain injury was assessed after 72 h by classical global histopathology, Purkinje cell count, and apoptotic cell counts in the hippocampus and cerebellum. Results Global injury was nearly 10-fold greater in the awake group compared with the anaesthetised group (P=0.021). Hypothermia was neuroprotective in the anaesthetised pigs but not the awake pigs. In the hippocampus, the density of cleaved caspase-3-positive cells was increased in awake compared with anaesthetised pigs in normothermia. In the cerebellum, Purkinje cell density was reduced in the awake pigs irrespective of treatment, and the number of cleaved caspase-3-positive Purkinje cells was greatly increased in hypothermic awake pigs. We detected no difference in cleaved caspase-3 in the granular cell layer or microglial reactivity across the groups. Conclusions Our study provides novel insights into the significance of anaesthesia/sedation during hypothermia for achieving optimal neuroprotection.

• Wu, Chelsea Q.; Cowan, Frances M.; Jary, Sally; Thoresen, Marianne; Chakkarapani, Ela & Spencer, Arthur P. C. (2023). Cerebellar growth, volume and diffusivity in children cooled for neonatal encephalopathy without cerebral palsy. Scientific Reports. 13(1). doi: 10.1038/s41598-023-41838-3. Full text in Research Archive Show summary

  Abstract Children cooled for HIE and who did not develop cerebral palsy (CP) still underperform at early school age in motor and cognitive domains and have altered supra-tentorial brain volumes and white matter connectivity. We obtained T1-weighted and diffusion-weighted MRI, motor (MABC-2) and cognitive (WISC-IV) scores from children aged 6–8 years who were cooled for HIE secondary to perinatal asphyxia without CP (cases), and controls matched for age, sex, and socioeconomic status. In 35 case children, we measured cerebellar growth from infancy (age 4–15 days after birth) to childhood. In childhood, cerebellar volumes were measured in 26 cases and 23 controls. Diffusion properties (mean diffusivity, MD and fractional anisotropy, FA) were calculated in 24 cases and 19 controls, in 9 cerebellar regions. Cases with FSIQ ≤ 85 had reduced growth of cerebellar width compared to those with FSIQ &gt; 85 ( p  = 0.0005). Regional cerebellar volumes were smaller in cases compared to controls ( p  &lt; 0.05); these differences were not significant when normalised to total brain volume. There were no case–control differences in MD or FA. Interposed nucleus volume was more strongly associated with IQ in cases than in controls ( p  = 0.0196). Other associations with developmental outcome did not differ between cases and controls.

• Gundersen, Julia Kristine; Sabir, Hemmen; Wood, Thomas Ragnar; Osredkar, Damjan; Falck, Mari & Løberg, Else Marit [Show all 9 contributors for this article] (2023). Restraint stress during neonatal hypoxia-ischemia alters brain injury following normothermia and hypothermia. Physiological Reports. 11(1), p. 1–12. doi: 10.14814/phy2.15562. Full text in Research Archive Show summary

  Abstract Rodent models of neonatal hypoxic–ischemic (HI) injury require a subset of animals to be immobilized for continuous temperature monitoring during the insult and subsequent treatment. Restrained animals are discarded from the analysis due to the effect of restraint on the brain injury as first demonstrated by Thoresen et al 1996. However, the effects of restraint on responses to hypothermic (HT) post‐insult therapy are not well described. We examine the effects of restraint associated with different probe placements on HI brain injury. We have conducted a meta‐analysis of 23 experiments comparing probe rats (skin n  = 42, rectal n  = 35) and free‐moving matched non‐probe controls ( n  = 80) that underwent HI injury (left common carotid artery ligation and 90 min 8% O 2 ) at postnatal day 7 (P7), followed by 5 h of NT (37°C) or HT (32°C). On P14, brain regions were analyzed for injury (by neuropathology and area loss), microglial reactivity and brain‐derived neurotrophic factor (BDNF). HI injury was mitigated in NT skin and rectal probe rats, with greater neuroprotection among the rectal probe rats. Following HT, the skin probe rats maintained the restraint‐associated neuroprotection, while brain injury was significantly exacerbated among the rectal probe rats. Microglial reactivity strongly correlated with the acquired injury, with no detectable difference between the groups. Likewise, we observed no differences in BDNF signal intensity. Our findings suggest a biphasic neuroprotection from restraint stress, which becomes detrimental in combination with HT and the presumed discomfort from the rectal probe. This finding is useful in highlighting unforeseen effects of common experimental designs or routine clinical management.

• Wortinger, Laura Anne; Shadrin, Alexey; Szabo, Attila; Nerland, Stener; Smelror, Runar & Jørgensen, Kjetil Nordbø [Show all 13 contributors for this article] (2023). The impact of placental genomic risk for schizophrenia and birth asphyxia on brain development. Translational Psychiatry. 13(1). doi: 10.1038/s41398-023-02639-4. Full text in Research Archive Show summary

  The placenta plays a role in fetal brain development, and pregnancy and birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size and higher risk of developing schizophrenia (SZ), but whether birth asphyxia and placental genomic risk factors associated with SZ are related and how they might impact brain development is unclear. 433 adult patients with SZ and 870 healthy controls were clinically evaluated and underwent brain magnetic resonance imaging. Pregnancy and birth information were obtained from the Medical Birth Registry of Norway. Polygenic risk scores (PRS) from the latest genomewide association study in SZ were differentiated into placental PRS (PlacPRS) and non-placental PRS. If the interaction between PRSs and birth asphyxia on case-control status was significant, neonatal head circumference (nHC) and adult intracranial volume (ICV) were further evaluated with these variables using multiple regression. PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with SZ (t = 2.10, p = 0.018). We found a significant interaction between PlacPRS and birth asphyxia on nHC in the whole sample (t = −2.43, p = 0.008), with higher placental PRS for SZ associated with lower nHC in those with birth asphyxia. This relationship was specific to males (t = −2.71, p = 0.005) and also found with their adult ICV (t = −1.97, p = 0.028). These findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to SZ. This knowledge might lead to new strategies of treatment and prevention in SZ.

• Whitelaw, Andrew George Lindsay & Thoresen, Marianne (2023). Therapeutic Hypothermia for Hypoxic-Ischemic Brain Injury Is More Effective in Newborn Infants than in Older Patients: Review and Hypotheses. Therapeutic Hypothermia and Temperature Management. ISSN 2153-7658. 13(4). doi: 10.1089/ther.2023.0050. Full text in Research Archive
• Robb, Thomas J.; Tonks, James; Spencer, Arthur P. C.; Jary, Sally; Whitfield, Charlotte K. & Thoresen, Marianne [Show all 8 contributors for this article] (2022). Communication skills in children aged 6–8 years, without cerebral palsy cooled for neonatal hypoxic-ischemic encephalopathy. Scientific Reports. 12(1). doi: 10.1038/s41598-022-21723-1. Full text in Research Archive Show summary

  Abstract We assessed communication skills of 48 children without cerebral palsy (CP) treated with therapeutic hypothermia (TH) for neonatal hypoxic-ischemic encephalopathy (HIE) (cases) compared to 42 controls at early school-age and examined their association with white matter diffusion properties in both groups and 18-month Bayley-III developmental assessments in cases. Parents completed a Children’s Communication Checklist (CCC-2) yielding a General Communication Composite (GCC), structural and pragmatic language scores and autistic-type behavior score. GCC ≤ 54 and thresholds of structural and pragmatic language score differences defined language impairment. Using tract-based spatial statistics (TBSS), fractional anisotropy (FA) was compared between 31 cases and 35 controls. Compared to controls, cases had lower GCC ( p  = 0.02), structural ( p  = 0.03) and pragmatic language score ( p  = 0.04) and higher language impairments ( p  = 0.03). GCC correlated with FA in the mid-body of the corpus callosum, the cingulum and the superior longitudinal fasciculus ( p  &lt; 0.05) in cases. Bayley-III Language Composite correlated with GCC (r = 0.34, p  = 0.017), structural (r = 0.34, p  = 0.02) and pragmatic (r = 0.32, p  = 0.03) language scores and autistic-type behaviors (r = 0.36, p  = 0.01).

• Phillips, Thomas; Menassa, David; Grant, Simon; Cohen, Nicki & Thoresen, Marianne (2021). The effects of Xenon gas inhalation on neuropathology in a placental-induced brain injury model in neonates: A pilot study. Acta Paediatrica. ISSN 0803-5253. 110(1), p. 119–122. doi: 10.1111/apa.15486. Full text in Research Archive
• Sabir, Hemmen; Bonifacio, Sonia L.; Gunn, Alistair J.; Thoresen, Marianne & Chalak, Lina F. (2021). Unanswered questions regarding therapeutic hypothermia for neonates with neonatal encephalopathy. Seminars in Fetal & Neonatal Medicine. ISSN 1744-165X. 26(5). doi: 10.1016/j.siny.2021.101257. Full text in Research Archive
• Thoresen, Marianne; Jary, Sally; Walløe, Lars; Karlsson, Mathias; Martinez-Biarge, Miriam & Chakkarapani, Ela [Show all 7 contributors for this article] (2021). MRI combined with early clinical variables are excellent outcome predictors for newborn infants undergoing therapeutic hypothermia after perinatal asphyxia. EClinicalMedicine. 36. doi: 10.1016/j.eclinm.2021.100885. Full text in Research Archive Show summary

  Background Binary prediction-models for outcome [death, cognition, presence and severity of cerebral palsy (CP)], using MRI and early clinical data applicable for individual outcome prediction have not been developed. Methods From Dec 1st 2006 until Dec 31st 2013, we recruited 178 infants into a population-based cohort with moderate or severe hypoxic-ischaemic encephalopathy (HIE) including postnatal collapse (PNC, n = 12) and additional diagnoses (n = 12) using CoolCap/TOBY-trial entry-criteria including depressed amplitude-integrated EEG (aEEG). Early clinical/biochemical variables and MRI scans (median day 8) were obtained in 168 infants. Injury severity was scored for cortex, basal ganglia/thalami (BGT), white matter (WM) and posterior limb of the internal capsule, summating to a total injury score (TIS, range 0–11). Outcome was categorized as adverse or favourable at 18–24 months from Bayley-III domains (cut-off 85) and neurological examination including CP classification. Findings HIE and entry-aEEG severity were stable throughout the study. Outcome was favourable in 133/178 infants and adverse in 45/178: 17 died, 28 had low Cognition/Language scores, (including 9 with severe CP and 6 mild); seven had mild CP with favourable cognitive outcome. WMxBGT product scores and TIS were strong outcome predictors, and prediction improved when clinical/biochemical variables were added in binary logistic regression. The Positive Predictive Value for adverse outcome was 88%, increasing to 95% after excluding infants with PNC and additional diagnoses. Using WMxBGT in the regression predicted 8 of the 9 children with severe CP. Interpretation Binary logistic regression with WMxBGT or TIS and clinical variables gave excellent outcome prediction being 12% better than single variable cross-tabulation. Our MRI scoring and regression models are readily accessible and deserve investigation in other cohorts for group and individual prediction. Funding We thank the National Health Service (NHS) and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Lærdal Foundation for Acute Medicine and charitable donations for their support for cooling therapy.

• Spencer, Arthur P.C.; Brooks, Jonathan C.W.; Masuda, Naoki; Byrne, Hollie; Lee-Kelland, Richard & Jary, Sally [Show all 10 contributors for this article] (2021). Motor function and white matter connectivity in children cooled for neonatal encephalopathy. NeuroImage: Clinical. 32. doi: 10.1016/j.nicl.2021.102872. Full text in Research Archive Show summary

  Therapeutic hypothermia reduces the incidence of severe motor disability, such as cerebral palsy, following neonatal hypoxic-ischaemic encephalopathy. However, cooled children without cerebral palsy at school-age demonstrate motor deficits and altered white matter connectivity. In this study, we used diffusion-weighted imaging to investigate the relationship between white matter connectivity and motor performance, measured using the Movement Assessment Battery for Children-2, in children aged 6–8 years treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy at birth, who did not develop cerebral palsy (cases), and matched typically developing controls. Correlations between total motor scores and diffusion properties in major white matter tracts were assessed in 33 cases and 36 controls. In cases, significant correlations (FDR-corrected P < 0.05) were found in the anterior thalamic radiation bilaterally (left: r = 0.513; right: r = 0.488), the cingulate gyrus part of the left cingulum (r = 0.588), the hippocampal part of the left cingulum (r = 0.541), and the inferior fronto-occipital fasciculus bilaterally (left: r = 0.445; right: r = 0.494). No significant correlations were found in controls. We then constructed structural connectivity networks, for 22 cases and 32 controls, in which nodes represent brain regions and edges were determined by probabilistic tractography and weighted by fractional anisotropy. Analysis of whole-brain network metrics revealed correlations (FDR-corrected P < 0.05), in cases, between total motor scores and average node strength (r = 0.571), local efficiency (r = 0.664), global efficiency (r = 0.677), clustering coefficient (r = 0.608), and characteristic path length (r = -0.652). No significant correlations were found in controls. We then investigated edge-level association with motor function using the network-based statistic. This revealed subnetworks which exhibited group differences in the association between motor outcome and edge weights, for total motor scores (P = 0.0109) as well as for balance (P = 0.0245) and manual dexterity (P = 0.0233) domain scores. All three of these subnetworks comprised numerous frontal lobe regions known to be associated with motor function, including the superior frontal gyrus and middle frontal gyrus. The subnetwork associated with total motor scores was highly left-lateralised. These findings demonstrate an association between impaired motor function and brain organisation in school-age children treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.

• Wortinger, Laura Anne; Barth, Claudia; Nerland, Stener; Jørgensen, Kjetil Nordbø; Shadrin, Alexey & Szabo, Attila [Show all 11 contributors for this article] (2021). Association of Birth Asphyxia With Regional White Matter Abnormalities Among Patients With Schizophrenia and Bipolar Disorders. JAMA Network Open. 4(12). doi: 10.1001/jamanetworkopen.2021.39759. Full text in Research Archive Show summary

  Importance: White matter (WM) abnormalities are commonly reported in psychiatric disorders. Whether peripartum insufficiencies in brain oxygenation, known as birth asphyxia, are associated with WM of patients with severe mental disorders is unclear. Objective: To examine the association between birth asphyxia and WM in adult patients with schizophrenia and bipolar disorders (BDs) compared with healthy adults. Design, setting, and participants: In this case-control study, all individuals participating in the ongoing Thematically Organized Psychosis project were linked to the Medical Birth Registry of Norway (MBRN), where a subset of 271 patients (case group) and 529 healthy individuals (control group) had undergone diffusion-weighted imaging (DWI). Statistical analyses were performed from June 16, 2020, to March 9, 2021. Exposures: Birth asphyxia was defined based on measures from standardized reporting at birth in the MBRN. Main outcomes and measures: Associations between birth asphyxia and WM regions of interest diffusion metrics, ie, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), were compared between groups using analysis of covariance, adjusted for age, age squared, and sex. Results: Of the 850 adults included in the study, 271 were in the case group (140 [52%] female individuals; mean [SD] age, 28.64 [7.43] years) and 579 were in the control group (245 [42%] female individuals; mean [SD] age, 33.54 [8.31] years). Birth asphyxia measures were identified in 15% to 16% of participants, independent of group. The posterior limb of the internal capsule (PLIC) showed a significant diagnostic group × birth asphyxia interaction (F(1, 843) = 11.46; P = .001), reflecting a stronger association between birth asphyxia and FA in the case group than the control group. RD, but not AD, also displayed a significant diagnostic group × birth asphyxia interaction (F(1, 843) = 9.28; P = .002) in the PLIC, with higher values in patients with birth asphyxia and similar effect sizes as observed for FA. Conclusions and relevance: In this case-control study, abnormalities in the PLIC of adult patients with birth asphyxia may suggest a greater susceptibility to hypoxia in patients with severe mental illness, which could lead to myelin damage or impeded brain development. Echoing recent early-stage schizophrenia studies, abnormalities of the PLIC are relevant to psychiatric disorders, as the PLIC contains important WM brain pathways associated with language, cognitive function, and sensory function, which are impaired in schizophrenia and BDs.

• Dingley, John; Okano, Satomi; Lee-Kelland, Richard; Scull-Brown, Emma; Thoresen, Marianne & Chakkarapani, Ela (2020). Closed circuit xenon delivery for 72h in neonatal piglets following hypoxic insult using an ambient pressure automated control system: Development, technical evaluation and pulmonary effects. PLOS ONE. doi: 10.1371/journal.pone.0224447. Full text in Research Archive Show summary

  Background Therapeutic hypothermia (TH) for 72h is the standard treatment following neonatal encephalopathy (NE). However, one-third do not benefit and adjunctive therapies are urgently needed. Xenon enhances neuroprotection with TH when administered at 50% concentration within 5hours of hypoxia in experimental studies. Delayed initiation (~10 hours of age) of 30% xenon for 24 hours during TH did not improve early adverse biomarkers in a clinical trial of Xenon+TH vs TH. After hypoxia-ischemia, excitotoxic injury via N-methyl-D-aspartate receptor overactivation lasts days. Since xenon partially inhibits this receptor, we hypothesised that giving 50% xenon throughout the entire 72h TH and rewarming periods would enhance neuroprotection. Xenon costs $30/litre, so a closed-circuit breathing system is desirable with automated fresh gas delivery. Methods Seven mechanically ventilated newborn pigs were randomized to receive 50% inhaled xenon for 72h during hypothermia (rectal-temperature 35°C) and subsequent rewarming following a global hypoxic-ischemic insult (XeHT, N = 4) or under normothermia for 72h (rectal-temperature 38.5°C) following sham insult (XeNT, N = 3). An automated fresh gas delivery system injected oxygen/air/xenon boluses into a closed-circuit based on measured gas concentrations. Results and discussion Median (IQR) xenon consumption was 0.31 L/h (0.18, 0.50) and 0.34L/h (0.32, 0.49) for hypothermic and normothermic groups respectively, 0.34L/h (0.25, 0.53) overall. 92% of 9626 xenon and 69% of 9635 oxygen measurements were within 20% variation from targets. For xenon concentration, the median absolute performance errors for the XeHT and XeNT groups were 6.14% and 3.84% respectively and 4.31% overall. For oxygen these values were 13.42%, 15.05% and 12.4% respectively. There were no adverse pulmonary pathophysiology findings. Clinical problems over the total period included three related to sensors, seven breathing system leaks, ten partial and one complete tracheal tube occlusion episodes. Conclusion The automated controller functioned as intended maintaining an inhaled xenon concentration close to the 50% target for 72-78h at a xenon cost of $11.1/h.

• Wood, Thomas Ragnar; Gundersen, Julia Kristine; Falck, Mari; Maes, Elke; Osredkar, Damjan & Løberg, Else Marit [Show all 9 contributors for this article] (2020). Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis. Scientific Reports. 10:10833, p. 1–13. doi: 10.1038/s41598-020-67532-2. Full text in Research Archive Show summary

  Therapeutic hypothermia (HT) is standard care for term infants with hypoxic–ischaemic (HI) encephalopathy. However, the efficacy of HT in preclinical models, such as the Vannucci model of unilateral HI in the newborn rat, is often greater than that reported from clinical trials. Here, we report a meta-analysis of data from every experiment in a single laboratory, including pilot data, examining the effect of HT in the Vannucci model. Across 21 experiments using 106 litters, median (95% CI) hemispheric area loss was 50.1% (46.0–51.9%; n = 305) in the normothermia group, and 41.3% (35.1–44.9%; n = 317) in the HT group, with a bimodal injury distribution. Median neuroprotection by HT was 17.6% (6.8–28.3%), including in severe injury, but was highly-variable across experiments. Neuroprotection was significant in females (p < 0.001), with a non-significant benefit in males (p = 0.07). Animals representing the median injury in each group within each litter (n = 277, 44.5%) were also analysed using formal neuropathology, which showed neuroprotection by HT throughout the brain, particularly in females. Our results suggest an inherent variability and sex-dependence of the neuroprotective response to HT, with the majority of studies in the Vannucci model vastly underpowered to detect true treatment effects due to the distribution of injury.

• Wassink, Guido; Davidson, Joanne O.; Dhillon, Simerdeep K.; Zhou, Kelly; Bennet, Laura & Thoresen, Marianne [Show all 7 contributors for this article] (2019). Therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy. Current Neurology and Neuroscience Reports. ISSN 1528-4042. 19:2(2), p. 1–10. doi: 10.1007/s11910-019-0916-0. Full text in Research Archive
• Frikstad, Kari-Anne; Molinari, Elisa; Thoresen, Marianne; Ramsbottom, Simon A; Hughes, Frances & Letteboer, Stef J.F. [Show all 16 contributors for this article] (2019). A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling. Cell reports. 28(7), p. 1907–1922.e6. doi: 10.1016/j.celrep.2019.07.025. Full text in Research Archive
• Walløe, Lars; Hjort, Nils Lid & Thoresen, Marianne (2019). Why results from Bayesian Statistical analyses of clinical trials with a strong prior and small sample sixes may be misleading. Acta Paediatrica. ISSN 0803-5253. p. 1190–1191. doi: 10.1111/apa.14800. Full text in Research Archive
• Chakkarapani, Ela & Thoresen, Marianne (2019). Brain and whole body cooling, MacDonald's Atlas of Procedures in Neonatology. Lamy, Wolters Kluwer. ISSN 9781496394255. Full text in Research Archive
• Gunn, Alistair J & Thoresen, Marianne (2019). Neonatal encephalopathy and hypoxic-ischemic encephalopathy. Handbook of Clinical Neurology. ISSN 0072-9752. 162, p. 217–237. doi: 10.1016/B978-0-444-64029-1.00010-2. Full text in Research Archive
• Jary, Sally; Lee-Kelland, Richard; Tonks, James; Cowan, Frances Mary; Thoresen, Marianne & Chakkarapani, Elavazhagan (2019). Motor performance and cognitive correlates in children cooled for neonatal encephalopathy without cerebral palsy at school age. Acta Paediatrica. ISSN 0803-5253. doi: 10.1111/apa.14780. Full text in Research Archive
• Lee-Kelland, Richard; Jary, Sally; Tonks, James; Cowan, Frances Mary; Thoresen, Marianne & Chakkarapani, Ela (2019). School-age outcomes of children without cerebral palsy cooled for neonatal hypoxic-ischaemic encephalopathy in 2008-2010. Archives of Disease in Childhood: Fetal and Neonatal Edition. ISSN 1359-2998. doi: 10.1136/archdischild-2018-316509. Full text in Research Archive
• Tonks, James; Cloke, Grace; Lee-Kelland, Richard; Jary, Sally; Thoresen, Marianne & Cowan, Frances [Show all 7 contributors for this article] (2019). Attention and visuo-spatial function in children without cerebral palsy who were cooled for neonatal encephalopathy: a case-control study. Journal of Building Performance Simulation. ISSN 1940-1493. 33(7), p. 894–898. doi: 10.1080/02699052.2019.1597163. Full text in Research Archive Show summary

  Attention and visuo-spatial function in children without cerebral palsy who were cooled for neonatal encephalopathy: a case-Control study

• Walløe, Lars; Hjort, Nils Lid & Thoresen, Marianne (2019). Start cooling as soon as possible. Acta Paediatrica. ISSN 0803-5253. 108(4), p. 771–771. doi: 10.1111/apa.14710. Full text in Research Archive
• El-Dib, Mohamed; Terrie, E; Inder, Terrie E; Chalak, Lina F; Massaro, An N & Thoresen, Marianne [Show all 7 contributors for this article] (2018). Should therapeutic hypothermia be offered to babies With mild neonatal encephalopathy in the first 6 hours after birth? Pediatric Research. ISSN 0031-3998. doi: 10.1038/s41390-019-0291-1. Full text in Research Archive Show summary

  Therapeutic hypothermia for mild NE

• Sabir, Hemmen; Dingley, John; Scull-Brown, Emma; Chakkarapani, Ela & Thoresen, Marianne (2018). Fentanyl induces cerebellar internal granular cell layer apoptosis in healthy newborn pigs. Frontiers in Neurology. 9(MAY). doi: 10.3389/fneur.2018.00294. Full text in Research Archive Show summary

  Background: Opioids like fentanyl are regularly used in neonates for analgesia and sedation. So far, they have been reported to be safe and eligible to use. The cerebellum has become a focus of neurodevelopmental research within the last years, as it is known to play an important role in long-lasting motor, cognitive, and other behavioral changes. The cerebellar cortex is of major importance in the coordinative role of the cerebellum and highly vulnerable to injury and impaired growth. Objective: This study was performed to evaluate the apoptotic effect of intravenous fentanyl infusion on the cerebellum in healthy newborn pigs. Methods: Thirteen healthy pigs ( < median 12 h old) were randomized into (1) 24 h of intravenous fentanyl at normothermia (NTFe, n = 6) or (2) non-ventilated controls at normothermia (NTCTR, n = 7). Cerebellar sections were morphologically assessed after staining with hematoxylin–eosin. In addition, paired sections were immuno-stained for cell death [Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphate nick-end labeling (TUNEL)], and positive cells were counted in defined areas of the internal granular cell layer. In total, cells in three cerebellar gyri were counted. Results: We found that there was an increase in cells with apoptotic morphology in the internal granular cell layer in the NTFe group. For quantification, we found a significant increase in cell death in group (1) [median (range) number of caspase-3-positive cell group (1) 8 (1–22) vs. group (2) 1 (1–6) and TUNEL-positive cells (1) 6 (1–10) vs. (2) 1 (0–4)]. In both groups, there was no difference in the number of Purkinje cells. Both groups had comparable and stable physiological parameters throughout the 24 h period. Conclusion: Twenty-four hours of continuous intravenous fentanyl infusion increased apoptosis in the internal granular cell layer in the cerebellum of healthy newborn pigs.

• Walløe, Lars; Hjort, Nils Lid & Thoresen, Marianne (2018). Major concerns about late hypothermia study. Acta Paediatrica. ISSN 0803-5253. doi: 10.1111/apa.14640. Full text in Research Archive
• Falck, Mari; Osredkar, Damjan; Wood, Thomas Ragnar; Maes, Elke; Flatebø, Torun & Sabir, Hemmen [Show all 7 contributors for this article] (2018). Neonatal Systemic Inflammation Induces Inflammatory Reactions and Brain Apoptosis in a Pathogen-Specific Manner. Neonatology. ISSN 1661-7800. 113(3), p. 212–220. doi: 10.1159/000481980. Full text in Research Archive
• Thoresen, Marianne (2018). Combining two good treatments makes it worse. (Commentary on Interaction between hypothermia and delayed mesenchymal stem cell therapy in neonatal hypoxic-ischemic brain injury). Brain, Behavior, and Immunity. ISSN 0889-1591. doi: 10.1016/j.bbi.2018.04.008. Full text in Research Archive
• Falck, Mari; Osredkar, Damjan; Maes, Elke; Flatebø, Torun; Wood, Thomas Ragnar & Walløe, Lars [Show all 8 contributors for this article] (2018). Hypothermia is neuroprotective after severe hypoxic-ischaemic brain injury in neonatal rats pre-exposed to PAM3CSK4. Developmental Neuroscience. ISSN 0378-5866. 40(3), p. 189–197. doi: 10.1159/000487798. Full text in Research Archive Show summary

  BACKGROUND: Preclinical research on the neuroprotective effect of hypothermia (HT) after perinatal asphyxia has shown variable results, depending on comorbidities and insult severity. Exposure to inflammation increases vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury, and could be one explanation for those neonates whose injury is unexpectedly severe. Gram-negative type inflammatory exposure by lipopolysaccharide administration prior to a mild HI insult results in moderate brain injury, and hypothermic neuroprotection is negated. However, the neuroprotective effect of HT is fully maintained after gram-positive type inflammatory exposure by PAM3CSK4 (PAM) pre-administration in the same HI model. Whether HT is neuroprotective in severe brain injury with gram-positive inflammatory pre-exposure has not been investigated. METHODS: 59 seven-day-old rat pups were subjected to a unilateral HI insult, with left carotid artery ligation followed by 90-min hypoxia (8% O2 at Trectal 36°C). An additional 196 pups received intraperitoneal 0.9% saline (control) or PAM1 mg/kg, 8 h before undergoing the same HI insult. After randomisation to 5 h normothermia (NT37°C) or HT32°C, pups survived 1 week before they were sacrificed by perfusion fixation. Brains were harvested for hemispheric and hippocampal area loss analyses at postnatal day 14, as well as immunostaining for neuron count in the HIP CA1 region. RESULTS: Normothermic PAM animals (PAM-NT) had a comparable median area loss (hemispheric: 60% [95% CI 33-66]; hippocampal: 61% [95% CI 29-67]) to vehicle animals (Veh-NT) (hemispheric: 58% [95% CI 11-64]; hippocampal: 60% [95% CI 19-68]), which is defined as severe brain injury. Furthermore, mortality was low and similar in the two groups (Veh-NT 4.5% vs. PAM-NT 6.6%). HT reduced hemispheric and hippocampal injury in the Veh group by 13 and 28%, respectively (hemispheric: p = 0.048; hippocampal: p = 0.042). HT also provided neuroprotection in the PAM group, reducing hemispheric injury by 22% (p = 0.03) and hippocampal injury by 37% (p = 0.027). CONCLUSION: In these experiments with severe brain injury, Toll-like receptor-2 triggering prior to HI injury does not have an additive injurious effect, and there is a small but significant neuroprotective effect of HT. HT appears to be neuroprotective over a continuum of injury severity in this model, and the effect size tapers off with increasing area loss. Our results indicate that gram-positive inflammatory exposure prior to HI injury does not negate the neuroprotective effect of HT in severe brain injury.

• Liu, Xun; Jary, Sally; Cowan, Frances & Thoresen, Marianne (2017). Reduced infancy and childhood epilepsy following hypothermia-treated neonatal encephalopathy. Epilepsia. ISSN 0013-9580. 58(11), p. 1902–1911. doi: 10.1111/epi.13914. Full text in Research Archive
• Skranes, Janne Helen; Løhaugen, Gro; Schumacher, Eva Margrethe; Osredkar, Damjan; Server, Andrés & Cowan, Frances Mary [Show all 9 contributors for this article] (2017). Amplitude-Integrated Electroencephalography Improves the Identification of Infants with Encephalopathy for Therapeutic Hypothermia and Predicts Neurodevelopmental Outcomes at 2 Years of Age. Journal of Pediatrics. ISSN 0022-3476. 187, p. 34–42. doi: 10.1016/j.jpeds.2017.04.041. Full text in Research Archive
• Thoresen, Marianne; Gunn, A J; Robertson, Nicola J; Laptook, Abbot R; Barks, J D & Wassink, Guido [Show all 7 contributors for this article] (2017). Therapeutic hypothermia translates from ancient history in to practice. Pediatric Research. ISSN 0031-3998. 81(1-2), p. 202–209. doi: 10.1038/pr.2016.198. Full text in Research Archive
• Falck, Mari; Osredkar, Damjan; Maes, Elke; Flatebø, Torun; Wood, Thomas Ragnar & Sabir, Hemmen [Show all 7 contributors for this article] (2017). Hypothermic neuronal rescue from infection-sensitised hypoxic-ischaemic brain injury is pathogen dependent. Developmental Neuroscience. ISSN 0378-5866. 39(1-4), p. 238–247. doi: 10.1159/000455838. Full text in Research Archive
• Wood, Thomas Ragnar; Hobbs, C; Brun, AC; Falck, Mari; Løberg, Else Marit & Thoresen, Marianne (2017). Rectal temperature in the first five hours after hypoxia-ischaemia critically affetcs neuropathological outcomes in neonatale rats. Pediatric Research. ISSN 0031-3998. doi: 10.1038/pr.2017.51. Full text in Research Archive
• Tann, Cally J.; Martinello, KA; Sadoo, S; Lawn, JN; Seale, AC & Vega-Poblete, M [Show all 22 contributors for this article] (2017). Neonatal encephalopathy With goup B streptpococcal disease worldwide: Systematic review, investigator Group datasets and Meta-analysis. Clinical Infectious Diseases. ISSN 1058-4838. p. 173–189. doi: 10.1093/cid/cix662. Full text in Research Archive
• Elstad, Maja; Liu, Xun & Thoresen, Marianne (2016). Heart rate response to therapeutic hypothermia in infants with hypoxic–ischaemic encephalopathy. Resuscitation. ISSN 0300-9572. 106, p. 53–57. doi: 10.1016/j.resuscitation.2016.06.023. Full text in Research Archive
• Wood, Thomas Ragnar; Smit, Elisa; Maes, Elke; Osredkar, Damjan; Falck, Mari & Elstad, Maja [Show all 7 contributors for this article] (2016). Monitoring of cerebral blood flow during hypoxia-ischemia and resuscitation in the neonatal rat using laser speckle imaging. Physiological Reports. 4(7), p. 1–14. doi: 10.14814/phy2.12749. Full text in Research Archive Show summary

  Neonatal hypoxic‐ischemic encephalopathy (HIE) is associated with alterations in cerebral blood flow (CBF) as a result of perinatal asphyxia. The extent to which CBF changes contribute to injury, and whether treatments that ameliorate these changes might be neuroprotective, is still unknown. Higher throughput techniques to monitor CBF changes in rodent models of HIE can help elucidate the underlying pathophysiology. We developed a laser speckle imaging (LSI) technique to continuously monitor CBF in six postnatal‐day 10 (P10) rats simultaneously before, during, and after unilateral hypoxia‐ischemia (HI, ligation of the left carotid artery followed by hypoxia in 8% oxygen). After ligation, CBF to the ligated side fell by 30% compared to the unligated side (P < 0.0001). Hypoxia induced a bilateral 55% reduction in CBF, which was partially restored by resuscitation. Compared to resuscitation in air, resuscitation in 100% oxygen increased CBF to the ligated side by 45% (P = 0.033). Individual variability in CBF response to hypoxia between animals accounted for up to 24% of the variability in hemispheric area loss to the ligated side. In both P10 and P7 models of unilateral HI, resuscitation in 100% oxygen did not affect hemispheric area loss, or hippocampal CA1 pyramidal neuron counts, after 1‐week survival. Continuous CBF monitoring using LSI in multiple rodents simultaneously can screen potential treatment modalities that affect CBF, and provide insight into the pathophysiology of HI.

• Wood, Thomas Ragnar; Osredkar, Damjan; Puchades, Maja Amedjkouh; Maes, Elke; Falck, Mari & Flatebø, Torun [Show all 9 contributors for this article] (2016). Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia. Scientific Reports. 6. doi: 10.1038/srep23430. Full text in Research Archive Show summary

  Therapeutic hypothermia (HT) is standard care for moderate and severe neonatal hypoxic-ischaemic encephalopathy (HIE), the leading cause of permanent brain injury in term newborns. However, the optimal temperature for HT is still unknown, and few preclinical studies have compared multiple HT treatment temperatures. Additionally, HT may not benefit infants with severe encephalopathy. In a neonatal rat model of unilateral hypoxia-ischaemia (HI), the effect of five different HT temperatures was investigated after either moderate or severe injury. At postnatal-day seven, rat pups underwent moderate or severe HI followed by 5 h at normothermia (37 °C), or one of five HT temperatures: 33.5 °C, 32 °C, 30 °C, 26 °C, and 18 °C. One week after treatment, neuropathological analysis of hemispheric and hippocampal area loss, and CA1 hippocampal pyramidal neuron count, was performed. After moderate injury, a significant reduction in hemispheric and hippocampal loss on the injured side, and preservation of CA1 pyramidal neurons, was seen in the 33.5 °C, 32 °C, and 30 °C groups. Cooling below 33.5 °C did not provide additional neuroprotection. Regardless of treatment temperature, HT was not neuroprotective in the severe HI model. Based on these findings, and previous experience translating preclinical studies into clinical application, we propose that milder cooling should be considered for future clinical trials.

• Kochanek, P; Kitagawa, RS; Batchelor, P & Thoresen, Marianne (2016). Central Nervous System Injury and Temperature Management. Therapeutic Hypothermia and Temperature Management. ISSN 2153-7658. 6(3), p. 112–115. doi: 10.1089/ther.2016.29014.pjk. Full text in Research Archive
• Hemmen, Sabir; Wood, Thomas Ragnar; Gill, Hannah; Liu, Xun; Dingley, John & Thoresen, Marianne (2016). Xenon depresses aEEG background voltage activity whilst maintaining cardiovascular stability in sedated healthy newborn pigs. Journal of the Neurological Sciences. ISSN 0022-510X. 363, p. 140–144. doi: 10.1016/j.jns.2016.02.051. Full text in Research Archive Show summary

  Background Changes in electroencephalography (EEG) voltage range are used to monitor the depth of anaesthesia, as well as predict outcome after hypoxia-ischaemia in neonates. Xenon is being investigated as a potential neuroprotectant after hypoxic-ischaemic brain injury, but the effect of Xenon on EEG parameters in children or neonates is not known. This study aimed to examine the effect of 50% inhaled Xenon on background amplitude-integrated EEG (aEEG) activity in sedated healthy newborn pigs. Methods Five healthy newborn pigs, receiving intravenous fentanyl sedation, were ventilated for 24 h with 50%Xenon, 30%O2 and 20%N2 at normothermia. The upper and lower voltage-range of the aEEG was continuously monitored together with cardiovascular parameters throughout a 1 h baseline period with fentanyl sedation only, followed by 24 h of Xenon administration. Results The median (IQR) upper and lower aEEG voltage during 1 h baseline was 48.0 μV (46.0–50.0) and 25.0 μV (23.0–26.0), respectively. The median (IQR) aEEG upper and lower voltage ranges were significantly depressed to 21.5 μV (20.0–26.5) and 12.0 μV (12.0–16.5) from 10 min after the onset of 50% Xenon administration (p = 0.002). After the initial Xenon induced depression in background aEEG voltage, no further aEEG changes were seen over the following 24 h of ventilation with 50% xenon under fentanyl sedation. Mean arterial blood pressure and heart rate remained stable. Conclusion Mean arterial blood pressure and heart rate were not significantly influenced by 24 h Xenon ventilation. 50% Xenon rapidly depresses background aEEG voltage to a steady ~ 50% lower level in sedated healthy newborn pigs. Therefore, care must be taken when interpreting the background voltage in neonates also receiving Xenon.

• Sabir, Hemmen; Osredkar, Damjan; Maes, Elke; Wood, Thomas Ragnar & Thoresen, Marianne (2016). Xenon combined with therapeutic hypothermia is not neuroprotective after severe hypoxia-ischemia in neonatal rats. PLOS ONE. 11(6). doi: 10.1371/journal.pone.0156759. Full text in Research Archive
• Gunn, Alistair J & Thoresen, Marianne (2015). Animal studies of neonatal hypothermic neuroprotection have translated well in to practice. Resuscitation. ISSN 0300-9572. 97, p. 88–90. doi: 10.1016/j.resuscitation.2015.03.026. Full text in Research Archive
• Hoque, Nicholas; Liu, Xun; Chakkarapani, Elavazhagan & Thoresen, Marianne (2015). Minimal systemic hypothermia combined with selective head cooling evaluated in a pig model of hypoxia-ischemia. Pediatric Research. ISSN 0031-3998. 77(5), p. 674–680. doi: 10.1038/pr.2015.31. Full text in Research Archive
• Smit, Elisa; Liu, Xun; Jary, Sally; Cowan, Frances & Thoresen, Marianne (2015). Cooling neonates who do not fulfil the standard cooling criteria - short and long term outcomes. Acta Paediatrica. ISSN 0803-5253. 104(2), p. 138–145. doi: 10.1111/apa.12784. Full text in Research Archive
• Aquilina, Kristian & Thoresen, Marianne (2015). A newborn piglet survival model of post-hemorrhagic ventricular dilatation. In Yager, Jerome Y. (Eds.), Animal Models of Neurodevelopmental Disorders. Humana Press. ISSN 9781493927081. doi: 10.1007/978-1-4939-2709-8_10. Full text in Research Archive
• Chakkarapani, Elavazhagan & Thoresen, Marianne (2015). The Newborn Pig Global Hypoxic-Ischemic Model of Perinatal Brain and Organ Injury. In Yager, Jerome Y. (Eds.), Animal Models of Neurodevelopmental Disorders. Humana Press. ISSN 9781493927081. doi: 10.1007/978-1-4939-2709-8_12. Full text in Research Archive
• Osredkar, Damjan; Sabir, Hemmen; Falck, Mari; Wood, Thomas Ragnar; Maes, Elke & Flatebø, Torun [Show all 8 contributors for this article] (2015). Hypothermia Does Not Reverse Cellular Responses Caused by Lipopolysaccharide in Neonatal Hypoxic-Ischaemic Brain Injury. Developmental Neuroscience. ISSN 0378-5866. 37(4-5), p. 390–397. doi: 10.1159/000430860. Full text in Research Archive
• Liu, Xun; Dingley, John; Scull-Brown, Emma & Thoresen, Marianne (2015). Adding 5 hours delayed xenon to delayed hypothermia treatment improves long term function in neonatal rats surviving to adulthood. Pediatric Research. ISSN 0031-3998. 77, p. 779–783. doi: 10.1038/pr.2015.49. Full text in Research Archive
• Whitelaw, Andrew; Osredkar, Damjan & Thoresen, Marianne (2015). Neurological & Neuromuscular Disorders. In MacDonald, Mhairi G. & Seshia, Mary M. K. (Ed.), Avery's Neonatology: Pathophysiology and Management of the Newborn (Seventh Edition). Lippincott Williams & Wilkins. ISSN 9781451192681. p. 994–1016. Full text in Research Archive
• Smit, Elisa; Liu, Xun; Gill, Hannah; Jary, Sally; Wood, Thomas Ragnar & Thoresen, Marianne (2015). The effect of resuscitation in 100% oxygen on brain injury in a newborn rat model of severe hypoxic-ischaemic encephalopathy. Resuscitation. ISSN 0300-9572. 96, p. 214–219. doi: 10.1016/j.resuscitation.2015.07.050. Full text in Research Archive
• Jary, Sally; Smit, Elisa; Liu, Xun; Cowan, Frances & Thoresen, Marianne (2015). Less severe cerebral palsy outcomes in infants treated with therapeutic hypothermia. Acta Paediatrica. ISSN 0803-5253. 104(12), p. 1241–1247. doi: 10.1111/apa.13146. Full text in Research Archive
• Thoresen, Marianne & Sabir, Hemmen (2015). Epilepsy: Neonatal seizures still lack safe and effective treatment. Nature Reviews Neurology. ISSN 1759-4758. 11(6), p. 311–312. doi: 10.1038/nrneurol.2015.74. Full text in Research Archive

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• Wu, Chelsea Q.; Cowan, Frances M.; Jary, Sally; Thoresen, Marianne; Chakkarapani, Ela & Spencer, Arthur P. C. (2023). Author Correction: Cerebellar growth, volume and diffusivity in children cooled for neonatal encephalopathy without cerebral palsy (Scientific Reports, (2023), 13, 1, (14869), 10.1038/s41598-023-41838-3). Scientific Reports. 13(1). doi: 10.1038/s41598-023-49211-0. Full text in Research Archive
• Bjertnaes, Lars J.; Hauge, Anton; Thoresen, Marianne & Walløe, Lars (2021). Prioritized brain circulation during ergometer cycling with apnea and face immersion in ice-cold water: A case report. International Medical Case Reports Journal. 14, p. 675–681. doi: 10.2147/IMCRJ.S317404. Full text in Research Archive Show summary

  Background: Successful cardiopulmonary resuscitation after drowning or avalanche is often attributed to hypothermia-induced decrease in metabolism, which adapts the oxygen demand to the amount supplied under cardiac compression. Four decades ago, we speculated if oxygen-sparing mechanisms like those found in marine mammals, may improve cerebral oxygenation during acute airway blockade in humans. We investigated hemodynamic changes during steady state ergometer cycling with intermittent periods of apnea and face immersion (AFI) in ice-cold water. During AFI, heart rate (HR) dropped by 58% whereas average blood velocity (ABV) determined by means of a Doppler ultrasound velocity meter (UNIDOP University of Oslo, Oslo, Norway) fell by 85% in the radial artery and rose by 67% in the vertebral artery. Similar changes occured in radial artery ABV, albeit more slowly, when the test subject only held his breath while cycling. When he breathed via a snorkel during face immersion, HR remained unchanged while radial artery ABV fell transiently and subsequently returned to its pre-immersion level. These findings later were confirmed by other investigators. Moreover, a recent study revealed that the seal even has a system for selective brain cooling during the dive.<p> <p>Conclusion: Our research has confirmed prioritized cerebral circulation during AFI in cold water. We hypothesize that these changes may improve brain oxygenation due both to greater blood flow and possibly also to faster brain cooling, as demonstrated in diving seals.

• Thoresen, Marianne & Chakkarapani, Ela (2020). Association between neonatal neuroimaging, 18month cognitive and school-age full-scale IQ scores in children without cerebral palsy, cooled for neonatal encephalopathy. Full text in Research Archive
• Thoresen, Marianne; Wood, TR; Gundersen, J; Falck, Mari; Maes, Elke & Osredkar, Damjan [Show all 9 contributors for this article] (2020). Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic-ischaemic brain injury: a single laboratory meta-analysis. Full text in Research Archive
• Thoresen, Marianne (2018). <li value="209"> Thoresen M. On BBC 11th July 2018: http://www.bristolhealthpartners.org.uk/blog/2018/06/26/i-pushed-all-i-could-out-came-a-baby-who-was-pale-limp-and-did-not-cry/1102. [TV]. BBC. Full text in Research Archive
• Thoresen, Marianne; Bel, Frank van; Murray, D; Saliba, E; Buonocore, G & Hellstrøm-Westas, L [Show all 7 contributors for this article] (2018). Postnatal management of newborn infants with hypoxic ischaemic encephalopathy (HIE). Full text in Research Archive Show summary

  The goal is to reduce long-term effects of hypoxic ischaemic brain injury. Moderate to severe perinatal asphyxia in term and near term infants is one of the most important causes of neonatal death and adverse motor and cognitive outcome, with an incidence of 2-20 per 1000 live born infants, depending in which part of the world they are born. (1) Until recently, therapy was limited to stabilisation of the newborn infant and treatment of hypoxic ischaemic encephalopathy (HIE) induced seizures. Reduction of the body temperature to 33.5°C is the only established therapy which has shown a decrease in adverse outcomes after perinatal asphyxia (death or substantial disability at 18 months of age) from about 66% for non-cooled infants to 50% in cooled infants. (2,3) Intensive research is ongoing to explore (pharmacological) neuroprotective interventions which could be used in addition to hypothermia to improve outcome. (4–7)

• Thoresen, Marianne (2018). Hva oppnår vi ved nedkjøling av nyfødte med oksygenmangel. Full text in Research Archive
• Hollung, Sandra Julsen & Thoresen, Marianne (2018). Forekomsten og alvorlighetsgraden av cerebral parese har gått ned. [TV]. NRK Dagsrevyen. Full text in Research Archive
• Thoresen, Marianne (2018). The past and future of Neonatal Neuroprotection. Full text in Research Archive
• Thoresen, Marianne (2017). Reduced sub-cortical grey matter volume is Associated With functional outcome at 6-8 years in children without cerebral palsy, who were cooled for neonatal encephalopathy. Full text in Research Archive
• Thoresen, Marianne; Falck, Mari & Maes, Elke (2017). Pathogen specific changes in core temperature and neuroinflammation in the neonatal rat. Full text in Research Archive
• Thoresen, Marianne (2017). Selection Criteria for 3 days of Therapeutic Hypothermia (TH) treatment after newborn asphyxia is based on aEEG depression. At 2 years, only 2% of TH infants have seizures needing regular AED treatment in a large SWE cohort'. Full text in Research Archive
• Thoresen, Marianne (2017). Entry criteria for Therapeutic are drifting - does it matter? Full text in Research Archive
• Thoresen, Marianne (2017). Tackling perinatal asphyxia. Does keeping the newborn brain cold after lack of oxygen always reduce brain injury? Full text in Research Archive
• Thoresen, Marianne (2017). Targeted Temperature management in the very young. Full text in Research Archive
• Thoresen, Marianne (2017). Gases for the brain. Full text in Research Archive
• Thoresen, Marianne (2017). Are small brains different from adults - why is therapeutic hypothermia so effective in newborns? Full text in Research Archive
• Thoresen, Marianne (2017). CARDIOVASCULAR RESPONSE AND SEIZURE FREQUENCY OF 78 HOURS XENON INHALATION WITH HYPOTHERMIA FOLLOWING GLOBAL HYPOXIC-ISCHAEMIA: FEASIBILITY. Full text in Research Archive
• Thoresen, Marianne & Falck, Mari (2017). Hypothermia plus human Umbilical-Cord Blood Cells is neuroprotective in a severe neonatal hypoxicischaemic brain injury model. Full text in Research Archive
• Thoresen, Marianne (2017). Epilepsy and the need for drug treatment in infancy and early school years after perinatal asphyxia and therapeutic hypothermia. Full text in Research Archive
• Smit, Elisa; Wood, Thomas Ragnar; Elstad, Maja; Liu, Xun & Thoresen, Marianne (2016). The effect of resuscitation in 100% Oxygen on cerebral blood flow and neuropathology in a newborn rat model of hypoxia-ischaemia. Full text in Research Archive
• Thoresen, Marianne; Basu, S K; Kaiser, J R; Guffey, D; Minard, C G & Guillet, Ronnie [Show all 7 contributors for this article] (2016). Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap Study. Archives of Disease in Childhood: Fetal and Neonatal Edition. ISSN 1359-2998. p. 149–155. doi: 10.1136/archdischild-2015-308733. Full text in Research Archive
• Falck, Mari; Maes, Elke; Flatebo, Torun; Wood, Thomas Ragnar; Sabir, Hemmen & Osredkar, Damjan [Show all 7 contributors for this article] (2016). Gram-positive Septicemia Sensitises The Neonatal Brain To Hypoxic-ischemic Injury, Without Inhibiting The Neuroprotective Effect Of Hypothermia. Full text in Research Archive
• Thoresen, Marianne & Worcester, BBC Radio Herefordshire & (2016). Interview following-up on progress of a baby who had been enrolled in a clinical trial. Full text in Research Archive
• Wood, Thomas Ragnar; Skranes, Janne Helen; Falck, Mari; Lohaugen, GC; Stiris, Tom & Loberg, EM [Show all 8 contributors for this article] (2016). Core Temperature After Neonatal Hypoxia-Ischaemia Predicts Long-term Cerebral Injury. Full text in Research Archive
• Lee-Kelland, Richard; Dingley, John; Okano, S; Scull-Brown, Emma; Thoresen, Marianne & Chakkarapani, Ela (2016). Xenon as Neuroprotection: A Demonstration of an Automated Delivery System. Full text in Research Archive
• Chakkarapani, Ela & Thoresen, Marianne (2016). C-Reactive Protein Response in Infants Cooled for Neonatal Encephalopathy Is Delayed in Females More Than Males. Full text in Research Archive
• Thoresen, Marianne (2016). Hypothermia and beyond. (Perinatal Asphyxia). Full text in Research Archive
• Thoresen, Marianne (2016). Cooling the right children with the optimal protocol using valid short and long term outcome examinations - are we getting any better? Full text in Research Archive
• Thoresen, Marianne (2016). Xenon and hypothermia in neonates. Full text in Research Archive
• Falck, Mari; Osredkar, Damjan; Maes, Elke; Wood, Thomas Ragnar; Puchades, Maja Amedjkouh & Sabir, Hemmen [Show all 7 contributors for this article] (2015). Systemic Inflammation Negates Hypothermic Neuroprotection in a Neonatal HIE-model. Full text in Research Archive
• Sabir, Hemmen; Maes, Elke; Liu, Xun; Dingley, John & Thoresen, Marianne (2015). Fentanyl induces cerebellar internal granular cell layer apoptosis in healthy newborn pigs. Full text in Research Archive
• Lee-Kelland, Richard; Chakkarapani, Ela; Jary, Sally; Liu, Xun & Thoresen, Marianne (2015). Temperature Instability Post Rewarming in Neonates Who Have Received Therapeutic Hypothermia. Full text in Research Archive
• Thoresen, Marianne (2015). Optimal resuscitation followed by optimal hypothermia with and without added xenon inhalation. Full text in Research Archive
• Falck, Mari; Osredkar, Damjan & Thoresen, Marianne (2015). Hypothermia does not reverse cellular responses caused by lipopolysaccharide in neonatal hypoxic ischemic brain injury. Full text in Research Archive
• Chakkarapani, Ela; Aquilina, Julian; Lee-Kelland, Richard; Jary, Sally; Liu, Xun & Thoresen, Marianne (2015). Morphine exposure and neurodevelopment outcome in cooled neonatal encephalopathy infants with mild cerebral dysfunction. Full text in Research Archive
• Wood, Thomas Ragnar; Osredkar, Damjan; Flatebø, Torun; Falck, Mari; Maes, Elke & Thoresen, Marianne (2015). Temperature Dependence Of Hypothermic Neuroprotection in a Rat Model of Neonatal Hypoxic Ischaemic Enchephopathy. Full text in Research Archive
• Thoresen, Marianne; Chakkarapani, Ela; Walløe, Lars; Løberg, Else Marit; Maes, Elke & Liu, Xun [Show all 7 contributors for this article] (2015). No cardiac protection from hypothermia or xenon inhalation after hypoxia-ischemia in newborn pigs. Full text in Research Archive
• Thoresen, Marianne (2015). Hypothermia after perinatal asphyxia; do we select and cool the right babies with the optimal cooling protocol and follow up agreements? Full text in Research Archive
• Wood, Thomas Ragnar; Osredkar, Damjan; Flatebø, Torun; Falck, Mari; Maes, Elke & Thoresen, Marianne (2015). Temperature Dependence Of Hypothermic Neuroprotection In A R Model Of Neonatal Hypoxic Ischaemic Encephalopathy. Full text in Research Archive
• Sabir, Hemmen; Osredkar, Damjan; Maes, Elke; Wood, Thomas Ragnar & Thoresen, Marianne (2015). Therapeutic Hypothermia Combined With Inhaled Xenon in Newborn Rats: the Ongoing Challenge following severe hypoxicischemic brain injury. Full text in Research Archive
• Thoresen, Marianne (2015). Editorial: Cooling after perinatal asphyxia. Seminars in Fetal & Neonatal Medicine. ISSN 1744-165X. 20(2). doi: 10.1016/j.siny.2015.01.003. Full text in Research Archive
• Thoresen, Marianne (2015). Optimal hypothermia treatment: an update from experimental and clinical research. Full text in Research Archive
• Thoresen, Marianne & Gundersen, Julie K (2021). Morphine and fentanyl exposure during therapeutic hypothermia do not affect neurodevelopmental outcome at 18-24 months of age. Abstract ID: 3539552. Pediatric Academic Society. Full text in Research Archive
• Thoresen, Marianne & Jary, Sally (2021). Motor correlates of brain structural connectivity in school-age children treated with therapeutic hypothermia for neonatal encephalopathy. Abstract ID: 3539104. Pediatric Academic Society. Full text in Research Archive
• Thoresen, Marianne (2021). Corpus callosum morphology, microstructure and outcomes in children without cerebral palsy cooled for neonatal hypoxic-ischemic encephalopathy. Abstract ID: 3538308. Pediatric Academic Society. Full text in Research Archive
• Thoresen, Marianne (2018). European Standards of Care for Newborn Health:Postnatal management of newborn infants with hypoxic ischaemic encephalopathy (HIE). Issued by: European Foundation for the Care of Newborn Infants (EFCNI). November 2018. European standard of care for newborn health. Full text in Research Archive

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