Early Axonal Injury and Delayed Cytotoxic Cerebral Edema are Associated With Microglial Activation in a Mouse Model of Sepsis Sepsis-induced brain injury is associated with an acute deterioration of mental status resulting in cognitive impairment and acquisition of new functional limitations in sepsis survivors. However, the exact nature of brain injury in this setting is often subtle and remains to be fully characterized both in pre-clinical studies and at the bedside. Given the translation potential for the use of magnetic resonance imaging (MRI)1 to define sepsis-induced brain injury, we sought to determine and correlate the cellular changes with neuroradiographic presentations in a classic murine model of sepsis induced by cecal ligation and puncture (CLP)2. Sepsis was induced in 6–10-week-old male C57/BL6 mice by CLP. We used immunohistochemistry (IHC)3 to define neuropathology in a mouse model of sepsis along with parallel studies using MRI, focusing on cerebral edema, blood-brain barrier (BBB)4 disruption, and microglial activation on days 1 and 4 days after CLP. We demonstrate that septic mice had evidence of early axonal injury, inflammation and robust microglial activation on day 1 followed by cytotoxic edema on day 4 in the cortex, thalamus, and hippocampus in the absence of BBB disruption. We note the superiority of the MRI to detect subtle brain injury and cytotoxic cerebral edema in comparison to the traditional gold standard assessment, i.e., percent brain water (wet-dry weight method). We conclude that inflammatory changes in the septic brain can be detected in real-time, and further studies are needed to understand axonal injury and the impact of inhibition of microglial activation on the development of cerebral edema. Address reprint requests to Rajesh K. Aneja, MD, University of Pittsburgh, Pittsburgh, PA, United States. E-mail: anejar@upmc.edu Received 16 May, 2019 Revised 5 June, 2019 Accepted 30 August, 2019 This study was supported by: Shock Society Research Investigator Award for Early Scientists (DP) NICHD T32 training grant 5T32HD040686 (DP, AMA, PMK) NIGMS R01GM098474 (RKA) NINDS NS 087978 (PMK) Department of Defense (DoD) W81XWH1810070 (YLW) American Heart Association (AHA) 18CDA34140024 (YLW) This work was presented at the Shock Society 39th Annual Conference on Shock; June 11-14, 2016; Austin, TX. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society

Pharmacokinetics, Pharmacodynamics and Safety of Nivolumab in Patients With Sepsis-induced immunosuppression: A multicenter, open-label phase 1/2 study Background: Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. Methods: In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks [Q2W]). Results: Single 480 and 960 mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480 mg (132 μg/mL) was similar to the predicted concentration at the end of infusion with 3 mg/kg Q2W (117 μg/mL). The concentration on Day 28 after 960 mg (33.1 μg/mL) was within the predicted trough concentration range for 3 mg/kg Q2W (90% prediction interval 19.0 to 163 μg/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480 and 960 mg groups, respectively. Drug-related AEs were observed in only one patient in the 480 mg group. No deaths related to nivolumab occurred. Conclusions: A single dose of 960 mg nivolumab appeared to be well-tolerated and sufficient to maintain nivolumab blood concentrations. Both 480 and 960 mg nivolumab seemed to improve immune system indices over time. Trial registration: JAPIC, JapicCTI-173600 Address reprint requests to Eizo Watanabe, MD, PhD, Department of General Medical Science, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba 260-8670, Japan. E-mail: watanabee@faculty.chiba-u.jp Received 28 May, 2019 Revised 14 June, 2019 Accepted 23 August, 2019 Conflicts of interest and source of funding: This study was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Ono Pharmaceutical Co., Ltd. was involved in the design of the study; collection, analysis, and interpretation of data; and in drafting the manuscript. Bristol-Myers Squibb did not have a role in the study design; data collection, analysis and interpretation; nor writing of the manuscript. EW received personal fees and non-financial support from Ono Pharmaceutical Co., Ltd., during the conduct of the study; and grants, personal fees and non-financial support from Asahi Kasei Pharma, and personal fees from Alexion Pharma, outside the submitted work. ON received grants and personal fees from Ono Pharmaceutical Co., Ltd., during the conduct of the study; and grants from Maruishi Pharmaceutical Co., Ltd., Fuso Pharmaceutical Industries, Ltd., Asahi Kasei Pharma, and Japan Blood Products Organization, outside the submitted work. YK received personal fees from Ono Pharmaceutical Co., Ltd., during the conduct of the study; and grants and personal fees from Ono Pharmaceutical Co., Ltd., grants from Japan Blood Products Organization, and grants from Asahi Kasei Pharma, outside the submitted work. MO, TO and TH received personal fees from Ono Pharmaceutical Co., Ltd., during the conduct of the study. SO received personal fees from Ono Pharmaceutical Co., Ltd., during the conduct of the study; and personal fees from Ono Pharmaceutical Co., Ltd., outside the submitted work. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 © 2019 by the Shock Society

Critical Role of Mortalin/GRP75 In Endothelial Cell Dysfunction Associated With Acute Lung Injury Mortalin/GRP75 (glucose regulated protein 75), a member of heat shock protein 70 (Hsp70) family of chaperones, is involved in several cellular processes including proliferation and signaling, and plays a pivotal role in cancer and neurodegenerative disorders. In this study, we sought to determine the role of mortalin/GRP75 in mediating vascular inflammation and permeability linked to the pathogenesis of acute lung injury (ALI). In an aerosolized bacterial lipopolysaccharide (LPS) inhalation mouse model of ALI, we found that administration of mortalin/GRP75 inhibitor MKT-077, both prophylactically and therapeutically, protected against PMN influx into alveolar airspaces, microvascular leakage and expression of pro-inflammatory mediators such as IL-1β, E-selectin and TNFα. Consistent with this, thrombin-induced inflammation in cultured human endothelial cells (EC) was also protected upon before and after treatment with MKT-077. Similar to pharmacological inhibition of mortalin/GRP75, siRNA-mediated depletion of mortalin/GRP75 also blocked thrombin-induced expression of proinflammatory mediators such as ICAM-1 and VCAM-1. Mechanistic analysis in EC revealed that inactivation of mortalin/GRP75 interfered with the binding of the liberated NF-κB to the DNA, thereby leading to inhibition of downstream expression of adhesion molecules, cytokines and chemokines. Importantly, thrombin-induced Ca2+ signaling and EC permeability were also prevented upon mortalin/GRP75 inactivation/depletion. Thus, this study provides evidence for a novel role of mortalin/GRP75 in mediating EC inflammation and permeability associated with ALI. Address reprint requests to Fabeha Fazal, PhD, Department of Pediatrics, Box 850, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642. E-mail: Fabeha_Fazal@URMC.Rochester.edu Received 8 May, 2019 Revised 24 May, 2019 Accepted 29 August, 2019 Author contributions: F.F, A.L. and A.R. conceived and designed the experiments. A.L and P.S performed the experiments (equal contribution). F.F analyzed the data and drafted the manuscript. F.F, D.Y and A.R edited and approved the final version of the manuscript. Conflict of interest: No conflict of interest, financial or otherwise, are declared by the authors The authors declare that they have no competing interests. © 2019 by the Shock Society

Venous-To-Arterial Carbon Dioxide Partial Pressure Difference: Predictor of Septic Patient Prognosis Depending on Central Venous Oxygen Saturation This study aimed to assess the viability of using the venous-to-arterial carbon dioxide partial pressure difference (P(v–a)CO2) to predict clinical worsening of septic shock, depending on central venous oxygen saturation (ScvO2). The prospective, observational, multicentric study conducted in three intensive care units (ICU) included all patients with a septic shock episode during the first six hours, with 122 patients assessed. Clinical worsening was defined as an increase of sequential organ failure assessment (SOFA) scores ≥1 (ΔSOFA ≥1) within two days. To assess the ability of P(v–a)CO2 to predict clinical worsening, univariate and multivariate analyses were performed according to ΔSOFA. A receiver operating characteristic (ROC) analysis was used to confirm model predictions. Associations between P(v–a)CO2 and mortality were explored using correlations. Using multivariate analyses, two independent factors associated with ΔSOFA ≥1 were identified: an averaged six-hour value of lactate concentration (Lac [1–6]) (odds ratios [OR], 2.43 [95% confidence interval (CI), 1.20–4.89]; p = 0.013) and an averaged six-hour value of P(v–a)CO2 (P(v–a)CO2 [1–6]) (OR, 1.49 [95% CI, 1.04–2.15]; p = 0.029). ROC analysis confirmed that Lac [1–6] and P(v–a)CO2 [1–6] were significantly associated with ΔSOFA ≥1, while ScvO2 [1–6] was not. Finally, ΔSOFA ≥1 was associated with higher 28-day (76% vs. 10%, p = 0.001) and ICU (83% vs. 12%, p = 0.001) mortality rates, which were higher in patients with P(v–a)CO2 [1–6] > 5.8 mmHg (57% vs. 33%; p = 0.012). In conclusion, P(v–a)CO2 may help predict outcomes for septic shock patients regardless of ScvO2 values. Address reprint requests to Marc Leone, MD, PhD, Service d’Anesthésie et de Réanimation, Hôpital Nord, Chemin des Bourrely, 13015 Marseille, France. E-mail: marc.leone@ap-hm.fr Received 4 June, 2019 Revised 26 June, 2019 Accepted 23 August, 2019 Conflicts of interest and source of funding: No conflict of interest in relation to the submitted study. Funding: Assistance Publique Hôpitaux de Marseille This paper contains sufficient information to comply with the ARRIVE guidelines. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society

Association of Vitamin D Deficiency with Profound Cardiogenic Shock In Patients Resuscitated from Sudden Cardiac Arrest Background: Vitamin D deficiency is associated with various cardiovascular diseases, including sudden cardiac arrest (SCA). Profound cardiogenic shock is associated with morbidity and mortality in patients with SCA. This study investigated the association of vitamin D deficiency with profound cardiogenic shock in patients resuscitated from SCA. Materials and Methods: We enrolled patients who were successfully resuscitated from out-of-hospital cardiac arrests of a presumed cardiac cause. Profound cardiogenic shock was defined as refractory hypotension requiring high-dose vasopressor infusion (norepinephrine >0.5 mcg/kg/min) despite adequate intravascular volume replacement. Vitamin D levels were measured as plasma 25(OH)D concentrations and severe vitamin D deficiency was defined as 25(OH)D <10 ng/mL. Results: A total of 237 subjects (179 men (76%), mean age 56.5 ± 16.5 years) were included in this study. The first monitored rhythm was shockable in 160 subjects (68%). Mean arrest time and CPR times were 25.6 ± 15.7 and 22.8 ± 15.0 minutes, respectively. Profound cardiogenic shock was observed in 100 subjects (42%). The mean vitamin D level was 12.3 ± 6.7 ng/mL, and vitamin D deficiency was diagnosed in 109 subjects (46%). In profound cardiogenic shock subjects, vitamin D levels were significantly lower (10.7 ± 7.0 vs. 13.4 ± 6.2 ng/mL, p = 0.002) and severe vitamin D deficiency was observed more frequently (63% vs. 34%, p < 0.001). Subjects with profound cardiogenic shock were likely to have longer arrest times (29.5 ± 17.0 vs. 22.7 ± 14.0 minutes, p = 0.001), left ventricular systolic dysfunction (LVEF < 40%, 73% vs. 38%, p < 0.001), and baseline renal dysfunction (65% vs. 37%, p < 0.001). Multivariate logistic analysis indicated that vitamin D deficiency was significantly associated with profound cardiogenic shock after SCA (OR 2.71, 95% CI 1.42–5.18, p = 0.003) after adjusting for confounding variables. Conclusions: Severe vitamin D deficiency was strongly associated with profound cardiogenic shock and mortality in patients resuscitated from SCA. Address reprint requests to Jin Wi, MD, PhD, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon, Korea 21565. E-mail: caesar@gilhospital.com Received 10 July, 2019 Revised 4 August, 2019 Accepted 23 August, 2019 Conflict of interest: The authors have no financial conflicts of interest. © 2019 by the Shock Society

EP2 Receptor Blockade Attenuates COX-2 Upregulation During Intestinal Inflammation High levels of PGE2 have been implicated in the pathogenesis of intestinal inflammatory disorders such as necrotizing enterocolitis (NEC) and peritonitis. However, PGE2 has a paradoxical effect: its low levels promote intestinal homeostasis, whereas high levels may contribute to pathology. These concentration-dependent effects are mediated by four receptors, EP1-EP4. In this study, we evaluate the effect of blockade of the low affinity pro-inflammatory receptors EP1 and EP2 on expression of COX-2, the rate limiting enzyme in PGE2 biosynthesis, and on gut barrier permeability using cultured enterocytes and three different models of intestinal injury. PGE2 upregulated COX-2 in IEC-6 enterocytes, and this response was blocked by the EP2 antagonist PF-04418948, but not by the EP1 antagonist ONO-8711 or EP4 antagonist E7046. In the neonatal rat model of NEC, EP2 antagonist and low dose of COX-2 inhibitor Celecoxib, but not EP1 antagonist, reduced NEC pathology as well as COX-2 mRNA and protein expression. In the adult mouse endotoxemia and cecal ligation/puncture models, EP2, but not EP1 genetic deficiency decreased COX-2 expression in the intestine. Our results indicate that the EP2 receptor plays a critical role in the positive feedback regulation of intestinal COX-2 by its end-product PGE2 during inflammation and may be a novel therapeutic target in the treatment of NEC. Address reprint requests to Anatoly Grishin, PhD, Children's Hospital Los Angeles MS35, 4650 Sunset Blvd, Los Angeles, CA 90027. E-mail: agrishin5725@gmail.com This study was supported by NIH Grant AI 014032 to H.R.F. Authors declare no conflict of interested in association with this study. The authors report no conflicts of interest. © 2019 by the Shock Society

The Diagnostic and Prognostic Value of Supar in Patients With Sepsis: A Systematic Review and Meta-Analysis Background: Soluble urokinase-type plasminogen activator receptor (suPAR) has the potential to diagnose infectious diseases. Due to the lack of reliable biomarkers and the importance of timely diagnosis for sepsis treatment, we conducted this systematic review and meta-analysis to evaluate the value of suPAR diagnosis and prognosis for sepsis. Methods: PubMed, Embase, Web of Science and Cochrane Library databases were searched for studies, which reported the value of suPAR diagnosis and/or prognosis in patients with sepsis. Results: 30 studies involving 6906 patients were included. Sensitivity and specificity of suPAR for diagnosing sepsis were 0.76 [95% confidence interval (CI): 0.63–0.86] and 0.78 (95%CI: 0.72–0.83), respectively. The area under the summary receiver operating characteristic curve (AUC) was 0.83 (95%CI: 0.80–0.86). Pooled sensitivity and specificity for predicting mortality were 0.74 (95%CI: 0.67–0.80) and 0.70 (95%CI: 0.63–0.76), respectively, with AUC of 0.78 (95%CI: 0.74–0.82). In addition, AUC for differentiating sepsis from systemic inflammatory response syndrome (SIRS) was 0.81 (95%CI: 0.77–0.84), and the sensitivity and specificity were 0.67 (95%CI: 0.58–0.76) and 0.82 (95%CI: 0.73–0.88) respectively. Conclusion: suPAR is a feasible biomarker for timely diagnosis and prognosis of sepsis. Compared to effective value of procalcitonin (PCT) identified by previous meta-analysis, suPAR has similar clinical guiding value, while suPAR exhibits higher specificity, which can facilitate the deficiencies of PCT. suPAR also shows a diagnostic value in differentiating sepsis from SIRS. Considering the lack of biomarkers for sepsis and the similar clinical value of suPAR and PCT, suPAR should be considered as a biomarker in clinical practice for sepsis. Address reprint requests to Jian Liu, Gansu Provincial Hospital, Donggang West Road, Lanzhou 730000, China. E-mail: medecinliu@sina.com. Received 31 May, 2019 Revised 25 June, 2019 Accepted 5 August, 2019 The authors declare that they have no competing interests. Funding: The authors remain independently of any funding influence. Competing interests: The authors have no competing of interest nor any financial interest in any product mentioned in this paper. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society

Transfusion of Anaerobically or Conventionally Stored Blood After Hemorrhagic Shock Background: Resuscitation from hemorrhagic shock (HS) by blood transfusion restores oxygen (O2) delivery and provides hemodynamic stability. Current regulations allow red blood cells (RBCs) to be stored and used for up to 42 days. During storage, RBCs undergo many structural and functional changes. These storage lesions have been associated with adverse events and increased mortality after transfusion, increasing the need for improved RBC storage protocols. This study evaluates the efficacy of anaerobically stored RBCs to resuscitate rats from severe HS compared with conventionally stored RBCs. Methods and results: Rat RBCs were stored under anaerobic, anaerobic/hypercapnic, or conventional conditions for a period of 3 weeks. Hemorrhage was induced by controlled bleeding, shock was maintained for 30 min, and RBCs were transfused to restore and maintain blood pressure near the prhemorrhage level. All storage conditions met current regulatory 24-h posttransfusion recovery requirements. Transfusion of anaerobically stored RBCs required significantly less RBC volume to restore and maintain hemodynamics. Anaerobic or anaerobic/hypercapnic RBCs restored hemodynamics better than conventionally stored RBCs. Resuscitation with conventionally stored RBCs impaired indices of left ventricular cardiac function, increased hypoxic tissue staining and inflammatory markers, and affected organ function compared with anaerobically stored RBCs. Conclusions: Resuscitation from HS via transfusion of anaerobically stored RBCs recovered cardiac function, restored hemodynamic stability, and improved outcomes. Address reprint requests to Pedro Cabrales, 9500 Gilman Dr., PFBH 182, La Jolla, CA 92093. E-mail: pcabrales@ucsd.edu Received 13 March, 2019 Revised 1 April, 2019 Accepted 15 May, 2019 Authors’ contributions: ATW and PC designed the experimental studies; ATW performed experiments and acquired data. ATW, VPJ, and AL analyzed data. TN and ADA acquired and analyzed metabolomics data. TY and AD generated technology for ex vivo oxygen-controlled preservation of RBCs and provided reagents. ATW, VPJ, ADA, and PC wrote the manuscript. Reagents were provided by Hemanext for completion of the study. Hemanext did not participate in implementation of the study. Additional funding was provided by NIH grants from the Heart Lung and Blood Institute, T32-HL105373, R01-HL126945, and R01 HL138116. The authors would like to disclose that TY and AD are a part of Hemanext. ADA is a consultant for Hemanext. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society

Adenosine 5’-Monophosphate Protects From Hypoxia By Lowering Mitochondrial Metabolism and Oxygen Demand ABSTRCT Ischemia and reperfusion injury following severe trauma or cardiac arrest are major causes of organ damage in intensive care patients. The brain is particularly vulnerable because hypoxia rapidly damages neurons due to their heavy reliance on oxidative phosphorylation. Therapeutic hypothermia can reduce ischemia-induced brain damage, but cooling procedures are slow and technically difficult to perform in critical care settings. It has been previously reported that injection of naturally occurring adenosine 5’-monophosphate (AMP) can rapidly induce hypothermia in mice. We studied the underlying mechanisms and found that AMP transiently reduces the heart rate, respiratory rate, body temperature, and the consciousness of adult male and female C57BL/6J mice. Adding AMP to mouse or human neuronal cell cultures dose-dependently reduced the membrane potential (ΔΨm) and Ca2+ signaling of mitochondria in these cells. AMP treatment increased intracellular AMP levels and activated AMP-activated protein kinase (AMPK), which resulted in the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and of mitochondrial and cytosolic Ca2+ signaling in resting and stimulated neurons. Pretreatment with an intraperitoneal injection of AMP almost doubled the survival time of mice under hypoxic (6% O2) or anoxic (<1% O2) conditions when compared to untreated mice. These findings suggest that AMP induces a hypometabolic state that slows mitochondrial respiration, reduces oxygen demand, and delays the processes that damage mitochondria in the brain and other organs following hypoxia and reperfusion. Further examination of these mechanisms may lead to new treatments that preserve organ function in critical care patients. Address reprint requests to Wolfgang G. Junger, PhD, Harvard Medical School, Beth Israel Deaconess Medical Center, Department of Surgery, 330 Brookline Avenue, Boston, MA 02215, USA. E-mail: wjunger@bidmc.harvard.edu Received 10 July, 2019 Revised 24 July, 2019 Accepted 19 August, 2019 Source of Funding: The study was supported in part by grants from the National Institutes of Health, GM-51477, GM-60475, GM-116162, AI-080582, and T32 GM-103702 (to W.G.J.), and the National Natural Science Foundation of China (81701564) and the Applied Basic Research Program of the Science and Technology Department of Sichuan Province (2018JY0676; to X.L.). Conflicts of interest: The authors have no conflicts of interest to declare. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society

Conditioned Contextual Freezing is A Neurobehavioral Biomarker of Axonal Injury Indicated by Reduced Fractional Anisotropy In A Mouse Model of Blast-Induced Mild Traumatic Brain Injury Mild Traumatic Brain Injury (TBI) is an important public health problem generated by closed head injury. This study is focused on the impact of blast-induced mild TBI on auditory trace and delay fear conditioning, models of declarative and non-declarative memory, respectively, and the correlation of conditioned freezing and fractional anisotropy, a measure of axonal state. A supersonic helium pressure wave was generated by a shock tube to blast 8 week old male mice on Day 1 for 1.4 msec with an incident pressure of 16 psi, corresponding to a reflected pressure of 56.5 psi at the mouse head. On Day 3, the mice were subjected to auditory trace- or delay- fear conditioning. On Day 4, contextual freezing in the trained context, and pre-cue and cued freezing in a novel context were determined. After cardiac perfusion on Day 5, ex vivo images were obtained with diffusion tensor imaging at 14.1 Tesla. We observed that delay fear conditioning prevented or reversed the decrease in fractional anisotropy in both the medial and lateral corpus callosum suggesting axonal stabilization of potentially behavioral therapeutic significance. Moderately strong and statistically significant Pearson correlations were found between fractional anisotropy and contextual freezing in the medial and lateral corpus callosum of blasted and sham-blasted delay- or trace- fear conditioned mice. Thus, contextual freezing is a neurobehavioral biomarker for axonal injury in mild TBI and is a reliable and high-throughput behavioral assay for the evaluation of potential therapeutics to treat mild TBI. Address reprint requests to Joachim Spiess, PhD, MD, Cortrop Incorporated, Encinitas, CA 92024. E-mail: joachim.spiess@gmail.com Received 29 May, 2019 Revised 14 June, 2019 Accepted 23 July, 2019 Support: NIH grants RO1NS059879 (CW), NS10RR13880 (AMW), MH047340 (JFD), and Max Planck Society (JS). Author contributions: J.S. initiated the project, designed the program, participated in the design of the behavior and DTI experiments including the effect of behavior therapy, worked out the details of the blast procedure, interpreted all data, carried out the blast experiments, wrote most of the manuscript. C.W. participated in the design of the program, designed the behavior experiments, participated in the design of the behavior experiments modifying FA, performed data analysis of the behavior and DTI experiments, interpreted the behavior and DTI data and integrated them by determining their correlation, interpreted the relationship of the behavior experiments and the protective effect of the behavior paradigms, participated in writing the manuscript, carried out the behavior experiments and the cardiac perfusion. P.H.R. participated in the overall design of the program, designed the shock tube, worked out all physical details of the shock tube function, backed the day to day operation of the blast procedure, designed and performed all pressure measurements, analyzed the pressure curve of each mouse. F.R.L. participated in the design of the DTI experiments, carried out these experiments, analyzed them and compared them with the behavior experiments. A.M.W. participated in the design of the program, designed the DTI experiments, analyzed the DTI data, interpreted the DTI experiments and interpreted their relationship to the behavior experiments and the protective effect of the behavior paradigms. J.F.D. participated in the design of the program, participated in the design of the behavior and DTI experiments, interpreted all data and contributed to potential effects of behavior therapy. © 2019 by the Shock Society