Dissociation of Cerebral Blood Flow and Femoral Artery Blood Pressure Pulsatility After Cardiac Arrest and Resuscitation in a Rodent Model: Implications for Neurological Recovery.

Background Impaired neurological function affects 85% to 90% of cardiac arrest (CA) survivors. Pulsatile blood flow may play an important role in neurological recovery after CA. Cerebral blood flow (CBF) pulsatility immediately, during, and after CA and resuscitation has not been investigated. We characterized the effects of asphyxial CA on short-term (<2 hours after CA) CBF and femoral arterial blood pressure (ABP) pulsatility and studied their relationship to cerebrovascular resistance (CVR) and short-term neuroelectrical recovery. Methods and Results Male rats underwent asphyxial CA followed by cardiopulmonary resuscitation. A multimodal platform combining laser speckle imaging, ABP, and electroencephalography to monitor CBF, peripheral blood pressure, and brain electrophysiology, respectively, was used. CBF and ABP pulsatility and CVR were assessed during baseline, CA, and multiple time points after resuscitation. Neuroelectrical recovery, a surrogate for neurological outcome, was assessed using quantitative electroencephalography 90 minutes after resuscitation. We found that CBF pulsatility differs significantly from baseline at all experimental time points with sustained deficits during the 2 hours of postresuscitation monitoring, whereas ABP pulsatility was relatively unaffected. Alterations in CBF pulsatility were inversely correlated with changes in CVR, but ABP pulsatility had no association to CVR. Interestingly, despite small changes in ABP pulsatility, higher ABP pulsatility was associated with worse neuroelectrical recovery, whereas CBF pulsatility had no association. Conclusions Our results reveal, for the first time, that CBF pulsatility and CVR are significantly altered in the short-term postresuscitation period after CA. Nevertheless, higher ABP pulsatility appears to be inversely associated with neuroelectrical recovery, possibly caused by impaired cerebral autoregulation and/or more severe global cerebral ischemia

Spatiotemporal propagation of cerebral hemodynamics during and after resuscitation from cardiac arrest

Cardiac arrest (CA) affects over 500,000 people in the United States. Although resuscitation efforts have improved, poor neurological outcome is the leading cause of morbidity in CA survivors, and only 8.3% of out-of-hospital CA survivors have good neurological recovery. Therefore, a detailed understanding of the brain before, during, and after CA and resuscitation is critical. We have previously shown, in a preclinical model of asphyxial CA, that measurement of cerebral blood flow (CBF) is essential to better understand what happens to the brain during CA and resuscitation. We have shown that CBF data can be used to predict the time when brain electrical activity resumes. Moreover, we have described CBF characteristics after resuscitation, including the hyperemic peak and stabilized hypoperfusion. Overall, our previous work focused on the study of the temporal evolution of CBF dynamics. To provide a more complete picture of CBF dynamics associated with CA and resuscitation, we postulate that both the temporal and spatial evolution of CBF dynamics must be understood. To investigate spatiotemporal dynamics, we used laser speckle imaging (LSI) to image rats (n = 6) that underwent either 5- or 7-min asphyxial CA, followed by cardiopulmonary resuscitation (CPR) until return of spontaneous circulation (ROSC). During induction of global cerebral ischemia through CA, we have observed two periods during which a decrease in CBF propagates in space in a cranial window over the right hemisphere. The first period of time is during CA and the second is after the hyperemic peak, before stabilized hypoperfusion occurs post-ROSC. Figure 1 shows a representative rat blood flow maps of the spatial propagation during CA (top row) and after ROSC (bottom row). For each row, the leftmost image shows CBF at t = 0min, and each subsequent image to the right is the time after the initial image. The arrows on the images represent the propagation direction in which CBF decreases. In this example, during CA, the propagation direction is down and to the left (posterior-medial anatomically), while after ROSC it is down and to the right (posterior-laterally, anatomically). Please click Additional Files below to see the full abstract

Capacitative Calcium Entry Deficits and Elevated Luminal Calcium Content in Mutant Presenilin-1 Knockin Mice

Dysregulation of calcium signaling has been causally implicated in brain aging and Alzheimer's disease. Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease. To elucidate the cellular mechanisms underlying these disturbances, we studied calcium signaling in fibroblasts isolated from mutant PS1 knockin mice. Mutant PS1 knockin cells exhibited a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation. These cells also showed significant impairments in capacitative calcium entry (CCE, also known as store-operated calcium entry), an important cellular signaling pathway wherein depletion of intracellular calcium stores triggers influx of extracellular calcium into the cytosol. Notably, deficits in CCE were evident after agonist stimulation, but not if intracellular calcium stores were completely depleted with thapsigargin. Treatment with ionomycin and thapsigargin revealed that calcium levels within the ER were significantly increased in mutant PS1 knockin cells. Collectively, our findings suggest that the overfilling of calcium stores represents the fundamental cellular defect underlying the alterations in calcium signaling conferred by presenilin mutations

SERCA pump activity is physiologically regulated by presenilin and regulates amyloid β production

In addition to disrupting the regulated intramembraneous proteolysis of key substrates, mutations in the presenilins also alter calcium homeostasis, but the mechanism linking presenilins and calcium regulation is unresolved. At rest, cytosolic Ca2+ is maintained at low levels by pumping Ca2+ into stores in the endoplasmic reticulum (ER) via the sarco ER Ca2+-ATPase (SERCA) pumps. We show that SERCA activity is diminished in fibroblasts lacking both PS1 and PS2 genes, despite elevated SERCA2b steady-state levels, and we show that presenilins and SERCA physically interact. Enhancing presenilin levels in Xenopus laevis oocytes accelerates clearance of cytosolic Ca2+, whereas higher levels of SERCA2b phenocopy PS1 overexpression, accelerating Ca2+ clearance and exaggerating inositol 1,4,5-trisphosphate–mediated Ca2+ liberation. The critical role that SERCA2b plays in the pathogenesis of Alzheimer's disease is underscored by our findings that modulating SERCA activity alters amyloid β production. Our results point to a physiological role for the presenilins in Ca2+ signaling via regulation of the SERCA pump

Using a multimodal platform to investigate the role of spreading depolarization and hemodynamics in neurological recovery

Acute brain injury, such as traumatic brain injury, stroke, and subarachnoid hemorrhage exhibit spreading depolarizations (SDs). SDs have been associated with worsening neuronal injury and are thought to contribute towards overall worse neurological outcome. SDs during global cerebral ischemia and its implications on neurological recovery following reperfusion are poorly understood. We investigated the role of SDs in a global cerebral ischemia model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). To induce SD, rats underwent asphyxial CA (ACA) for 5-, 7-, or 8-min, which was followed by CPR. Previous studies used electrocorticography (ECoG) to detect SDs. We used a multimodal platform of ECoG, laser speckle imaging (LSI), and spatial frequency domain imaging (SFDI) to continuously monitor rats during SD and recovery. We measured brain electrophysiology, cerebral blood flow (CBF), tissue scattering, and cerebral metabolic rate of oxygen (CMRO2). Neurological outcome was measured 90min post-CPR using quantitative ECoG (i.e. information quantity (IQ)) and 24h post-CPR using behavioral tests (i.e. Neurological Deficit Score; NDS). SDs were manually detected after applying a 1Hz low-pass filter on ECoG (Fig 1A, red number 2) and with tissue scattering from SFDI (Fig 1B, bottom, spatial increase in tissue scattering from right to left). SDs typically occurred within 2-3min after onset of asphyxia, during which vasoconstriction of cerebral vessels, waves of spreading ischemia and scattering, and abrupt changes in CMRO2 were visualized. Interestingly, rats with earlier SD showed better neurological recovery (NDS) (Fig 1C). In addition to earlier SD being associated with better neurological recovery, we also found that less total CBF prior to SD (Fig 1D) and a smaller change in tissue scattering (Fig 1E) during SD were associated with better neurological recovery (ECoG IQ). Although SDs have typically been perceived to be harmful and detrimental to neurological outcome, our data provides evidence that earlier SDs may have neuroprotective potential. These data provide support for the earliest known biomarker of neurological outcome post-CA. These findings may lead to novel therapies to modulate SDs during CA and acute brain injury that improve neurological outcome

The Curing Coma Campaign: Framing Initial Scientific Challenges—Proceedings of the First Curing Coma Campaign Scientific Advisory Council Meeting

Abstract: Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the “grand challenge” of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the “curing coma community” to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients

Abstract Number ‐ 113: A Lateral Medullary Infarct Complicated by Central Hypoventilation Syndrome

Introduction A 43‐year‐old male with no known past medical history presented to a primary stroke center for sudden onset headache, nausea, vomiting, and dizziness while driving. A computed tomography angiogram of the head and neck revealed a left vertebral artery occlusion, and the patient was transferred to our comprehensive stroke center for further evaluation and treatment. Upon arrival at our facility, the patient was noted to have a national institute of health stroke scale score of 7 with left facial droop, dysarthria, and right upper extremity dysmetria. A cerebral angiogram revealed a tortuous left vertebral artery with dissection in the V4 segment. Subsequent brain diffusion weighted imaging revealed an acute infarct in the right lateral medulla measuring 1.4cm and several acute cerebellar infarcts. (fig. 1) In the postangiography period, the patient had dysphagia, sialorrhea, multiple aspiration episodes, and oral secretions requiring early tracheostomy and percutaneous endoscopic gastrostomy on hospital day (HD) #6. The subsequent hospital course was complicated by prolonged singultus lasting until HD #23 and repetitive vomiting requiring a transition from a gastric to a gastro‐jejunal feeding tube. Methods A central hypoventilation syndrome (CHS) prolonged ventilator weaning. Despite preserved ability to take large‐volume voluntary breaths, the patient experienced multiple episodes of sleep‐associated apnea and rapid shallow breathing pattern during daily spontaneous breathing trials (SBT). The apnea episodes were registered with ventilator apnea alarms set at 20 seconds. This pattern continued when attempting an SBT utilizing a T‐piece adaptor. The ability to maintain adequate minute ventilation in an asleep state subsequently improved, and the patient was able to tolerate 48 hours of spontaneous breathing with no apnea on HD #35. Results Few cases of CHS secondary to lateral medullary infarction (LMI) have been documented in the literature.(1‐3) As the respiratory drive originates from neurons in the latero‐rostro‐ventral medulla, infarcts in this brainstem region may lead to respiratory failure. More specifically to our patient, ataxic breathing may result from lesions in the rostro‐ventral medulla with yawning and hiccups being seen in lesions to the posterolateral medulla.(4) As our patient presented with a sizable 1.4cm lesion, likely impairing these brainstem centers, it is expected that his symptoms would account for multiple respiratory symptoms. The unique feature of the acquired CHS in the setting of LMI is its unilateral location implying lateralization of the respiratory control. In addition to the aforementioned symptoms, his lesion likely led to prolonged weaning from the ventilator as has been described previously.(5) Conclusions This case raises awareness regarding potentially disastrous complications of the lateral medullary syndrome like central hypoventilation syndrome. We urge caution and careful evaluation of patients with lateral medullary infarctions for disorders of the respiratory control system