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Introduction Traumatic brain injuries are of concern to the sports and military communities because of the age of the participants and costly burden to society. To markedly reduce the impact of traumatic brain injury and its sequela (TBI-S), it is necessary to determine the initial vulnerability of individuals as well as identify new technologies that indicate early signs of TBI-S. Materials and Methods Currently, diverse methods have been used by the authors and others in laboratory settings to reveal early signs of persistent TBI-S including simulation modeling of the effect of rapid deceleration on the deviatoric strain (shear force) imposed on specific brain regions, auditory evoked potential (AEP) measurements to determine injury to the auditory cortex optokinetic nystagmus (OKN) measures sensitive to vestibular trauma, and optical coherence tomography (OCT) measures that reveal changes in central visual function obtained noninvasively by examination of the retina. Results Simulation studies provided technical information on maximal deviatoric strain at the base of the sulci and interface of gray and white matter consistent with results from neuropathology and from magnetic resonance imaging. The AEP and OKN reveal measurable injury to similar regions below the Sylvian fissure including auditory cortex and midbrain, and the OCT reveals changes to the retina consistent with forceful deceleration effects. Conclusions The studies and results are consistent with prior work demonstrating that noninvasive tests may be sensitive to the presence of TBI-S, potentially in the training field as advances in the portability of test instruments are underway. When combined with baseline data gathered from individuals in quantitative form, key variances can emerge. Therefore, it is hypothesized that AEP, OKN, and OCT, taken together, may yield faster objective and quantitative neurophysiological measures serving as a “signature” of neural injury and more indicative of potentially persistent TBI-S—recommending larger scale longitudinal studies.

We have previously characterized the reproducibility of brain tumor relative cerebral blood volume (rCBV) using a dynamic susceptibility contrast magnetic resonance imaging digital reference object across 12 sites using a range of imaging protocols and software platforms. As expected, reproducibility was highest when imaging protocols and software were consistent, but decreased when they were variable. Our goal in this study was to determine the impact of rCBV reproducibility for tumor grade and treatment response classification. We found that varying imaging protocols and software platforms produced a range of optimal thresholds for both tumor grading and treatment response, but the performance of these thresholds was similar. These findings further underscore the importance of standardizing acquisition and analysis protocols across sites and software benchmarking.

Background: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow–derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy. Methods: This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications. Results: There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, –0.3 to 0.8; P =0.330). There were no significant differences between the groups on any of the secondary efficacy measures. Conclusions: Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337.

Traumatic brain injury (TBI) has become a concern in sports, automobile accidents and combat operations. A better understanding of the mechanics leading to a TBI is required to cope with both the short-term life-threatening effects and long-term effects of TBIs, such as the development chronic traumatic encephalopathy (CTE). Kornguth et al., 2017 proposed that an inflammatory and autoimmune process initiated by a water hammer effect at the bases of the sulci of the brain is a mechanism of TBI leading to CTE. A major objective of this study is to investigate whether the water hammer effect is present due to blunt impacts through the use of computational models. Frontal blunt impacts were simulated with 2D finite element models developed to capture the biofidelic geometry of a human head. The models utilized the Arbitrary Lagrangian Eulerian (ALE) method to model a layer of cerebrospinal fluid (CSF) as a deforming fluid allowing for CSF to move in and out of sulci. During the simulated impacts, CSF was not observed to be driven into the sulci during the transient response. However, elevated shear strain levels near the base of the sulci were exhibited. Further, increased shear strain was present when differentiation between white and gray matter was taken into account. Both of the results support clinical observations of Kornguth et al., 2017.

The use of rCBV as a response metric in clinical trials has been hampered, in part, due to variations in the biomarker consistency and associated interpretation across sites, stemming from differences in image acquisition and post-processing methods. This study leveraged a dynamic susceptibility contrast magnetic resonance imaging digital reference object to characterize rCBV consistency across 12 sites participating in the Quantitative Imaging Network (QIN), specifically focusing on differences in site-specific imaging protocols (IPs, n = 17), and PMs (n = 19) and differences due to site-specific IPs and PMs (n = 25). Thus, high agreement across sites occurs when 1 managing center processes rCBV despite slight variations in the IP. This result is most likely supported by current initiatives to standardize IPs. However, marked intersite disagreement was observed when site-specific software was applied for rCBV measurements. This study's results have important implications for comparing rCBV values across sites and trials, where variability in PMs could confound the comparison of therapeutic effectiveness and/or any attempts to establish thresholds for categorical response to therapy. To overcome these challenges and ensure the successful use of rCBV as a clinical trial biomarker, we recommend the establishment of qualifying and validating site- and trial-specific criteria for scanners and acquisition methods (eg, using a validated phantom) and the software tools used for dynamic susceptibility contrast magnetic resonance imaging analysis (eg, using a digital reference object where the ground truth is known).

Objectives:To assemble an algorithm that will describe a “Signature” predictive of an individual’s vulnerability to persistent traumatic brain injury (TBI)Subjects and Methods:Studies of athletes and warriors who are subjected to repeated head impacts with rapid acceleration/deceleration forces are used to assist in the diagnosis and management of TBI-affected individuals. Data from multiple areas, including clinical, anatomical, magnetic resonance imaging, cognitive function, and biochemical analyses, are integrated to provide a Signature of persistent TBI.Results:Studies to date indicate that susceptibility to TBI results from an interaction between host genetic and structural vulnerability factors and force and torque of impact on the head and torso. The host factors include molecular markers affecting immune and inflammatory responses to stress/insult as well as anatomical features such as the degree of transcortical fiber projections and vascular malformations. The host response to forceful impact includes the release of intracellular neural proteins and nucleic acids into the cerebrospinal fluid and vascular compartment as well as mobilization of cytokines and macrophages into the central nervous system with subsequent activation of microglia and inflammatory responses including autoimmune processes. Maximum impact to the base of the sulci via a “water hammer effect” is consistent with the localization of microvascular and inflammatory responses in the affected brain region.Conclusions:An assessment of an individuals’ predisposition to persistent TBI with delayed cognitive deficits and behavioral changes requires an understanding of host vulnerability (genetic factors and brain structure) and external stressors (force and torque of impact as well as repetitive head injury and time interval between impacts). An algorithm that has utility in predicting vulnerability to TBI will include qualitative and quantitative measures of the host factors weighted against post impact markers of neural injury. Implementation of the resulting “Signature” of vulnerability at early stages of injury will help inform athletes and warriors, along with commanders and management, of the risk/benefit approaches that will markedly diminish health care costs to the nation and suffering to this population. This report attempts to define a strategy to create such an algorithm.

Background— We examined the influence of catheter ablation and periprocedural anticoagulation regimen on trajectory of migraine in atrial fibrillation patients with or without migraine history. Methods and Results— Forty patients with (group 1: 64±8 years; men 78%) and 85 (group 2: 61±10 years; men 73%) without migraine history undergoing atrial fibrillation-ablation were enrolled. Migraine status and quality of life were evaluated using standardized questionnaires. Diffusion magnetic resonance imaging of brain was performed for all at pre and 24 hours post procedure. Catheter ablation was performed with (88, 70%) or without (37, 30%) continuous warfarin treatment. Fifty-four patients (11 and 43 from groups 1 and 2, respectively) had subtherapeutic international normalized ratio on procedure day. At 17±5 months follow-up, from group 1, 25 (63%) reported no migraine, 10 (25%) had P P Conclusions— In most patients, migraine symptoms improved substantially after catheter ablation. Interestingly, the only cases of new migraine and aggravation of pre-existent headache had subtherapeutic international normalized ratio during the procedure and new cerebral infarcts.

Background The magnitude of treatment effect in acute stroke depends on several factors, including time from symptom onset (TFSO) to treatment and severity of the initial insult. Objective To report further evaluation of NeuroFlo therapy, focusing on the effect of time and stroke severity. Methods SENTIS was a prospective randomized trial (N=515) comparing standard medical therapy with/without NeuroFlo therapy. For this analysis, we evaluated outcomes in groups of patients based on TFSO and stroke severity: patients randomized 10 h with mild (NIHSS 14) symptoms at randomization. 90-Day mRS (modified Rankin Scale) scores and stroke-related death rates were compared between treatment groups. Results For patients randomized 10 h and NIHSS >14 (n=42) (OR=7.10, CI 1.13 to 44.55, p=0.036). Conclusions The results of our analysis support the importance of careful selection of outcome measures and the impact that rapid treatment and initial stroke severity have on outcome. Clinical trial registration URL://http.clinicaltrials.gov.Unique identifier: NCT00119717.

Recent randomized clinical trials1–5 established the superiority of endovascular recanalization techniques, specifically mechanical embolectomy, compared with best medical therapy alone for the treatment of patients with emergent large vessel occlusion (ELVO) stroke. ELVO stroke is defined as a stroke secondary to anterior circulation large vessel occlusion (LVO) of the internal carotid, middle cerebral (M1 segments) arteries documented by imaging, without large completed infarct and presenting within 6 hours of symptom onset.6 Given the overwhelming clinical evidence provided by these trials, recent American Heart Association (AHA) guidelines concluded that “embolectomy needs to be performed as rapidly as possible for the greatest clinical benefit, and is best when performed within 6 h from onset of symptoms” (AHA class I, level of evidence A).6 In addition, cost modeling derived from trial outcomes data and claims databases in the USA strongly suggests that cost-effectiveness and an overall societal benefit is associated with investment in access to these endovascular techniques.7 Rapid access to endovascular services depends upon optimization of prehospital stroke care and transport within stroke systems of care, focusing on the unique needs of patients with ELVO through their diagnostic investigation and treatment pathway. The Society of NeuroInterventional Surgery (SNIS) proposed process time metrics for ELVO stroke treatment, including door to IV tissue plasminogen activator (t-PA) of

Introduction/purpose: A significant complication in the intervention of acute ischemic stroke is hemorrhagic transformation (HT). It has been postulated that perfusion permeability imaging showing increased blood brain barrier permeability can be used to predict hemorrhagic transformation and possibly alter therapies. Materials and Methods: We retrospectively reviewed 1040 sequential CT perfusion scans with permeability surface area product maps calculated using the Patlak model for all patients that exhibited stroke like symptoms between October 2011 and November 2012. The size of the permeability surface product was ranked on a qualitative three-part scale of small, moderate and large permeability changes. A change smaller than 25% of the image was considered a small result. A moderate result is a permeability change that is approximately 25% of the image. A large permeability change exceeds 25% of the image. Follow up non-contrast CT images (>24 hours but Results: There was a positive increase in permeability maps in 142 of the 1040 cases. The size of the permeability change was moderate to large in 101 of the positive cases (71%). Hemorrhagic transformation was observed in 12 patients that showed an increase in permeability surface product (8.4%). Of the cases that resulted in HT, nine (75%) resulted in an HI1 and HI2 subtypes. There were three (25%) of the more severe parenchymal hemorrhages (PH1, PH2) observed. Out of the 12 positive hemorrhagic transformations four (33%) were treated with iv-TPA and two (17%) received endovascular thrombectomies, while six (50%) did not receive TPA or endovascular intervention. Of the major parenchymal hemorrhages (PH1/2) two occurred after iv-TPA treatment of the stroke, with the other arising after endovascular thrombectomy. No difference was found in the size or degree of the permeability changes and the incidence of HT. Conclusions: Elevated permeability on CT perfusion imaging had no relevant predictive value for hemorrhagic transformation in acute ischemic stroke at our institution.

The magnitude of treatment effect in acute stroke depends on several factors, including time from symptom onset (TFSO) to treatment and severity of the initial insult.To report further evaluation of NeuroFlo therapy, focusing on the effect of time and stroke severity.SENTIS was a prospective randomized trial (N=515) comparing standard medical therapy with/without NeuroFlo therapy. For this analysis, we evaluated outcomes in groups of patients based on TFSO and stroke severity: patients randomized6 h, 6-10 h, and10 h with mild (NIHSS8), moderate (8-14), and severe (14) symptoms at randomization. 90-Day mRS (modified Rankin Scale) scores and stroke-related death rates were compared between treatment groups.For patients randomized6 h TFSO (n=128), the OR for mRS 0-2 was 3.11 (CI 1.30 to 7.46, p=0.011) for treated versus non-treated patients. In patients with disease of moderate severity (NIHSS 8-14, n=214), NeuroFlo-treated patients were more likely to have a good outcome (mRS 0-2; OR=1.84, CI 1.02 to 3.33, p=0.043). The stroke-related death rate was better in the treated group with TFSO10 h and NIHSS14 (n=42) (OR=7.10, CI 1.13 to 44.55, p=0.036).The results of our analysis support the importance of careful selection of outcome measures and the impact that rapid treatment and initial stroke severity have on outcome.

Background and Purpose— Fewer than 5% of patients with acute ischemic stroke are currently treated, and there is need for additional treatment options. A novel catheter treatment (NeuroFlo) that increases cerebral blood flow was tested to 14 hours. Methods— The Safety and Efficacy of NeuroFlo in Acute Ischemic Stroke trial is a randomized trial of the safety and efficacy of NeuroFlo treatment in improving neurological outcome versus standard medical management. The primary safety end point was the incidence of serious adverse events through 90 days. The primary efficacy end point on a modified intent-to-treat population was a global disability end point at 90 days. Secondary end points included mortality, intracranial hemorrhage, modified Rankin scale score outcome of 0 to 2, and modified Rankin scale shift analysis. Results— Between October 2005 and January 2010, 515 patients were enrolled at 68 centers in 9 countries. The primary efficacy end point did not reach statistical significance (OR, 1.17; CI, 0.81–1.67; P =0.407). The primary safety end point did not show a difference in serious adverse events ( P =0.923). Ninety-day mortality was 11.3% (26/230) in treatment and 16.3% (42/257) in control ( P =0.087). Post hoc analyses showed that patients presenting within 5 hours (OR, 3.33; CI, 1.31–8.48), with NIHSS score 8 to 14 (OR, 1.80; CI, 0.99–3.30), or older than age 70 years (OR, 2.02; CI, 1.02–4.03) had better modified Rankin scale score outcomes of 0 to 2; additionally, there were fewer stroke-related deaths in treatment compared to control groups (7.4%=17/230; 14.4%=37/257). Conclusions— The trial met its primary safety end point but not its primary efficacy end point. Signals of treatment effect were suggested on all-cause mortality, in patients presenting early, older than age 70 years, or with moderate strokes, but these require confirmation. Clinical Trial Registration Information— URL: http://clinicaltrials.gov . Unique identifier: NCT00119717.

This study examined the influence of catheter ablation (CA) on the incidence and severity of migraine in atrial fibrillation (AF) patients with or without pre-ablation migraine-history. Thirty-six consecutive AF patients with history of migraine (group 1, 64±8 years, male 78%, 52% paroxysmal AF)