Background and Objectives: IL-6 (interleukin 6) is a proinflammatory cytokine and an established biomarker in acute brain injury. We sought to determine whether admission IL-6 levels are associated with severity and functional outcome after spontaneous intracerebral hemorrhage (ICH). Methods: We performed an exploratory analysis of the recombinant activated FAST trial (Factor VII for Acute ICH). Patients with admission serum IL-6 levels were included. Regression analyses were used to assess the associations between IL-6 and 90-day modified Rankin Scale. In secondary analyses, we used linear regression to evaluate the association between IL-6 and baseline ICH and perihematomal edema volumes. Results: Of 841 enrolled patients, we included 552 (66%) with available admission IL-6 levels (mean age 64 [SD 13], female sex 203 [37%]). IL-6 was associated with poor outcome (modified Rankin Scale, 4–6; per additional 1 ng/L, odds ratio, 1.30 [95% CI, 1.04–1.63]; P =0.02) after adjustment for known predictors of outcome after ICH and treatment group. IL-6 was associated with ICH volume after adjustment for age, sex, and ICH location, and this association was modified by location (multivariable interaction, P =0.002), with a stronger association seen in lobar (β, 12.51 [95% CI, 6.47–18.55], P <0.001) versus nonlobar (β 5.32 [95% CI, 3.36–7.28], P <0.001) location. IL-6 was associated with perihematomal edema volume after adjustment for age, sex, ICH volume, and ICH location (β 1.22 [95% CI, 0.15–2.29], P =0.03). Treatment group was not associated with IL-6 levels or outcome. Conclusions: In the FAST trial population, higher admission IL-6 levels were associated with worse 90-day functional outcome and larger ICH and perihematomal edema volumes.

Objective:To determine the leading causes of death in ICH survivors, we used administrative data from three large US states to identify adult survivors of a first-time spontaneous ICH and track all hospital readmissions resulting in death.Methods:We performed a longitudinal analysis of prospectively collected claims data from hospitalizations in California (2005-2011), New York (2005-2014) and Florida (2005-2014). Adult, state residents admitted with a non-traumatic ICH who survived to discharge were included. Patients were followed for a primary outcome of any readmission resulting in death. The cause of death was defined as the primary diagnosis assigned at discharge. Multivariable cox proportional hazards and multinomial logistic regression were used to determine factors associated with the risk and cause for death.Results:Of 72,432 ICH survivors (mean age 68 [SD 16], 48% female), 12,753 (18%) died during a median follow-up period of 4.0 years (IQR 2.3-6.3). The leading causes of death were infection (34%), recurrent intracranial hemorrhage (14%), cardiac disease (8%), respiratory failure (8%), and ischemic stroke (5%). Death in patients with AF was more likely to be caused by ischemic stroke (OR 2.4, 95% CI 1.9-2.9, p<0.001) and less likely caused by recurrent intracranial hemorrhage (OR 0.7, 95% CI 0.6-0.8, p<0.001) compared to patients without AF.Conclusions:Infection is the leading cause of death in all ICH survivors. Survivors with AF were at increased risk for death by ischemic stroke. These findings will help to prioritize interventions aimed to improve long-term survival and recovery in ICH survivors.

there are currently no rapid, operant pain behaviors in rodents that use a self-report to directly engage higher-order brain circuitry. We have developed a pain detection assay consisting of a lick behavior in response to optogenetic activation of predominantly nociceptive peripheral afferent nerve fibers in head-restrained transgenic mice expressing ChR2 in TRPV1 containing neurons. TRPV1-ChR2-EYFP mice (n = 5) were trained to provide lick reports to the detection of light-evoked nociceptive stimulation to the hind paw. Using simultaneous video recording, we demonstrate that the learned lick behavior may prove more pertinent in investigating brain driven pain processes than the reflex behavior. Within sessions, the response bias of transgenic mice changed with respect to lick behavior but not reflex behavior. Furthermore, response similarity between the lick and reflex behaviors diverged near perceptual threshold. our nociceptive lick-report detection assay will enable a host of investigations into the millisecond, single cell, neural dynamics underlying pain processing in the central nervous system of awake behaving animals. The importance of the brain in nociception has been theorized since Descartes' Treatise of Man 1. Melzack and Wall, whose gate control theory highlights the role of the spinal cord in pain processing, acknowledged the need for the myriad, interconnected brain areas to synthesize the perception of pain 2. Advances in human neural recording technologies have allowed scientists to test theories describing how brain circuits map onto pain 3. Human functional MRI (fMRI) has shown that perceived pain correlates with activation of primary somatosensory cortices, anterior cingulate cortex, and other brain regions implicated in the discriminatory and affective components of pain 4,5. Electroencephalography (EEG) and magnetoencephalography (MEG) have implicated the regulation of specific oscillatory components, for example alpha oscillations in the sensorimotor cortex, in pain perception 6. While techniques such as fMRI, EEG, and MEG paint a macroscopic picture of brain dynamics, these techniques cannot achieve the cellular or temporal resolution necessary for elucidating the neural circuits underlying pain perception. Genetic manipulations 7 and in vivo neural recordings in rodents are foundational in this respect as they afford the granularity required to characterize neural circuit activity and therapeutic outcomes 8-10. Unfortunately, the inability to compare behavioral outputs between animal and human studies presents a significant barrier for clinical translation of experimental results. Pain in humans is primarily measured using verbal self-reports, such as the visual analogue scale 11 , while pain in rodents is inferred from behavioral signals of discomfort, such as reflex behaviors 11,12. Reflex behaviors, like the hind paw withdrawal, are used to characterize evoked pain. Although reflex behaviors have been shown to positively correlate with self-reports of pain in humans 13 , decerebrated ...