Intracranial Pressure is a Better Predictor of Mortalitythan Cerebral Perfusion Pressure

Objective: To evaluate whether elevated intracranial pressure (ICP) or depressed cerebral perfusion pressure (CPP) is a better predictor of intracranial compartment syndrome and long-term functional outcomes in blunt traumatic brain injury. Methods: This was a retrospective evaluation of data collected on 203 patients with blunt traumatic brain injury who were admitted to Miami Valley Hospital, a Level I trauma center, over a 2 years period, whose initial hospital management required an intracranial pressure monitor. Serial measurements of ICP and CPP were recorded during the patients’ hospital stay. These patients were then evaluated at 3,6,12 and 24 months post-injury to assess their outcome based on functional status, as defined by death vegetative state, severe disability, moderate disability and good recovery. Results: Utilizing an ICP cut-off value of 25 or greater and a CPP value of less than 60 at any point during the patients’ hospital course, ICP elevation consistently correlated with a higher percentage of deaths and persistent vegetative state than a depression in CPP value. Outcomes as measured by severe or moderate disability where similar in both groups. However, neither measure approached statistical significance. Conclusion: ICP appears to be a better predictor of intracranial compartment syndrome and extent of brain injury, predicting better than CPP values, the outcome of death or persistent vegetative state. This may help to predict prognosis, change management strategies and guide discussions with family, especially in the early phase of injur

Neural evidence for "intuitive prosecution": The use of mental state information for negative moral verdicts

Moral judgment depends critically on theory of mind (ToM), reasoning about mental states such as beliefs and intentions. People assign blame for failed attempts to harm and offer forgiveness in the case of accidents. Here we use fMRI to investigate the role of ToM in moral judgment of harmful vs. helpful actions. Is ToM deployed differently for judgments of blame vs. praise? Participants evaluated agents who produced a harmful, helpful, or neutral outcome, based on a harmful, helpful, or neutral intention; participants made blame and praise judgments. In the right temporo-parietal junction (right TPJ), and, to a lesser extent, the left TPJ and medial prefrontal cortex, the neural response reflected an interaction between belief and outcome factors, for both blame and praise judgments: The response in these regions was highest when participants delivered a negative moral judgment, i.e., assigned blame or withheld praise, based solely on the agent's intent (attempted harm, accidental help). These results show enhanced attention to mental states for negative moral verdicts based exclusively on mental state information.Athinoula A. Martinos Center for Biomedical ImagingSimons FoundationNational Science Foundation (U.S.)John Merck Scholars Progra

A Phenotypic Small-Molecule Screen Identifies an Orphan Ligand-Receptor Pair that Regulates Neural Stem Cell Differentiation

SummaryHigh-throughput identification of small molecules that selectively modulate molecular, cellular, or systems-level properties of the mammalian brain is a significant challenge. Here we report the chemical genetic identification of the orphan ligand phosphoserine (P-Ser) as an enhancer of neurogenesis. P-Ser inhibits neural stem cell/progenitor proliferation and self-renewal, enhances neurogenic fate commitment, and improves neuronal survival. We further demonstrate that the effects of P-Ser are mediated by the group III metabotropic glutamate receptor 4 (mGluR4). siRNA-mediated knockdown of mGluR4 abolished the effects of P-Ser and increased neurosphere proliferation, at least in part through upregulation of mTOR pathway activity. We also found that P-Ser increases neurogenesis in human embryonic stem cell-derived neural progenitors. This work highlights the tremendous potential of developing effective small-molecule drugs for use in regenerative medicine or transplantation therapy

Analysis of graft survival in a trial of stem cell transplant in ALS

Objective The first US Food and Drug Administration–approved clinical trial to treat amyotrophic lateral sclerosis ( ALS ) with neural stem cell–based therapy is in progress. The goal of the current study was to identify and assess the survival of human spinal cord–derived neural stem cells ( HSSC s) transplanted into the spinal cord in patients with ALS . Methods Spinal cords transplanted with HSSCs were examined from six autopsy cases. Homogenized tissues were interrogated for the presence of donor versus recipient DNA using real‐time PCR methods ( qPCR ). Fluorescence in situ hybridization (FISH) was performed using DNA probes for XY chromosomes to identify male donor HSSCs in one female case, and immunohistochemistry (IHC) was used to characterize the identified donor cells. Results Genomic DNA from donor HSSC s was identified in all cases, comprising 0.67–5.4% of total tissue DNA in patients surviving 196 to 921 days after transplantation. In the one female patient a “nest” of cells identified on H&E staining were XY ‐positive by FISH , confirming donor origin. A subset of XY ‐positive cells labeled for the neuronal marker NeuN and stem cell marker SOX 2. Interpretation This is the first study to identify human neural stem cells transplanted into a human spinal cord. Transplanted HSSC s survived up to 2.5 years posttransplant. Some cells differentiated into neurons, while others maintained their stem cell phenotype. This work is a proof of concept of the survival and differentiation of human stems cell transplanted into the spinal cord of ALS patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109593/1/acn3134.pd

The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study

Background: Post-traumatic headache (PTH) is one of the most common and long-lasting symptoms following mild traumatic brain injury (TBI). However, the pathological mechanisms underlying the development of persistent PTH remain poorly understood. The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients. Methods: Adult mild TBI patients recruited from Level I Emergency Department Trauma Centers completed study sessions at 1-2 weeks, 1-month, and 4-months post mild TBI. Participants completed the following outcome measures during each session: conditioned pain modulation to measure endogenous pain inhibitory capacity, temporal summation of pain and pressure pain thresholds of the head to measure sensitization of the head, Pain Catastrophizing Scale, Center for Epidemiological Studies - Depression Scale, and a standardized headache survey. Participants were classified into persistent PTH (PPTH) and no-PPTH groups based on the 4-month data. Results: The results revealed that mild TBI patients developing persistent PTH exhibited significantly diminished pain inhibitory capacity, and greater depression and pain catastrophizing following injury compared to those who do not develop persistent PTH. Furthermore, logistic regression indicated that headache pain intensity at 1-2 weeks and pain inhibitory capacity on the conditioned pain modulation test at 1-2 weeks predicted persistent PTH classification at 4 months post injury. Conclusions: Overall, the results suggested that persistent PTH is characterized by dysfunctional alterations in endogenous pain modulatory function and psychological processes in the early stages following mild TBI, which likely exacerbate risk for the maintenance of PTH

Physical activity behavior in the first month after mild traumatic brain injury is associated with physiological and psychological risk factors for chronic pain

Objective: The purpose of this study was to determine whether self-reported physical activity (PA) in the first month after mild traumatic brain injury (mTBI) predicts endogenous pain modulatory function and pain catastrophizing at 1 to 2 weeks and 1 month after injury in patients with mTBI. Methods: Patients with mild traumatic brain injury completed study sessions at 1 to 2 weeks and 1 month after injury. Assessments included a headache survey, Pain Catastrophizing Scale, International Physical Activity Questionnaire-Short Form, and several quantitative sensory tests to measure endogenous pain modulatory function including conditioned pain modulation (CPM), temporal summation, and pressure pain thresholds of the head. Hierarchical linear regressions determined the relationship between the PA variables (predictors) and pain catastrophizing and pain modulation variables (dependent variables) cross-sectionally and longitudinally, while controlling for potential covariates. Results: In separate hierarchical regression models, moderate PA, walking, and total PA at 1 to 2 weeks after injury predicted pain inhibition on the CPM test at 1 month, after controlling for significant covariates. In addition, a separate regression revealed that minutes sitting at 1 month predicted CPM at 1 month. Regarding predicting pain catastrophizing, the regression results showed that sitting at 1 to 2 weeks after injury significantly predicted pain catastrophizing at 1 month after injury. Conclusion: Greater self-reported PA, especially moderate PA, 1 to 2 weeks after injury longitudinally predicted greater pain inhibitory capacity on the CPM test at 1 month after injury in patients with mTBI. In addition, greater sedentary behavior was associated with worse pain inhibition on the CPM test and greater pain catastrophizing at 1 month after injury

Dynamic causal modelling of effective connectivity during perspective taking in a communicative task

Previous studies have shown that taking into account another person's perspective to guide decisions is more difficult when their perspective is incongruent from one's own compared to when it is congruent. Here we used dynamic causal modelling (DCM) for functional magnetic resonance imaging (fMRI) to investigate effective connectivity between prefrontal and posterior brain regions in a task that requires participants to take into account another person's perspective in order to guide the selection of an action. Using a new procedure to score model evidence without computationally costly estimation, we conducted an exhaustive search for the best of all possible models. The results elucidate how the activity in the areas from our previously reported analysis (Dumontheil et al., 2010) are causally linked and how the connections are modulated by both the social as well as executive task demands of the task. We find that the social demands modulate the backward connections from the medial prefrontal cortex (MPFC) more strongly than the forward connections from the superior occipital gyrus (SOG) and the medial temporal gyrus (MTG) to the MPFC. This was also the case for the backward connection from the MTG to the SOG. Conversely, the executive task demands modulated the forward connections of the SOG and the MTG to the MPFC more strongly than the backward connections. We interpret the results in terms of hierarchical predictive coding

Neural Basis of Moral Elevation Demonstrated through Inter-Subject Synchronization of Cortical Activity during Free-Viewing

Most research investigating the neural basis of social emotions has examined emotions that give rise to negative evaluations of others (e.g. anger, disgust). Emotions triggered by the virtues and excellences of others have been largely ignored. Using fMRI, we investigated the neural basis of two "other-praising" emotions--Moral Elevation (a response to witnessing acts of moral beauty), and Admiration (which we restricted to admiration for physical skill).Ten participants viewed the same nine video clips. Three clips elicited moral elevation, three elicited admiration, and three were emotionally neutral. We then performed pair-wise voxel-by-voxel correlations of the BOLD signal between individuals for each video clip and a separate resting-state run. We observed a high degree of inter-subject synchronization, regardless of stimulus type, across several brain regions during free-viewing of videos. Videos in the elevation condition evoked significant inter-subject synchronization in brain regions previously implicated in self-referential and interoceptive processes, including the medial prefrontal cortex, precuneus, and insula. The degree of synchronization was highly variable over the course of the videos, with the strongest synchrony occurring during portions of the videos that were independently rated as most emotionally arousing. Synchrony in these same brain regions was not consistently observed during the admiration videos, and was absent for the neutral videos.Results suggest that the neural systems supporting moral elevation are remarkably consistent across subjects viewing the same emotional content. We demonstrate that model-free techniques such as inter-subject synchronization may be a useful tool for studying complex, context dependent emotions such as self-transcendent emotion

Efficient Transmission of Mixed Plasmodium falciparum/vivax Infections From Humans to Mosquitoes

BACKGROUND: In Southeast Asia, people are often coinfected with different species of malaria (Plasmodium falciparum [Pf] and Plasmodium vivax [Pv]) as well as with multiple clones of the same species. Whether particular species or clones within mixed infections are more readily transmitted to mosquitoes remains unknown. METHODS: Laboratory-reared Anopheles dirus were fed on blood from 119 Pf-infected Cambodian adults, with 5950 dissected to evaluate for transmitted infection. Among 12 persons who infected mosquitoes, polymerase chain reaction and amplicon deep sequencing were used to track species and clone-specific transmission to mosquitoes. RESULTS: Seven of 12 persons that infected mosquitoes harbored mixed Pf/Pv infection. Among these 7 persons, all transmitted Pv with 2 transmitting both Pf and Pv, leading to Pf/Pv coinfection in 21% of infected mosquitoes. Up to 4 clones of each species were detected within persons. Shifts in clone frequency were detected during transmission. However, in general, all parasite clones in humans were transmitted to mosquitoes, with individual mosquitoes frequently carrying multiple transmitted clones. CONCLUSIONS: Malaria diversity in human hosts was maintained in the parasite populations recovered from mosquitoes fed on their blood. However, in persons with mixed Pf/Pv malaria, Pv appears to be transmitted more readily, in association with more prevalent patent gametocytemia

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18