Multiracial Reading the Mind in the Eyes Test (MRMET): An inclusive version of an influential measure.

Can an inclusive test of face cognition meet or exceed the psychometric properties of a prominent less inclusive test? Here, we norm and validate an updated version of the influential Reading the Mind in the Eyes Test (RMET), a clinically significant neuropsychiatric paradigm that has long been used to assess theory of mind and social cognition. Unlike the RMET, our Multiracial Reading the Mind in the Eyes Test (MRMET) incorporates racially inclusive stimuli, nongendered answer choices, ground-truth referenced answers, and more accessible vocabulary. We show, via a series of large datasets, that the MRMET meets or exceeds RMET across major psychometric indices. Moreover, the reliable signal captured by the two tests is statistically indistinguishable, evidence for full interchangeability. We thus present the MRMET as a high-quality, inclusive, normed and validated alternative to the RMET, and as a case in point that inclusivity in psychometric tests of face cognition is an achievable aim. The MRMET test and our normative and validation data sets are openly available under a CC-BY-SA 4.0 license at osf.io/ahq6n.

Ecological Momentary Assessment of Cognition in Clinical and Community Samples: Reliability and Validity Study.

BACKGROUND: The current methods of evaluating cognitive functioning typically rely on a single time point to assess and characterize an individual's performance. However, cognitive functioning fluctuates within individuals over time in relation to environmental, psychological, and physiological contexts. This limits the generalizability and diagnostic utility of single time point assessments, particularly among individuals who may exhibit large variations in cognition depending on physiological or psychological context (eg, those with type 1 diabetes [T1D], who may have fluctuating glucose concentrations throughout the day). OBJECTIVE: We aimed to report the reliability and validity of cognitive ecological momentary assessment (EMA) as a method for understanding between-person differences and capturing within-person variation in cognition over time in a community sample and sample of adults with T1D. METHODS: Cognitive performance was measured 3 times a day for 15 days in the sample of adults with T1D (n=198, recruited through endocrinology clinics) and for 10 days in the community sample (n=128, recruited from TestMyBrain, a web-based citizen science platform) using ultrabrief cognitive tests developed for cognitive EMA. Our cognitive EMA platform allowed for remote, automated assessment in participants' natural environments, enabling the measurement of within-person cognitive variation without the burden of repeated laboratory or clinic visits. This allowed us to evaluate reliability and validity in samples that differed in their expected degree of cognitive variability as well as the method of recruitment. RESULTS: The results demonstrate excellent between-person reliability (ranging from 0.95 to 0.99) and construct validity of cognitive EMA in both the sample of adults with T1D and community sample. Within-person reliability in both samples (ranging from 0.20 to 0.80) was comparable with that observed in previous studies in healthy older adults. As expected, the full-length baseline and EMA versions of TestMyBrain tests correlated highly with one another and loaded together on the expected cognitive domains when using exploratory factor analysis. Interruptions had higher negative impacts on accuracy-based outcomes (ß=-.34 to -.26; all P values <.001) than on reaction time-based outcomes (ß=-.07 to -.02; P<.001 to P=.40). CONCLUSIONS: We demonstrated that ultrabrief mobile assessments are both reliable and valid across 2 very different clinic versus community samples, despite the conditions in which cognitive EMAs are administered, which are often associated with more noise and variability. The psychometric characteristics described here should be leveraged appropriately depending on the goals of the cognitive assessment (eg, diagnostic vs everyday functioning) and the population being studied.

Accurate Prediction of Momentary Cognition From Intensive Longitudinal Data.

BACKGROUND: Deficits in cognitive performance are implicated in the development and maintenance of psychopathology. Emerging evidence further suggests that within-person fluctuations in cognitive performance may represent sensitive early markers of neuropsychiatric decline. Incorporating routine cognitive assessments into standard clinical care-to identify between-person differences and monitor within-person fluctuations-has the potential to improve diagnostic screening and treatment planning. In support of these goals, it is critical to understand to what extent cognitive performance varies under routine, remote assessment conditions (i.e., momentary cognition) in relation to a wide range of possible predictors. METHODS: Using data-driven, high-dimensional methods, we ranked strong predictors of momentary cognition and evaluated out-of-sample predictive accuracy. Our approach leveraged innovations in digital technology, including ambulatory assessment of cognition and behavior 1) at scale (n = 122 participants, n = 94 females), 2) in naturalistic environments, and 3) within an intensive longitudinal study design (mean = 25.5 assessments/participant). RESULTS: Reaction time (R2 > 0.70) and accuracy (0.56 >R2 > 0.35) were strongly predicted by age, between-person differences in mean performance, and time of day. Effects of self-reported, intraindividual fluctuations in environmental (e.g., noise) and internal (e.g., stress) states were also observed. CONCLUSIONS: Our results provide robust estimates of effect size to characterize sources of cognitive variability, to support the identification of optimal windows for psychosocial interventions, and to possibly inform clinical evaluation under remote neuropsychological assessment conditions.

Association of Retrospectively Reported Concussion Symptoms with Objective Cognitive Performance in Former American-Style Football Players.

OBJECTIVE: Sustaining concussions has been linked to health issues later in life, yet evidence for associations between contact sports exposure and long-term cognitive performance is mixed. This cross-sectional study of former professional American-style football players tested the association of several measures of football exposure with later life cognitive performance, while also comparing the cognitive performance of former players to nonplayers. METHODS: In total, 353 former professional football players (Mage = 54.3) completed both (1) an online cognitive test battery measuring objective cognitive performance and (2) a survey querying demographic information, current health conditions, and measures of past football exposure, including recollected concussion symptoms playing professional football, diagnosed concussions, years of professional play, and age of first football exposure. Testing occurred an average of 29 years after former players' final season of professional play. In addition, a comparison sample of 5,086 male participants (nonplayers) completed one or more cognitive tests. RESULTS: Former players' cognitive performance was associated with retrospectively reported football concussion symptoms (rp = -0.19, 95% CI -0.09 to -0.29; p < 0.001), but not with diagnosed concussions, years of professional play, or age of first football exposure. This association could be due to differences in pre-concussion cognitive functioning, however, which could not be estimated based on available data. CONCLUSIONS: Future investigations of the long-term outcomes of contact sports exposure should include measures of sports-related concussion symptoms, which were more sensitive to objective cognitive performance than other football exposure measures, including self-reported diagnosed concussions.

Glycemic Variability and Fluctuations in Cognitive Status in Adults With Type 1 Diabetes (GluCog): Observational Study Using Ecological Momentary Assessment of Cognition.

BACKGROUND: Individuals with type 1 diabetes represent a population with important vulnerabilities to dynamic physiological, behavioral, and psychological interactions, as well as cognitive processes. Ecological momentary assessment (EMA), a methodological approach used to study intraindividual variation over time, has only recently been used to deliver cognitive assessments in daily life, and many methodological questions remain. The Glycemic Variability and Fluctuations in Cognitive Status in Adults with Type 1 Diabetes (GluCog) study uses EMA to deliver cognitive and self-report measures while simultaneously collecting passive interstitial glucose in adults with type 1 diabetes. OBJECTIVE: We aimed to report the results of an EMA optimization pilot and how these data were used to refine the study design of the GluCog study. An optimization pilot was designed to determine whether low-frequency EMA (3 EMAs per day) over more days or high-frequency EMA (6 EMAs per day) for fewer days would result in a better EMA completion rate and capture more hypoglycemia episodes. The secondary aim was to reduce the number of cognitive EMA tasks from 6 to 3. METHODS: Baseline cognitive tasks and psychological questionnaires were completed by all the participants (N=20), followed by EMA delivery of brief cognitive and self-report measures for 15 days while wearing a blinded continuous glucose monitor. These data were coded for the presence of hypoglycemia (<70 mg/dL) within 60 minutes of each EMA. The participants were randomized into group A (n=10 for group A and B; starting with 3 EMAs per day for 10 days and then switching to 6 EMAs per day for an additional 5 days) or group B (N=10; starting with 6 EMAs per day for 5 days and then switching to 3 EMAs per day for an additional 10 days). RESULTS: A paired samples 2-tailed t test found no significant difference in the completion rate between the 2 schedules (t17=1.16; P=.26; Cohen dz=0.27), with both schedules producing >80% EMA completion. However, more hypoglycemia episodes were captured during the schedule with the 3 EMAs per day than during the schedule with 6 EMAs per day. CONCLUSIONS: The results from this EMA optimization pilot guided key design decisions regarding the EMA frequency and study duration for the main GluCog study. The present report responds to the urgent need for systematic and detailed information on EMA study designs, particularly those using cognitive assessments coupled with physiological measures. Given the complexity of EMA studies, choosing the right instruments and assessment schedules is an important aspect of study design and subsequent data interpretation.

Evaluating the Reliability and Validity of the Famous Faces Doppelgangers Test, a Novel Measure of Familiar Face Recognition.

Face recognition assessments that use images of celebrities require not only face recognition ability but also pop-culture knowledge and successful recall of identifying information. Here, we introduce a task designed to measure face recognition more specifically: the Famous Faces Doppelgangers Test (FFDT). Participants (N = 57,407) identified 40 celebrities paired with lookalike doppelgangers, allowing face recognition ability to be assessed without requiring information recall. In addition, participants reported whether they were familiar with each celebrity, allowing poor face recognition ability to be differentiated from low pop-culture knowledge. FFDT performance was reliable (rxx = .80), similar across participants of different racial and ethnic groups, and more highly correlated with memory for faces (r = .50) and self-reported face recognition ability (r = .48) than processing speed ability (r = .10). Thus, the FFDT is a reliable, valid, and specific measure of the ability to identify familiar faces, making it a promising new tool for assessing face recognition ability.

The TestMyBrain Digital Neuropsychology Toolkit: Development and Psychometric Characteristics.

INTRODUCTION: To allow continued administration of neuropsychological evaluations remotely during the pandemic, tests from the not-for-profit platform, TestMyBrain.org (TMB), were used to develop the TMB Digital Neuropsychology Toolkit (DNT). This study details the psychometric characteristics of the DNT, as well as the infrastructure and development of the DNT. METHOD: The DNT was primarily distributed for clinical use, with (72.8%) of individuals requesting access for clinical purposes. To assess reliability and validity of the DNT, anonymous data from DNT test administrations were analyzed and compared to a large, non-clinical normative sample from TMB. RESULTS: DNT test scores showed acceptable to very good split-half reliability (.68-.99). Factor analysis revealed three latent factors, corresponding to processing speed, working memory, and a broader general cognitive ability factor that included perceptual reasoning and episodic memory. Average test scores were slightly poorer for the DNT sample than for the TMB comparison sample, as expected given the clinical use of the DNT. CONCLUSIONS: Initial estimates of reliability and validity of DNT tests support their use as digital measures of neuropsychological functioning. Tests within cognitive domains correlated highly with each other and demonstrated good reliability and validity. Future work will seek to validate DNT tests in specific clinical populations and determine best practices for using DNT outcome measures to assess engagement and psychological symptomatology.

Cognitive test scores vary with choice of personal digital device.

Mobile- and web-based psychological research are a valuable addition to the set of tools available for scientific study, reducing logistical barriers for research participation and allowing the recruitment of larger and more diverse participant groups. However, this comes at the cost of reduced control over the technology used by participants, which can introduce new sources of variability into study results. In this study, we examined differences in measured performance on timed and untimed cognitive tests between users of common digital devices in 59,587 (Study 1) and 3818 (Study 2) visitors to TestMyBrain.org , a web-based cognitive testing platform. Controlling for age, gender, educational background, and cognitive performance on an untimed vocabulary test, users of mobile devices, particularly Android smartphones, showed significantly slower performance on tests of reaction time than users of laptop and desktop computers, suggesting that differences in device latency affect measured reaction times. Users of devices that differ in user interface (e.g. screen size, mouse vs. touchscreen) also show significant differences (p < 0.001) in measured performance on tests requiring fast reactions or fine motor movements. By quantifying the contribution of device differences to measured cognitive performance in an online setting, we hope to improve the accuracy of mobile- and web-based cognitive assessments, allowing these methods to be used more effectively.

Toward dynamic phenotypes and the scalable measurement of human behavior.

Precision psychiatry demands the rapid, efficient, and temporally dense collection of large scale and multi-omic data across diverse samples, for better diagnosis and treatment of dynamic clinical phenomena. To achieve this, we need approaches for measuring behavior that are readily scalable, both across participants and over time. Efforts to quantify behavior at scale are impeded by the fact that our methods for measuring human behavior are typically developed and validated for single time-point assessment, in highly controlled settings, and with relatively homogeneous samples. As a result, when taken to scale, these measures often suffer from poor reliability, generalizability, and participant engagement. In this review, we attempt to bridge the gap between gold standard behavioral measurements in the lab or clinic and the large-scale, high frequency assessments needed for precision psychiatry. To do this, we introduce and integrate two frameworks for the translation and validation of behavioral measurements. First, borrowing principles from computer science, we lay out an approach for iterative task development that can optimize behavioral measures based on psychometric, accessibility, and engagement criteria. Second, we advocate for a participatory research framework (e.g., citizen science) that can accelerate task development as well as make large-scale behavioral research more equitable and feasible. Finally, we suggest opportunities enabled by scalable behavioral research to move beyond single time-point assessment and toward dynamic models of behavior that more closely match clinical phenomena.

Hemifield-specific control of spatial attention and working memory: Evidence from hemifield crossover costs.

Attentional tracking and working memory tasks are often performed better when targets are divided evenly between the left and right visual hemifields, rather than contained within a single hemifield (Alvarez & Cavanagh, 2005; Delvenne, 2005). However, this bilateral field advantage does not provide conclusive evidence of hemifield-specific control of attention and working memory, because it can be explained solely from hemifield-limited spatial interference at early stages of visual processing. If control of attention and working memory is specific to each hemifield, maintaining target information should become more difficult as targets move between the two hemifields. Observers in the present study maintained targets that moved either within or between the left and right hemifields, using either attention (Experiment 1) or working memory (Experiment 2). Maintaining spatial information was more difficult when target items moved between the hemifields compared with when target items moved within their original hemifields, consistent with hemifield-specific control of spatial attention and working memory. However, this pattern was not found for maintaining identity information (e.g., color) in working memory (Experiment 3). Together, these results provide evidence that control of spatial attention and working memory is specific to each hemifield, and that hemifield-specific control is a unique signature of spatial processing.

Development of multiple object tracking via multifocal attention.

Multifocal attention is the ability to simultaneously attend to multiple objects, and is critical for typical functioning. Although adults are able to use multifocal attention, little is known about the development of this ability. In two experiments, we investigated multifocal attention in 6-8-year-old children and adults using a child-friendly, computerized multiple object tracking task designed to encourage the use of multifocal attention. We also investigated whether multifocal attention in children is deployed independently across left and right hemifields of vision, as in adults. Our results suggest that children's capacity for multifocal attention increases significantly across middle childhood. We also found evidence that at least one signature of hemifield-independent multifocal attention, the bilateral field advantage, can be observed in children. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Poststroke epilepsy following transient unilateral middle cerebral and common carotid artery occlusion in young adult and aged F344 rats.

The mechanisms of injured brain that establish poststroke seizures and epilepsy are not well understood, largely because animal modeling has had limited development. The main objective of this study was to determine whether an arterial occlusion model of cortical stroke in young adult and aged rats was capable of generating either focal or generalized epileptic seizures within 2 months of lesioning. Four- and 20-month-old male Fischer 344 (F344) sham-operated controls and those lesioned by transient (3 h) unilateral middle cerebral artery (MCA) and common carotid artery (CCA) occlusion (MCA/CCAo) were studied by video-EEG recordings up to 2 months post-procedure. The main findings were: 1) seizures (grade 3 and above) were recorded within 2 months in both young (4-month; 0.23/h) and aged (20-month; 1.93/h) MCA/CCAo rat groups; both MCA/CCAo rat groups had more seizures recorded than the respective control groups, i.e., no seizures in young controls and 0.52/h in old controls; 2) both age and infarction independently had effects on seizure frequency; however, there was no demonstrated interaction between the two factors; and 3) there was no difference in infarct volumes comparing 4- to 20-month-old MCA/CCAo animals. In addition, all lesioned and sham-operated animals demonstrated intermittent solitary myoclonic convulsions arising out of sleep. Morbidity and mortality of animals limited the extent to which the animals could be evaluated, especially 20-month-old animals. These results suggest that transient unilateral MCA/CCAo can result in poststroke epileptic seizures in both young adult and aged F344 rats within a relatively brief period of time following lesioning.

Training enhances attentional expertise, but not attentional capacity: Evidence from content-specific training benefits.

Cognitive training has become a billion-dollar industry with the promise that exercising a cognitive faculty (e.g., attention) on simple "brain games" will lead to improvements on any task relying on the same faculty. Although this logic seems sound, it assumes performance improves on training tasks because attention's capacity has been enhanced. Alternatively, training may result in attentional expertise-an enhancement of the ability to deploy attention to particular content-such that improvement on training tasks is specific to the features of the training context. The present study supported this attentional expertise hypothesis, showing that training benefits did not generalize fully from a trained attentional tracking task to untrained tracking tasks requiring a common attentional capacity, but differing in seemingly superficial features (i.e., retinotopic location and or motion type). This specificity suggests that attentional training benefits are linked to enhanced coordination between attentional processes and content-specific perceptual representations. Thus, these results indicate that shared attentional capacity between tasks is insufficient for producing generalized training benefits, and predict that generalization requires attentional expertise for content present in both training and outcome tasks.

Pilot Evaluation of Auricular Acupressure in End-Stage Lung Cancer Patients.

BACKGROUND: Dyspnea is a common symptom in end-stage lung cancer patients and is only infrequently controlled. Currently, the use of complimentary therapies using traditional Chinese medicine (TCM), including auricular application of Vaccaria segetalis (a small seed), is understudied. Acupressure using auricular Vaccaria segetalis application has been reported as effective in reducing dyspnea when applied to a specific area of the ear associated with lung function in the TCM paradigm. OBJECTIVE: The purpose of this feasibility study was to evaluate the effects of standardized auricular acupressure therapy using Vaccaria segetalis on dyspnea intensity and distress and oxygen saturation in end-stage lung cancer patients. METHODS: The experimental design was three conditions with eight measurement points in time. Patients were randomly assigned to one of three treatment conditions: (1) Standard Care (SC); (2) SC with Vaccaria segetalis taped to random auricular locations (placebo); and (3) SC with Vaccaria segetalis taped to the auricular location deemed specific to lung function in TCM. Subjects were 11 hospice patients with advanced lung cancer and dyspnea. Dyspnea intensity and distress were measured by the Cancer Dyspnea Scale (CDS) and oxygen saturation was measured by pulse oximeter at eight time points. RESULTS: Non-parametric statistical analyses suggest the presence of acupressure effects with medium to large effects and significant effect for dyspnea effort. CONCLUSIONS: This pilot information suggests the need for further study of auricular acupressure using Vaccaria segetalis in the dyspneic advanced lung cancer population.

Nitric oxide facilitates delivery and mediates improved outcome of autologous bone marrow mononuclear cells in a rodent stroke model.

BACKGROUND: Bone marrow mononuclear cells (MNC) represent an investigational treatment for stroke. The objective of this study was to determine the relevance of vasoactive mediators, generated in response to MNC injection, as factors regulating cerebral perfusion (CP), the biodistribution of MNC, and outcome in stroke. METHODS: Long Evans rats underwent transient middle cerebral artery occlusion. MNC were extracted from the bone marrow at 22 hrs and injected via the internal carotid artery or the femoral vein 2 hours later. CP was measured with MRI or continuous laser Doppler flowmetry. Serum samples were collected to measure vasoactive mediators. Animals were treated with the Nitric Oxide (NO) inhibitor, L-NAME, to establish the relevance of NO-signaling to the effect of MNC. Lesion size, MNC biodistribution, and neurological deficits were assessed. RESULTS: CP transiently increased in the peri-infarct region within 30 min after injecting MNC compared to saline or fibroblast control. This CP increase corresponded temporarily to serum NO elevation and was abolished by L-NAME. Pre-treatment with L-NAME reduced brain penetration of MNC and prevented MNC from reducing infarct lesion size and neurological deficits. CONCLUSIONS: NO generation in response to MNC may represent a mechanism underlying how MNC enter the brain, reduce lesion size, and improve outcome in ischemic stroke.

Proteasome Inhibitor Reduces Astrocytic iNOS Expression and Functional Deficit after Experimental Intracerebral Hemorrhage in Rats.

Intracerebral hemorrhage (ICH) is associated with perihematoma inflammation and edema. We have recently shown cell death and a robust activation of the proinflammatory transcription factor, nuclear factor-κB (NF-κB) in brain areas adjacent to the hematoma. Proteasome represents a key component necessary for the activation of NF-κB. The aim of our present study was to examine if selective proteasome inhibition with a clinically relevant agent, PS-519, might influence the ICH pathogenesis, and improve functional outcome. ICH was induced in Sprague-Dawley rats by the double blood injection method. PS-519 was administered intravenously 4 h and 15 min after induction of ICH. Behavioral testing was performed 3, 5, and 7 days later. The animals were sacrificed on day 7, and their brains were evaluated for hemorrhage size and inflammation using immunohistochemistry with antibody to various inflammatory markers. Treatment with PS-519 significantly (p < 0.05) reduced behavioral impairment post-ICH as determined by the footfault test. This effect was not due to difference in ICH volume. The improved functional status of PS-519 treated animals correlated positively (p < 0.01) with reduced expression of astroglial iNOS in areas adjacent to the hemorrhage 7 days post-ICH. No delayed changes in expression of OX-42 and ED-1 (microglia/macrophages marker), or vimentin (intermediate filament; marker of astroglia activation) were detected in animals treated with PS-519. This data suggests that modulation of proteasome-activated processes may represent a strategic target for treatment of ICH in humans.

Cytoprotective role of haptoglobin in brain after experimental intracerebral hemorrhage.

After intracerebral hemorrhage (ICH), hemoglobin (Hb) that is released from erythrocytes within the brain hematoma is highly cytotoxic and leads to severe brain edema and direct neuronal damage. Therefore, neutralization of Hb could represent an important target for reducing the secondary injury after ICH. Haptoglobin (Hp), an endogenous Hb-binding protein in blood plasma, is found in this study to be upregulated in the hematoma-affected brain after ICH. Both in vivo and in vitro studies indicate that Hp upregulation is primarily mediated by oligodendrocytes. Hp acts as a secretory protein capable of neutralizing the cell-free Hb. We also found in an "ICH-like" injury that Hp-KO mice show the most severe brain injury and neurological deficits, whereas Hp-Tg mice are the most resistant to ICH injury, suggesting that a higher Hp level is associated with the increased resistance of animals to hemolytic product-mediated brain injury after ICH. We conclude that brain-derived Hp plays a cytoprotective role after ICH, and Hp may represent a new potential therapeutic target for management of ICH.

Therapeutic time window and dose response of autologous bone marrow mononuclear cells for ischemic stroke.

Although mononuclear cells (MNCs) from bone marrow are being investigated in phase I clinical trials in stroke patients, dose response, therapeutic time window, and biodistribiton have not been well-characterized in animal stroke models. Long Evans rats underwent common carotid artery/middle cerebral artery occlusion (CCA/MCAo) and 24 hr later were randomized to receive saline IV or a bone marrow aspiration followed by an IV infusion of autologous separated MNCs (1 million, 10 million, or 30 million cells/kg). In another experiment, rats underwent CCAo/MCAo and were randomized at 24 hr, 72 hr, or 7 days after stroke to receive a saline injection or 10 million/kg MNCs. All animals were evaluated on the cylinder and corner tests up to 28 days. MNCs were tracked using Q-dot nanocrystals to monitor biodistribution. Animals treated with MNCs at 10 million and 30 million cells/kg at 24 hr after stroke had significant reductions in neurological deficits and lesion size compared with saline controls or animals treated with 1 million cells/kg. There was no difference in neurological deficits in the 10 and 30 million cell/kg groups at 28 days. Animals treated with MNCs at 72 hr but not at 7 days showed a significant reduction in neurological deficits by 28 days. Labeled MNCs were found in the brain, spleen, lung, liver, and kidney at 1 hr and exponentially decreased over the ensuing week. In conclusion, we found a maximum reduction in neurological deficits at 10 and 30 million cells/kg and a therapeutic time window up to 72 hr after stroke. © 2011 Wiley-Liss, Inc.

Low-Power 2-MHz Pulsed-Wave Transcranial Ultrasound Reduces Ischemic Brain Damage in Rats.

It is largely unknown whether prolonged insonation with ultrasound impacts the ischemic brain tissue by itself. Our goal was to evaluate safety and the effect of high-frequency ultrasound on infarct volume in rats. Thirty-two Long-Evans rats with permanent middle cerebral and carotid artery occlusions received either 2-MHz ultrasound at two levels of insonation power (128 or 10 mW) or no ultrasound (controls). We measured cerebral hemorrhage, indirect and direct infarct volume as well as edema volume at 24 h. No cerebral hemorrhages were detected in all animals. Exposure to low-power (10 mW) ultrasound resulted in a significantly decreased indirect infarct volume (p = 0.0039), direct infarct volume (p = 0.0031), and brain edema volume (p = 0.01) compared with controls. High-power (128 mW) ultrasound had no significant effects. An additional experiment with India ink showed a greater intravascular penetration of dye into ischemic tissues exposed to low-power ultrasound. Insonation with high-frequency, low-power ultrasound reduces ischemic brain damage in rat. Its effect on edema reduction and possible promotion of microcirculation could be used to facilitate drug and nutrient delivery to ischemic areas.

Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke.

Although several studies have provided evidence for the therapeutic potential of bone marrow-derived mononuclear cells (MNCs) in animal models of stroke, the mechanisms underlying their benefits remain largely unknown. We have determined the neuroprotective potential of MNCs in primary neuronal cultures exposed to various injuries in vitro. Cortical neurons in culture were exposed to oxygen-glucose deprivation, hypoxia, or hydrogen peroxide, and cell death was assayed by MTT, caspase-3 activation or TUNEL labelling at 24 hrs. Cultures were randomized to cotreatment with MNC-derived supernatants or media before injury exposure. In separate experiments, macrophage or microglial cultures were exposed to lipopolypolysacharide (LPS) in the presence and absence of MNC-derived supernatants. Neuronal cultures were then exposed to conditioned media derived from activated macrophages or microglia. Cytokines from the supernantants of MNC cultures exposed to normoxia or hypoxia were also estimated by enzyme-linked immunosorbant assay (ELISA). MNC-derived supernatants attenuated neuronal death induced by OGD, hypoxia, hydrogen peroxide, and conditioned macrophage/microglial media and contain a number of trophic factors, including interleukin-10, insulin-like growth factor-1, vascular endothelial growth factor, and stromal cell-derived factor-1. MNCs provide broad neuroprotection against a variety of injuries relevant to stroke.