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NASA NTRS1992

Evidence for a membrane defect in Alzheimer disease brain

To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.

NASA Discipline Regulatory Physiology↗

DOE OSTI2025

Investigating the FLASH Effect in a Rat Brain Organotypic Model With a Novel High-Energy Electron Beam

Ultrahigh dose rate (FLASH) radiation therapy is reported to reduce normal tissue toxicity while maintaining tumor control; however, mechanism(s) remain obscure. To study FLASH mechanisms in brain tissue, we developed a novel experimental platform featuring a specialized high-energy electron linear accelerator, High Intensity Gamma Ray Source (HIGS), paired with an organotypic ex vivo brain metastasis model. We varied interpulse spacing to modulate the mean dose rate (MDR) of our unique 35 MeV electron beam, while maintaining extremely high instantaneous dose rate (IDR). We characterized dosimetry and targeting accuracy of the FLASH beam with film dosimetry. We combined this FLASH beam with an organotypic rat brain slice/breast carcinoma coculture model of brain metastasis to assess effects on normal and neoplastic tissues. Live-cell and bioluminescence imaging demonstrated cancer cell growth effects, whereas normal tissue responses and immune activation were assessed using live-cell imaging, cytokine profiles, and confocal microscopy. Here, we performed comparison experiments with 20 MeV electrons from a Varian clinical linear accelerator (VCLA) using conventional dose rates. The highest IDR of the FLASH beam to date was 20.7 ± 0.6 MGy/s, with maximum MDR of 20.7 MGy/s delivered in 1 pulse of 1 µs duration. Beam targeting was accurate to <1 mm and reproducible. HIGS-FLASH and VCLA dose rates equivalently decreased cancer cell growth. HIGS-FLASH irradiation significantly increased tumor necrosis factor α and fractalkine levels and confocal microscopy revealed distinct changes in microglial morphology slices suggesting microglia activation. Our novel experimental platform produces extremely high dose rates and rapid normal/neoplastic tissue readouts for mechanistic research into the effects of FLASH radiation in the brain. HIGS-FLASH irradiation induces comparable cancer cell growth inhibition but differential effects on cytokines and microglial morphology, suggesting that acute innate immune responses may be involved in FLASH normal tissue effects in the brain.

Kay, Tyler V. [Duke University, Durham, NC (United↗

DOE OSTI2024

X-ray fluorescence mapping of brain tissue reveals the profound extent of trace element dysregulation in stroke pathophysiology

Abstract The brain is a privileged organ with regard to its trace element composition and maintains a robust barrier system to sequester this specialized environment from the rest of the body and the vascular system. Stroke is caused by loss of adequate blood flow to a region of the brain. Without adequate blood flow ischaemic changes begin almost immediately, triggering an ischaemic cascade, characterized by ion dysregulation, loss of function, oxidative damage, cellular degradation, and breakdown of the barrier that helps maintain this environment. Ion dysregulation is a hallmark of stroke pathophysiology and we observe that most elements in the brain are dysregulated after stroke. X-ray fluorescence-based detection of physiological changes in the neurometallome after stroke reveals profound ion dysregulation within the lesion and surrounding tissue. Not only are most elements significantly dysregulated after stroke, but the level of dysregulation cannot be predicted from a cell-level description of dysregulation. X-ray fluorescence imaging reveals that the stroke lesion retains <25% of essential K+ after stroke, but this element is not concomitantly elevated elsewhere in the organ. Moreover, elements like Na+, Ca2+, and Cl− are vastly elevated above levels available in normal brain tissue (>400%, >200%, and >150%, respectively). We hypothesize that weakening of the blood–brain barrier after stroke allows elements to freely diffuse down their concentration gradient so that the stroke lesion is in equilibrium with blood (and the compartments containing brain interstitial fluid and cerebrospinal fluid). The change observed for the neurometallome likely has consequences for the potential to rescue infarcted tissue, but also presents specific targets for treatment.

Biochemistry & Molecular Biology↗

DOE OSTI2024

Enhancing Acute Migraine Treatment: Exploring Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for the Nose-to-Brain Route

Migraine has a high prevalence worldwide and is one of the main disabling neurological diseases in individuals under the age of 50. In general, treatment includes the use of oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for mild attacks, and, for moderate or severe attacks, triptans or 5-HT1B/1D receptor agonists. However, the administration of antimigraine drugs in conventional oral pharmaceutical dosage forms is a challenge, since many molecules have difficulty crossing the blood-brain barrier (BBB) to reach the brain, which leads to bioavailability problems. Efforts have been made to find alternative delivery systems and/or routes for antimigraine drugs. In vivo studies have shown that it is possible to administer drugs directly into the brain via the intranasal (IN) or the nose-to-brain route, thus avoiding the need for the molecules to cross the BBB. In this field, the use of lipid nanoparticles, in particular solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has shown promising results, since they have several advantages for drugs administered via the IN route, including increased absorption and reduced enzymatic degradation, improving bioavailability. Furthermore, SLN and NLC are capable of co-encapsulating drugs, promoting their simultaneous delivery to the site of therapeutic action, which can be a promising approach for the acute migraine treatment. This review highlights the potential of using SLN and NLC to improve the treatment of acute migraine via the nose-to-brain route. First sections describe the pathophysiology and the currently available pharmacological treatment for acute migraine, followed by an outline of the mechanisms underlying the nose-to-brain route. Afterwards, the main features of SLN and NLC and the most recent in vivo studies investigating the use of these nanoparticles for the treatment of acute migraine are presented.

Torres, Joana (ORCID:0000000327276229)↗

NASA NTRS1999

GCR Transport in the Brain: Assessment of Self-Shielding, Columnar Damage, and Nuclear Reactions on Cell Inactivation Rates

Radiation shield design is driven by the need to limit radiation risks while optimizing risk reduction with launch mass/expense penalties. Both limitation and optimization objectives require the development of accurate and complete means for evaluating the effectiveness of various shield materials and body-self shielding. For galactic cosmic rays (GCR), biophysical response models indicate that track structure effects lead to substantially different assessments of shielding effectiveness relative to assessments based on LET-dependent quality factors. Methods for assessing risk to the central nervous system (CNS) from heavy ions are poorly understood at this time. High-energy and charge (HZE) ion can produce tissue events resulting in damage to clusters of cells in a columnar fashion, especially for stopping heavy ions. Grahn (1973) and Todd (1986) have discussed a microlesion concept or model of stochastic tissue events in analyzing damage from HZE's. Some tissues, including the CNS, maybe sensitive to microlesion's or stochastic tissue events in a manner not illuminated by either conventional dosimetry or fluence-based risk factors. HZE ions may also produce important lateral damage to adjacent cells. Fluences of high-energy proton and alpha particles in the GCR are many times higher than HZE ions. Behind spacecraft and body self-shielding the ratio of protons, alpha particles, and neutrons to HZE ions increases several-fold from free-space values. Models of GCR damage behind shielding have placed large concern on the role of target fragments produced from tissue atoms. The self-shielding of the brain reduces the number of heavy ions reaching the interior regions by a large amount and the remaining light particle environment (protons, neutrons, deuterons. and alpha particles) may be the greatest concern. Tracks of high-energy proton produce nuclear reactions in tissue, which can deposit doses of more than 1 Gv within 5 - 10 cell layers. Information on rates of cell killing from GCR, including patterns of cell killing from single particle tracks. can provide useful information on expected differences between proton and HZE tracks and clinical experiences with photon irradiation. To model effects on cells in the brain, it is important that transport models accurately describe changes in the GCR due to interactions in the cranium and proximate tissues. We describe calculations of the attenuated GCR particle fluxes at three dose-points in the brain and associated patterns of cell killing using biophysical models. The effects of the brain self-shielding and bone-tissue interface of the skull in modulating the GCR environment are considered. For each brain dose-point, the mass distribution in the surrounding 4(pi) solid angle is characterized using the CAM model to trace 512 rays. The CAM model describes the self-shielding by converting the tissue distribution to mass-equivalent aluminum, and nominal values of spacecraft shielding is considered. Particle transport is performed with the proton, neutron, and heavy-ion transport code HZETRN with the nuclear fragmentation model QMSFRG. The distribution of cells killed along the path of individual GCR ions is modeled using in vitro cell inactivation data for cells with varying sensitivity. Monte Carlo simulations of arrays of inactivated cells are considered for protons and heavy ions and used to describe the absolute number of cell killing events of various magnitude in the brain from the GCR. Included are simulations of positions of inactivated cells from stopping heavy ions and nuclear stars produced by high-energy ions most importantly, protons and neutrons.

Shavers, M. R.↗

NASA NTRS2015

Increased Brain Activation for Foot Movement During 70-Day 6 Deg Head-Down Bed Rest (HDBR): Evidence from Functional Magnetic Resonance Imaging (fMRI)

Bed rest has been widely used as a simulation of weightlessness in studying the effects of microgravity exposure on human physiology and cognition. Changes in muscle function and functional mobility have been reported to be associated with bed rest. Understanding the effect of bed rest on neural control of movement would provide helpful information for spaceflight. In the current study, we evaluated how the brain activation for foot movement changed as a function of bed rest. Eighteen healthy men (aged 25 to 39 years) participated in this HDBR study. They remained continuously in the 6deg head‐down tilt position for 70 days. Functional MRI was acquired during 1‐Hz right foot tapping, and repeated at 7 time points: 12 days pre‐, 8 days pre‐, 7 days in‐, 50 days in‐, 70 days in‐, 8 days post‐, and 12 days post‐ HDBR. In all 7 sessions, we observed increased activation in the left motor cortex, right cerebellum and right occipital cortex during foot movement blocks compared to rest. Compared to the pre‐HDBR baseline (1st and 2nd sessions), foot movement‐induced activation in the left hippocampus increased during HDBR. This increase emerged in the 4th session, enlarged in the 5th session, and remained significant in the 6th and 7th sessions. Furthermore, increased activation relative to the baseline in left precuneus was observed in the 5th, 6th and 7th sessions. In addition, in comparison with baseline, increased activation in the left cerebellum was found in the 4th and 5th sessions, whereas increased activation in the right cerebellum was observed in the 4th, 6th and 7th sessions. No brain region exhibited decreased activation during bed rest compared to baseline. The increase of foot movement related brain activation during HDBR suggests that in a long‐term head‐down position, more neural control is needed to accomplish foot movements. This change required a couple of weeks to develop in HDBR (between 3rd and 4th sessions), and did not return to baseline even 12 days after HDBR. The observed effect of bed rest on brain activation during a foot tapping task could be linked to HDBR related changes in brain structure that we have recently reported. The relationship between pre‐ and post‐ HDBR changes in brain activation and performance in a functional mobility test will also be presented.

Yuan, P.↗

NASA NTRS2017

Behavioral, Brain Imaging and Genomic Measures to Predict Functional Outcomes Post-Bed Rest and Space Flight

Astronauts experience sensorimotor disturbances during their initial exposure to microgravity and during the re-adaptation phase following a return to an Earth-gravitational environment. These alterations may disrupt crewmembers' ability to perform mission critical functional tasks requiring ambulation, manual control and gaze stability. Interestingly, astronauts who return from spaceflight show substantial differences in their abilities to readapt to a gravitational environment. The ability to predict the manner and degree to which individual astronauts are affected will improve the effectiveness of countermeasure training programs designed to enhance sensorimotor adaptability. For such an approach to succeed, we must develop predictive measures of sensorimotor adaptability that will allow us to foresee, before actual spaceflight, which crewmembers are likely to experience greater challenges to their adaptive capacities. The goals of this project are to identify and characterize this set of predictive measures. Our approach includes: 1) behavioral tests to assess sensory bias and adaptability quantified using both strategic and plastic-adaptive responses; 2) imaging to determine individual brain morphological and functional features, using structural magnetic resonance imaging (MRI), diffusion tensor imaging, resting state functional connectivity MRI, and sensorimotor adaptation task-related functional brain activation; and 3) assessment of genetic polymorphisms in the catechol-O-methyl transferase, dopamine receptor D2, and brain-derived neurotrophic factor genes and genetic polymorphisms of alpha2-adrenergic receptors that play a role in the neural pathways underlying sensorimotor adaptation. We anticipate that these predictive measures will be significantly correlated with individual differences in sensorimotor adaptability after long-duration spaceflight and exposure to an analog bed rest environment. We will be conducting a retrospective study, leveraging data already collected from relevant ongoing or completed bed rest and spaceflight studies. This data will be combined with predictor metrics that will be collected prospectively (as described for behavioral, brain imaging and genomic measures) from these returning subjects to build models for predicting post spaceflight and bed rest adaptive capability. In this presentation we will discuss the optimized set of tests for predictive metrics to be used for evaluating post mission adaptive capability as manifested in their outcome measures. Comparisons of model performance will allow us to better design and implement sensorimotor adaptability training countermeasures against decrements in post-mission adaptive capability that are customized for each crewmember's sensory biases, adaptive ability, brain structure, brain function, and genetic predispositions. The ability to customize adaptability training will allow more efficient use of crew time during training and will optimize training prescriptions for astronauts to mitigate the deleterious effects of spaceflight.

Mulavara, A. P.↗

NASA NTRS1987

Nutrients affecting brain composition and behavior

This review examines the changes in brain composition and in various brain functions, including behavior, that can follow the ingestion of particular foods or nutrients. It details those that are best understood: the increases in serotonin, catecholamine, or acetylcholine synthesis that can occur subsequent to food-induced increases in brain levels of tryptophan, tyrosine, or choline; it also discusses the various processes that must intervene between the mouth and the synapse, so to speak, in order for a nutrient to affect neurotransmission, and it speculates as to additional brain chemicals that may ultimately be found to be affected by changes in the availability of their nutrient precursors. Because the brain chemicals best known to be nutrient dependent overlap with those thought to underlie the actions of most of the drugs used to treat psychiatric diseases, knowledge of this dependence may help the psychiatrist to understand some of the pathologic processes occurring in his/her patients, particularly those with appetitive symptoms. At the very least, such knowledge should provide the psychiatrist with objective criteria for judging when to take seriously assertions that particular foods or nutrients do indeed affect behavior (e.g., in hyperactive children). If the food can be shown to alter neurotransmitter release, it may be behaviorally-active; however, if it lacks a discernible neurochemical effect, the likelihood that it really alters behavior is small.

NASA Program Space Medicine↗

DOE OSTI2024

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology

Abstract INTRODUCTION Factors responsible for the deposition of pathological tau in the brain are incompletely understood. This study links macroscale tau deposition in the human brain to cerebrospinal fluid (CSF) flow dynamics using resting‐state functional magnetic resonance imaging (rsfMRI). METHODS Low‐frequency (< 0.1 Hz) resting‐state global brain activity is coupled with CSF flow and potentially reflects CSF dynamics‐related clearance. We examined the correlation between rsfMRI measures of CSF inflow and global activity (gBOLD–CSF coupling) as a predictor, interacting with amyloid beta (Aβ), of tau and cortical thickness (dependent variables) across Alzheimer's Disease Neuroimaging Initiative (ADNI) participants from cognitively unimpaired through mild cognitive impairment (MCI) and Alzheimer's disease (AD). RESULTS Tau deposition in Aβ+ participants, accompanied by cortical thinning and cognitive decline, is associated with decreased gBOLD–CSF coupling. Tau mediates the relationship between coupling and thickness. DISCUSSION Findings suggest that resting‐state global brain activity and CSF movements comodulate Alzheimer's tau deposition, presumably related to CSF clearance. Highlights A non‐invasive functional magnetic resonance imaging (fMRI) assessment of a CSF clearance‐related process is carried out. Global brain activity is coupled with CSF inflow in human fMRI during resting state. Global fMRI–CSF coupling is correlated with tau in Alzheimer's disease (AD). This coupling measure is also associated with cortical thickness, mediated by tau.

Neurosciences & Neurology↗

DOE OSTI2024

Graph-Based Modeling for the Detection and Tracking of Sarin-Surrogate-Induced Neurotoxicity Using a Human-Relevant, In-Vitro Brain Model

Organophosphorus (OP) nerve agents are a chemical threat to the United States, to the civilian population (e.g., pesticides) and historically weaponized (e.g., sarin) as chemical warfare agents. The unprecedented, accelerated process from “bench-to-bedside” during the SARSCov2 pandemic has made it clear that technology and tools need to be readily available for immediate response. Advances in human organ tissue mimetic systems are a promising technology to evaluate the human-relevant response in vitro for basic and applied research and drug screening. In particular, current brain microphysiological systems (MPS) have the capability to monitor and detect changes in engineered human neural circuit activity. However, current data analytics approaches for these systems lack the granularity to functionally detect and distinguish the different mechanisms that occur in the brain following neurotoxicity, injury, and disease. The goal of this project was to advance the computational analytical capabilities of the brain MPS to detect functional changes in neural circuit structure at different stages of Sarin surrogate-induced neurotoxicity. We developed graph-based models to (1) identify the composition of the neural circuit structure; (2) detect and monitor how this structure changes following sarin-induced neurotoxicity; and (3) evaluate the analytical pipeline using known/promising oxime reactivators. Through experiments on the bMPS where in vitro neuronal cultures were exposed to a sarin surrogate, we demonstrated the capabilities of our computational pipeline to identify different responses in the functional networks of brain cells exposed to low and high concentrations of the nerve agent. We identified a biphasic response of human neural network activity following exposure to a sarin-surrogate that had not been reported in the literature before. The graph-based models and software developed in this project can be used for future studies that leverage the brain MPS technology, such as treatment efficacy assessment.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

Brain Therapeutic Shuttle

The blood-brain barrier helps protect the brain by limiting what can pass from the bloodstream into the central nervous system. While this protection is important for health, it can also prevent treatments from reaching the areas where they are needed. As a result, developing treatments for the brain can be challenging because many of them cannot cross the blood-brain barrier in sufficient amounts to reach the brain.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Single-cell and spatiotemporal transcriptomic profiling of brain immune infiltration following Venezuelan equine encephalitis virus infection

Neurotropic alphaviruses such as Venezuelan equine encephalitis virus (VEEV) are critical human pathogens that continually expand to naïve populations and for which there are no licensed vaccines or therapeutics. VEEV is highly infectious via the aerosol route and is a recognized weaponizable biothreat that causes neurological disease in humans. The neuropathology of VEEV has been attributed to an inflammatory immune response in the brain yet the underlying mechanisms and specific immune cell populations involved are not fully elucidated. This study uses single-cell RNA sequencing to produce a comprehensive transcriptional profile of immune cells isolated from the brain over a time course of infection in a mouse model of VEEV. Analyses reveal differentially activated subpopulations of microglia, including a distinct type I interferon-expressing subpopulation. This is followed by the sequential infiltration of myeloid cells and cytotoxic lymphocytes, also comprising subpopulations with unique transcriptional signatures. We identify a subpopulation of myeloid cells that form a distinct localization pattern in the hippocampal region whereas lymphocytes are widely distributed, indicating differential modes of recruitment, including that to specific regions of the brain. Altogether, this study provides a high-resolution analysis of the immune response to VEEV in the brain and highlights potential avenues of investigation for therapeutics that target neuroinflammation in the brain.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS1982

Chronic acceleration and brain density

Tests carried out on rabbits show that the effect of chronic acceleration is not uniform among the various tissues studied. Although body mass is reduced by the treatment, as expected, no change is apparent in brain mass or in the density of cerebrospinal fluid. Acceleration-induced changes are encountered in tissue density, the myocardium exhibiting a transient increase followed by an exponential decrease toward a limit and the brain showing an arithmetic increase in density with continued exposure to 2.5 G. The data are seen as suggesting that a specific brain load is not a regulated phenomenon and that no physiological processes occur to attenuate the increased load imposed by the hyperdynamic environment. An equation is derived indicating that the stimulus potential per unit of brain load increases with body size, even though brain density decreases and cerebrospinal fluid density increases.

Hoffman, L. F.↗

NASA NTRS1993

Co-transplantation of plasmid-transfected myoblasts and myotubes into rat brains enables high levels of gene expression long-term

We have previously proposed the use of primary muscle cells as a "platform," or "vehicle" for intracerebral transgene expression. Brain grafts of minced muscle, or cultured muscle cells persisted in rat brains for at least 6 mo without any decrease in graft size, or tumor formation. Stable, but moderate levels of intracerebral transgene expression were obtained by transplanting plasmid-transfected myotubes in culture. In the present study, high and stable levels of intracerebral transgene expression were achieved by the co-transplantation of plasmid-transfected myoblasts and myotubes in culture. Approximately 5 X 10(5) myoblasts and myotubes were transfected with 10 micrograms pRSVL plasmid DNA, and 30 micrograms Lipofectin (BRL), respectively. They were mixed together (total cell number was 1 million), and stereotactically injected into the caudate nucleus of an adult rat brain. The activity of luciferase, the product of transgene expression, was stable for at least 4 mo, and much higher than the levels in myotube grafts, or co-grafts of myoblasts and minced muscle. Presumably, the myotubes served as a framework on which the myoblasts can form myotubes. The sections of brains transplanted with co-graft of myoblasts, and myotubes transfected with pRSVLac-Z were stained immunofluorescently for beta-galactosidase activity. The muscle grafts contained beta-galactosidase positive myofibers 4 mo after transplantation. Such high and stable levels of in vivo expression after postnatal gene transfer have rarely been achieved. Primary muscle cells are useful vehicle for transgene expression in brains, and potentially valuable for gene therapy of degenerative neurological disorders.

NASA Program Space Biology↗

NASA NTRS2005

Activation of nuclear transcription factor-kappaB in mouse brain induced by a simulated microgravity environment

Microgravity induces inflammatory responses and modulates immune functions that may increase oxidative stress. Exposure to a microgravity environment induces adverse neurological effects; however, there is little research exploring the etiology of these effects resulting from exposure to such an environment. It is also known that spaceflight is associated with increase in oxidative stress; however, this phenomenon has not been reproduced in land-based simulated microgravity models. In this study, an attempt has been made to show the induction of reactive oxygen species (ROS) in mice brain, using ground-based microgravity simulator. Increased ROS was observed in brain stem and frontal cortex with concomitant decrease in glutathione, on exposing mice to simulated microgravity for 7 d. Oxidative stress-induced activation of nuclear factor-kappaB was observed in all the regions of the brain. Moreover, mitogen-activated protein kinase kinase was phosphorylated equally in all regions of the brain exposed to simulated microgravity. These results suggest that exposure of brain to simulated microgravity can induce expression of certain transcription factors, and these have been earlier argued to be oxidative stress dependent.

Non-NASA Center↗

NASA NTRS2003

Assessing blood brain barrier dynamics or identifying or measuring selected substances or toxins in a subject by analyzing Raman spectrum signals of selected regions in the eye

A non-invasive method for analyzing the blood-brain barrier includes obtaining a Raman spectrum of a selected portion of the eye and monitoring the Raman spectrum to ascertain a change to the dynamics of the blood brain barrier. Also, non-invasive methods for determining the brain or blood level of an analyte of interest, such as glucose, drugs, alcohol, poisons, and the like, comprises: generating an excitation laser beam (e.g., at a wavelength of 600 to 900 nanometers); focusing the excitation laser beam into the anterior chamber of an eye of the subject so that aqueous humor, vitreous humor, or one or more conjunctiva vessels in the eye is illuminated; detecting (preferably confocally detecting) a Raman spectrum from the illuminated portion of the eye; and then determining the blood level or brain level (intracranial or cerebral spinal fluid level) of an analyte of interest for the subject from the Raman spectrum. In certain embodiments, the detecting step may be followed by the step of subtracting a confounding fluorescence spectrum from the Raman spectrum to produce a difference spectrum; and determining the blood level and/or brain level of the analyte of interest for the subject from that difference spectrum, preferably using linear or nonlinear multivariate analysis such as partial least squares analysis. Apparatus for carrying out the foregoing methods are also disclosed.

Lambert, James L.↗

NASA NTRS2008

Assessing blood brain barrier dynamics or identifying or measuring selected substances, including ethanol or toxins, in a subject by analyzing Raman spectrum signals

A non-invasive method for analyzing the blood-brain barrier includes obtaining a Raman spectrum of a selected portion of the eye and monitoring the Raman spectrum to ascertain a change to the dynamics of the blood brain barrier.Also, non-invasive methods for determining the brain or blood level of an analyte of interest, such as glucose, drugs, alcohol, poisons, and the like, comprises: generating an excitation laser beam at a selected wavelength (e.g., at a wavelength of about 400 to 900 nanometers); focusing the excitation laser beam into the anterior chamber of an eye of the subject so that aqueous humor, vitreous humor, or one or more conjunctiva vessels in the eye is illuminated; detecting (preferably confocally detecting) a Raman spectrum from the illuminated portion of the eye; and then determining the blood level or brain level (intracranial or cerebral spinal fluid level) of an analyte of interest for the subject from the Raman spectrum. In certain embodiments, the detecting step may be followed by the step of subtracting a confounding fluorescence spectrum from the Raman spectrum to produce a difference spectrum; and determining the blood level and/or brain level of the analyte of interest for the subject from that difference spectrum, preferably using linear or nonlinear multivariate analysis such as partial least squares analysis. Apparatus for carrying out the foregoing methods are also disclosed.

Lambert, James L.↗

NASA NTRS2016

Behavioral, Brain Imaging and Genomic Measures to Predict Functional Outcomes Post - Bed Rest and Spaceflight

Astronauts experience sensorimotor disturbances during their initial exposure to microgravity and during the re-adaptation phase following a return to an Earth-gravitational environment. These alterations may disrupt crewmembers' ability to perform mission critical functional tasks requiring ambulation, manual control and gaze stability. Interestingly, astronauts who return from spaceflight show substantial differences in their abilities to readapt to a gravitational environment. The ability to predict the manner and degree to which individual astronauts would be affected would improve the effectiveness of countermeasure training programs designed to enhance sensorimotor adaptability. For such an approach to succeed, we must develop predictive measures of sensorimotor adaptability that will allow us to foresee, before actual spaceflight, which crewmembers are likely to experience the greatest challenges to their adaptive capacities. The goals of this project are to identify and characterize this set of predictive measures. Our approach includes: 1) behavioral tests to assess sensory bias and adaptability quantified using both strategic and plastic-adaptive responses; 2) imaging to determine individual brain morphological and functional features, using structural magnetic resonance imaging (MRI), diffusion tensor imaging, resting state functional connectivity MRI, and sensorimotor adaptation task-related functional brain activation; and 3) assessment of genotypic markers of genetic polymorphisms in the catechol-O-methyl transferase, dopamine receptor D2, and brain-derived neurotrophic factor genes and genetic polymorphisms of alpha2-adrenergic receptors that play a role in the neural pathways underlying sensorimotor adaptation. We anticipate that these predictive measures will be significantly correlated with individual differences in sensorimotor adaptability after long-duration spaceflight and exposure to an analog bed rest environment. We will be conducting a retrospective study, leveraging data already collected from relevant ongoing or completed bed rest and spaceflight studies. These data will be combined with predictor metrics that will be collected prospectively (as described for behavioral, brain imaging and genomic measures) from these returning subjects to build models for predicting post-mission (bed rest - non-astronauts or space flight - astronauts) adaptive capability as manifested in their outcome measures. To date we have completed a study on 15 normal subjects with all of the above measures. In this presentation we will discuss the optimized set of tests for predictive metrics to be used for evaluating post mission adaptive capability as manifested in their outcome measures. Comparisons of model performance will allow us to better design and implement sensorimotor adaptability training countermeasures against decrements in post-mission adaptive capability that are customized for each crewmember's sensory biases, adaptive capacity, brain structure and functional capacities, and genetic predispositions. The ability to customize adaptability training will allow more efficient use of crew time during training and will optimize training prescriptions for astronauts to ensure expected outcomes.

Mulavara, A. P.↗