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A data-driven approach for evaluating multi-modal therapy in traumatic brain injury.

ABSTRACT: Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with combinations of an anti-inflammatory agent (minocycline), a neurotrophic agent (LM11A-31), and physical therapy consisting of assisted exercise with or without botulinum toxin-induced limb constraint. Data was curated and analyzed in a linked workflow involving non-linear principal component analysis followed by hypothesis testing with a linear mixed model. Results revealed significant benefits of the neurotrophic agent LM11A-31 on learning and memory outcomes after traumatic brain injury. In addition, modulations of LM11A-31 effects by co-administration of minocycline and by the type of physical therapy applied reached statistical significance. These results suggest a combinatorial effect of drug and physical therapy interventions that was not evident by univariate analysis. The study designs and analytic techniques applied here form a structured, unbiased, internally validated workflow that may be applied to other combinatorial studies, both in animals and humans.

SUBMITTER: Haefeli J

PROVIDER: S-EPMC5311970 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A data-driven approach for evaluating multi-modal therapy in traumatic brain injury.

Haefeli Jenny J Ferguson Adam R AR Bingham Deborah D Orr Adrienne A Won Seok Joon SJ Lam Tina I TI Shi Jian J Hawley Sarah S Liu Jialing J Swanson Raymond A RA Massa Stephen M SM

Scientific reports 20170216

Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with ...[more]

PMID: 28205533

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Project description:Understanding recovery from TBI is complex, involving multiple systems and modalities. The current study applied modern data science tools to manage this complexity and harmonize large-scale data to understand relationships between gene expression and behavioral outcomes in a preclinical model of chronic TBI (cTBI). Data collected by the Moody Project for Translational TBI Research included rats with no injury (naïve animals with similar amounts of anesthetic exposure to TBI and sham-injured animals), sham injury, or lateral fluid percussion TBI, followed by recovery periods up to 12 months. Behavioral measures included locomotor coordination (beam balance neuroscore) and memory and cognition assessments (Morris water maze: MWM) at multiple timepoints. Gene arrays were performed using hippocampal and cortical samples to probe 45,610 genes. To reduce the high dimensionality of molecular and behavioral domains and uncover gene-behavior associations, we performed non-linear principal components analyses (NL-PCA), which de-noised the data. Genomic NL-PCA unveiled three interpretable eigengene components (PC2, PC3, and PC4). Ingenuity pathway analysis (IPA) identified the PCs as an integrated stress response (PC2; EIF2-mTOR, corticotropin signaling, etc.), inflammatory factor translation (PC3; PI3K-p70S6K signaling), and neurite growth inhibition (PC4; Rho pathways). Behavioral PCA revealed three principal components reflecting the contribution of MWM overall speed and distance, neuroscore/beam walk, and MWM platform measures. Integrating the genomic and behavioral domains, we then performed a 'meta-PCA' on individual PC scores for each rat from genomic and behavioral PCAs. This meta-PCA uncovered three unique multimodal PCs, characterized by robust associations between inflammatory/stress response and neuroscore/beam walk performance (meta-PC1), stress response and MWM performance (meta-PC2), and stress response and neuroscore/beam walk performance (meta-PC3). Multivariate analysis of variance (MANOVA) on genomic-behavioral meta-PC scores tested separately on cortex and hippocampal samples revealed the main effects of TBI and recovery time. These findings are a proof of concept for the integration of disparate data domains for translational knowledge discovery, harnessing the full syndromic space of TBI.

Project description:[18F]AV-1451 (aka 18F-Flortaucipir, [18F]T807) was developed for positron-emission tomography (PET) imaging of paired helical filaments of hyperphosphorylated tau, which are of interest in a range of neuropathologies, including traumatic brain injury (TBI). Magnetic resonance imaging (MRI) techniques like diffusion tensor imaging (DTI) and resting state functional connectivity assess structural and functional characteristics of the brain, complementing the molecular information that can be obtained by PET. The goal herein was to explore the utility of such multi-modal imaging in a case series based on a population of TBI subjects. This study probes the interrelationship between tau deposition, white matter integrity, and gray matter functional connectivity across the spectrum of TBI. Nineteen subjects (11 controls, five former contact sports athletes, one automotive accident, and two with military-related injury) underwent [18F]AV-1451 PET and magnetic resonance scanning procedures. [18F]AV-1451 distribution volume ratio (DVR) was estimated using the Logan method and the cerebellum as a reference region. Diffusion tractography images and fractional anisotropy (FA) images were generated using diffusion toolkit and FSL. Resting-state functional MRI (fMRI) analysis was based on a graph theory metric, namely weighted degree centrality. TBI subjects showed greater heterogeneity in [18F]AV-1451 DVR when compared with control subjects. In a subset of TBI subjects, areas with high [18F]AV-1451 binding corresponded with increased FA and diminished white matter tract density in DTI. Functional MRI results exhibited an increase in functional connectivity, particularly among local connections, in the areas where tau aggregates were more prevalent. In a case series of a diverse group of TBI subjects, brain regions with elevated tau burden exhibited increased functional connectivity as well as decreased white matter integrity. These findings portray molecular, microstructural, and functional corollaries of TBI that spatially coincide and can be measured in the living human brain using noninvasive neuroimaging techniques.

Project description:BackgroundDiffuse traumatic brain injury (TBI) is known to lead to microstructural changes within both white and grey matter detected in vivo with diffusion tensor imaging (DTI). Numerous studies have shown alterations in fractional anisotropy (FA) and mean diffusivity (MD) within prominent white matter tracts, but few have linked these to changes within the grey matter with confirmation via histological assessment. This is especially important as alterations in the grey matter may be predictive of long-term functional deficits.MethodsA total of 33 male Sprague Dawley rats underwent severe closed-head TBI. Eight animals underwent tensor-based morphometry (TBM) and DTI at baseline (pre-TBI), 24 hours (24 h), 7, 14, and 30 days post-TBI. Immunohistochemical analysis for the detection of ionised calcium-binding adaptor molecule 1 (IBA1) to assess microglia number and percentage of activated cells, β-amyloid precursor protein (APP) as a marker of axonal injury, and myelin basic protein (MBP) to investigate myelination was performed at each time-point.ResultsDTI showed significant alterations in FA and RD in numerous white matter tracts including the corpus callosum, internal and external capsule, and optic tract and in the grey-matter in the cortex, thalamus, and hippocampus, with the most significant effects observed at 14 D post-TBI. TBM confirmed volumetric changes within the hippocampus and thalamus. Changes in DTI were in line with significant axonal injury noted at 24 h post-injury via immunohistochemical analysis of APP, with widespread microglial activation seen within prominent white matter tracts and the grey matter, which persisted to 30 D within the hippocampus and thalamus. Microstructural alterations in MBP+ve fibres were also noted within the hippocampus and thalamus, as well as the cortex.ConclusionThis study confirms the widespread effects of diffuse TBI on white matter tracts which could be detected via DTI and extends these findings to key grey matter regions, with a comprehensive investigation of the whole brain. In particular, the hippocampus and thalamus appear to be vulnerable to ongoing pathology post-TBI, with DTI able to detect these alterations supporting the clinical utility in evaluating these regions post-TBI.

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A data-driven approach for evaluating multi-modal therapy in traumatic brain injury.

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A data-driven approach for evaluating multi-modal therapy in traumatic brain injury.

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