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Veterans of the 1991 Gulf War were potentially exposed to a variety of toxic chemicals, including sarin nerve agent and pesticides, which have been suspected to be involved in the development of Gulf War Illness (GWI). Several of these exposures cause a neuroinflammatory response in mice, which may serve as a basis for the sickness behavior-like symptoms seen in veterans with GWI. Furthermore, conditions mimicking the physiological stress experienced during the war can exacerbate this effect. While neuroinflammation has been observed post-exposure using animal models, it remains a challenge to evaluate neuroinflammation and its associated cellular and molecular changes in vivo in veterans with GWI. Here, we evaluated neuroimmune-associated alterations in intact brains, applying our existing GWI mouse model to rats, by exposing them to 4days of corticosterone (CORT; 200mg/L in the drinking water), to mimic high physiological stress, followed by a single injection of the sarin nerve agent surrogate, diisopropyl fluorophosphate (DFP; 1.5mg/kg, i.p.). Then, we evaluated the neuroinflammatory responses using qPCR of cytokine mRNA and also examined brain structure with a novel high-order diffusion MRI. We found a CORT-enhancement of DFP-induced neuroinflammation, extending our mouse GWI model to the rat. High order diffusion MRI revealed different patterns among the different treatment groups. Particularly, while the CORT+DFP rats had more restricted spatial patterns in the hippocampus and the hypothalamus, the highest and most wide-spread differences were shown in DFP-treated rats compared to the controls in the thalamus, the amygdala, the piriform cortex and the ventral tegmental area. The association of these diffusion changes with neuroinflammatory cytokine expression indicates the potential for GW-relevant exposures to result in connectivity changes in the brain. By transferring this high order diffusion MRI into in vivo imaging in veterans with GWI, we can achieve further insights on the trajectories of the neuroimmune response over time and its impacts on behavior and potential neurological damage.

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The rhesus monkey is a useful model for examining age-related as well as other neurological and developmental effects on the brain, because of the extensive neuroanatomical homology to the human brain, the reduced occurrence of neurological diseases such as Alzheimer’s disease as well as the possibility of obtaining relevant behavioral data and post-mortem tissue for histological analyses. In this study, cortical thickness measurements based on a cortical surface modeling technique were applied for the first time to investigate cortical thickness patterns in the rhesus monkey brain, and were used to evaluate regional age related effects across a wide range of ages. Age-related effects were observed in several cortical areas, in particular in the somatosensory and motor cortices, where a robust negative correlation of cortical thickness with age was observed, similar to that found in humans. In contrast, results for monkeys compared to humans show significant inter-species differences in cortical thickness patterns in the frontal and the inferior temporal regions.

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In the setting of profound ocular blindness, numerous lines of evidence demonstrate the existence of dramatic anatomical and functional changes within the brain. However, previous studies based on a variety of distinct measures have often provided inconsistent findings. To help reconcile this issue, we used a multimodal magnetic resonance (MR)-based imaging approach to provide complementary structural and functional information regarding this neuroplastic reorganization. This included gray matter structural morphometry, high angular resolution diffusion imaging (HARDI) of white matter connectivity and integrity, and resting state functional connectivity MRI (rsfcMRI) analysis. When comparing the brains of early blind individuals to sighted controls, we found evidence of co-occurring decreases in cortical volume and cortical thickness within visual processing areas of the occipital and temporal cortices respectively. Increases in cortical volume in the early blind were evident within regions of parietal cortex. Investigating white matter connections using HARDI revealed patterns of increased and decreased connectivity when comparing both groups. In the blind, increased white matter connectivity (indexed by increased fiber number) was predominantly left-lateralized, including between frontal and temporal areas implicated with language processing. Decreases in structural connectivity were evident involving frontal and somatosensory regions as well as between occipital and cingulate cortices. Differences in white matter integrity (as indexed by quantitative anisotropy, or QA) were also in general agreement with observed pattern changes in the number of white matter fibers. Analysis of resting state sequences showed evidence of both increased and decreased functional connectivity in the blind compared to sighted controls. Specifically, increased connectivity was evident between temporal and inferior frontal areas. Decreases in functional connectivity were observed between occipital and frontal and somatosensory-motor areas and between temporal (mainly fusiform and parahippocampus) and parietal, frontal, and other temporal areas. Correlations in white matter connectivity and functional connectivity observed between early blind and sighted controls showed an overall high degree of association. However, comparing the relative changes in white matter and functional connectivity between early blind and sighted controls did not show a significant correlation. In summary, these findings provide complimentary evidence, as well as highlight potential contradictions, regarding the nature of regional and large scale neuroplastic reorganization resulting from early onset blindness.

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