Mild traumatic brain injury afflicts over 2 million people annually and little can be done for the underlying injury. The Food and Drug Administration-approved drugs Minocycline plus N-acetylcysteine (MINO plus NAC) synergistically improved cognition and memory in a rat mild controlled cortical impact (mCCI) model of traumatic brain injury. The underlying cellular and molecular mechanisms of the drug combination are unknown. This study addressed the effect of the drug combination on white matter damage and neuroinflammation after mCCI. Brain tissue from mCCI rats given either sham-injury, saline, MINO alone, NAC alone, or MINO plus NAC was investigated via histology and qPCR at four time points (2, 4, 7, and 14 days post-injury) for markers of white matter damage and neuroinflammation. MINO plus NAC synergistically protected resident oligodendrocytes and decreased the number of oligodendrocyte precursor cells. Activation of microglia/macrophages (MP/MG) was synergistically increased in white matter two days post-injury after MINO plus NAC treatment. Patterns of M1 and M2 MP/MG were also altered after treatment. The modulation of neuroinflammation is a potential mechanism to promote remyelination and improve cognition and memory. These data also provide new and important insights into how drug treatments can induce repair after traumatic brain injury.
Blunt impact produces a heterogeneous brain injury in people and in animal models of traumatic brain injury. We report that a single closed head impact to adult C57/BL6 mice produced two injury syndromes (CHI-1 and CHI-2). CHI-1 mice spontaneously reinitiated breathing after injury while CHI-2 mice had prolonged apnea and regained breathing only after cardiopulmonary resuscitation and supplementation of 100% O2. The CHI-1 group significantly regained righting reflex more rapidly than the CHI-2 group. At 7 days post-injury, CHI-1, but not CHI-2 mice, acquired but had no long-term retention of an active place avoidance task. The behavioral deficits of CHI-1 and CHI-2 mice were retained one-month after the injury. CHI-1 mice had loss of hippocampal neurons and localized white matter injury at one month after injury. CHI-2 had a larger loss of hippocampal neurons and more widespread loss of myelin and axons. High-speed videos made during the injury were followed by assessment of breathing and righting reflex. These videos show that CHI-2 mice experienced a larger vertical g-force than CHI-1 mice. Time to regain righting reflex in CHI-2 mice significantly correlated with vertical g-force. Thus, physiological responses occurring immediately after injury can be valuable surrogate markers of subsequent behavioral and histological deficits.
Functional near infrared spectroscopy (fNIRS) measurements are confounded by signal components originating from multiple physiological causes, whose activities may vary temporally and spatially (across tissue layers, and regions of the cortex). Furthermore, the stimuli can induce evoked effects, which may lead to over or underestimation of the actual effect of interest. Here, we conducted a temporal, spectral, and spatial analysis of fNIRS signals collected during cognitive and hypercapnic stimuli to characterize effects of functional versus systemic responses. We utilized wavelet analysis to discriminate physiological causes and employed long and short source-detector separation (SDS) channels to differentiate tissue layers. Multi-channel measures were analyzed further to distinguish hemispheric differences. The results highlight cardiac, respiratory, myogenic, and very low frequency (VLF) activities within fNIRS signals. Regardless of stimuli, activity within the VLF band had the largest contribution to the overall signal. The systemic activities dominated the measurements from the short SDS channels during cognitive stimulus, but not hypercapnic stimulus. Importantly, results indicate that characteristics of fNIRS signals vary with type of the stimuli administered as cognitive stimulus elicited variable responses between hemispheres in VLF band and task-evoked temporal effect in VLF, myogenic and respiratory bands, while hypercapnic stimulus induced a global response across both hemispheres.
Functional near infrared spectroscopy (fNIRS) measurements are confounded by signal components originating from multiple physiological causes, whose activities may vary temporally and spatially (across tissue layers, and regions of the cortex). Furthermore, the stimuli can induce evoked effects, which may lead to over or underestimation of the actual effect of interest. Here, we conducted a temporal, spectral, and spatial analysis of fNIRS signals collected during cognitive and hypercapnic stimuli to characterize effects of functional versus systemic responses. We utilized wavelet analysis to discriminate physiological causes and employed long and short source-detector separation (SDS) channels to differentiate tissue layers. Multi-channel measures were analyzed further to distinguish hemispheric differences. The results highlight cardiac, respiratory, myogenic, and very low frequency (VLF) activities within fNIRS signals. Regardless of stimuli, activity within VLF band had the largest contribution to the overall signal. The systemic activities dominated the measurements from the short SDS channels during cognitive stimulus, but not hypercapnic stimulus. Importantly, results indicate that characteristics of fNIRS signals vary with type of the stimuli administered as cognitive stimulus elicited variable responses between hemispheres in VLF band and task-evoked temporal effect in VLF, myogenic and respiratory bands, while hypercapnic stimulus induced a global response across both hemispheres.
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