Persistent alterations in cerebrovascular reactivity in response to hypercapnia following pediatric mild traumatic brain injury.
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ABSTRACT:
SUBMITTER: Dodd AB
PROVIDER: S-EPMC7820694 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Traumatic brain injury (TBI) poses a major health challenge, with tens of millions of new cases reported globally every year. Brain damage resulting from TBI can vary significantly due to factors including injury severity, injury mechanism and exposure to repeated injury events. Therefore, there is need for robust blood biomarkers. Serum from Sprague Dawley rats was collected at several timepoints within 24 h of mild single or repeat closed head impacts. Serum samples were analyzed via ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) in positive and negative ion modes. Known lipid species were identified through matching to in-house tandem MS databases. Lipid biomarkers have a unique potential to serve as objective molecular measures of injury response as they may be liberated to circulation more readily than larger protein markers. Machine learning and feature selection approaches were used to construct lipid panels capable of distinguishing serum from injured and uninjured rats. The best multivariate lipid panels had over 90% cross-validated sensitivity, selectivity, and accuracy. These mapped onto sphingolipid signaling, autophagy, necroptosis and glycerophospholipid metabolism pathways, with Benjamini adjusted p-values less than 0.05. The novel lipid biomarker candidates identified provide insight into the metabolic pathways altered within 24 h of mild TBI.
| S-EPMC8878543 | biostudies-literature
Project description:Post-traumatic headaches (PTHs) are associated with mild traumatic brain injuries (mTBI) and may predict the persistence of concussion symptoms. Altered brain networks implicated in brain injury and the affective components of headache-related pain may underlie the resolution of PTH. This is a hypothesis-generating investigation to evaluate the extent to which pain symptom reporting and functional brain changes are different in a cohort of young mTBI patients with resolved (PTH-R) and persistent (PTH-P) post-traumatic headache symptoms relative to healthy controls. This was a cross-sectional investigation involving 59 participants between the ages of 12-24 (PTH-P, n = 21; PTH-R, n = 18; healthy control, n = 20). Participants had no significant history of pre-existing headaches, chronic pain, or psychiatric neurological conditions. The primary outcome was resting-state functional connectivity (RS-Fc) alterations between cohorts. Secondary outcomes were self-reported pain-related symptoms. Elevated scores were reported for fear of pain in both PTH cohorts. Using a false discovery rate of p = 0.05, the PTH-P cohort showed altered connectivity relative to healthy controls in brain regions such as the frontal, temporal, and cerebellar regions, as well as sub-cortical regions including the amygdala and accumbens. The PTH-R cohort showed altered RS-Fc between cerebellar and temporal lobe sub-regions. Our results indicate that a core network of brain regions implicated in the affective pain response are functionally altered in PTH cohorts. Results should be interpreted given limitations on sample size and multiple comparisons. Despite the resolution of symptoms, persons who experience PTH may experience ongoing functional brain abnormalities, which may underlie symptom chronification.
| S-EPMC8165471 | biostudies-literature
Project description:Incidences of repetitive mild TBI (r-mTBI), like those sustained by contact sports athletes and military personnel, are thought to be a risk factor for development of neurodegenerative disorders. Those suffering from chronic TBI-related illness demonstrate deficits in cerebrovascular reactivity (CVR), the ability of the cerebral vasculature to respond to a vasoactive stimulus. CVR is thus an important measure of traumatic cerebral vascular injury (TCVI), and a possible in vivo endophenotype of TBI-related neuropathogenesis. We combined laser speckle imaging of CVR in response to hypercapnic challenge with neurobehavioral assessment of learning and memory, to investigate if decreased cerebrovascular responsiveness underlies impaired cognitive function in our mouse model of chronic r-mTBI. We demonstrate a profile of blunted hypercapnia-evoked CVR in the cortices of r-mTBI mice like that of human TBI, alongside sustained memory and learning impairment, without biochemical or immunohistopathological signs of cerebral vessel laminar or endothelium constituent loss. Transient decreased expression of alpha smooth muscle actin and platelet-derived growth factor receptor β, indicative of TCVI, is obvious only at the time of the most pronounced CVR deficit. These findings implicate CVR as a valid preclinical measure of TCVI, perhaps useful for developing therapies targeting TCVI after recurrent mild head trauma.
| S-EPMC8142124 | biostudies-literature
Project description:BackgroundTraumatic cerebrovascular injury (TCVI), a common consequence of traumatic brain injury (TBI), presents an attractive therapeutic target. Because phosphodiesterase-5 (PDE5) inhibitors potentiate the action of nitric oxide (NO) produced by endothelial cells, they are candidate therapies for TCVI. This study aims to: (1) measure cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and change in CVR after a single dose of sildenafil (ΔCVR) in chronic TBI compared to uninjured controls; (2) examine the safety and tolerability of 8-week sildenafil administration in chronic symptomatic moderate/severe TBI patients; and as an exploratory aim, (3) assess the effect of an 8-week course of sildenafil on chronic TBI symptoms.MethodsForty-six subjects (31 chronic TBI, 15 matched healthy volunteers) were enrolled. Baseline CBF and CVR before and after administration of sildenafil were measured. Symptomatic TBI subjects then completed an 8-week double-blind, placebo-controlled, crossover trial of sildenafil. A neuropsychological battery and neurobehavioral symptom questionnaires were administered at each study visit.ResultsAfter a single dose of sildenafil, TBI subjects showed a significant increase in global CVR compared to healthy controls (P < 0.001, d = 0.9). Post-sildenafil CVR maps showed near-normalization of CVR in many regions where baseline CVR was low, predominantly within areas without structural abnormalities. Sildenafil was well tolerated. Clinical Global Impression (CGI) scale showed a trend toward clinical improvement while on sildenafil treatment.FindingsSingle-dose sildenafil improves regional CVR deficits in chronic TBI patients. CVR and ΔCVR are potential predictive and pharmacodynamic biomarkers of PDE5 inhibitor therapy for TCVI. Sildenafil is a potential therapy for TCVI.
| S-EPMC5899908 | biostudies-literature
Project description:Cerebrovascular reactivity (CVR) reflects the capacity of blood vessels to dilate and is an important marker for brain vascular reserve. It may provide a useful addition to the traditional baseline blood flow measurement when assessing vascular factors in brain disorders. Blood-oxygenation-level-dependent MRI under CO(2) inhalation offers a non-invasive and quantitative means to estimate CVR in humans. In this study, we investigated several important methodological aspects of this technique with the goal of optimizing the experimental and data processing strategies for clinical use. Comparing 4 min of 5% CO(2) inhalation (less comfortable) to a 1 min inhalation (more comfortable) duration, it was found that the CVR values were 0.31 +/- 0.05%/mmHg (N = 11) and 0.31 +/- 0.08%/mmHg (N = 9), respectively, showing no significant differences between the two breathing paradigms. Therefore, the 1 min paradigm is recommended for future application studies for patient comfort and tolerability. Furthermore, we have found that end-tidal CO(2) recording was useful for accurate quantification of CVR because it provided both timing and amplitude information regarding the input function to the brain vascular system, which can be subject-dependent. Finally, we show that inter-subject variations in CVR are of physiologic origin and affect the whole brain in a similar fashion. Based on this, it is proposed that relative CVR (normalized against the CVR of the whole brain or a reference tissue) may be a more sensitive biomarker than absolute CVR in clinical applications as it minimizes inter-subject variations. With these technological optimizations, CVR mapping may become a useful method for studies of neurological and psychiatric diseases.
| S-EPMC2726998 | biostudies-other
Project description:Injury to the neurovasculature is a feature of brain injury and must be addressed to maximize opportunity for improvement. Cerebrovascular dysfunction, manifested by reduction in cerebral blood flow (CBF), is a key factor that worsens outcome after traumatic brain injury (TBI), most notably under conditions of hypotension. We report here that a new class of antioxidants, poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), which are nontoxic carbon particles, rapidly restore CBF in a mild TBI/hypotension/resuscitation rat model when administered during resuscitation--a clinically relevant time point. Along with restoration of CBF, there is a concomitant normalization of superoxide and nitric oxide levels. Given the role of poor CBF in determining outcome, this finding is of major importance for improving patient health under clinically relevant conditions during resuscitative care, and it has direct implications for the current TBI/hypotension war-fighter victims in the Afghanistan and Middle East theaters. The results also have relevancy in other related acute circumstances such as stroke and organ transplantation.
| S-EPMC3458163 | biostudies-literature
Project description:Post-concussion syndrome has been related to axonal damage in patients with mild traumatic brain injury, but little is known about the consequences of injury on brain networks. In the present study, our aim was to characterize changes in functional brain networks following mild traumatic brain injury in patients with post-concussion syndrome using resting-state functional magnetic resonance imaging data. We investigated 17 injured patients with persistent post-concussion syndrome (under the DSM-IV criteria) at 6 months post-injury compared with 38 mild traumatic brain injury patients with no post-concussion syndrome and 34 healthy controls. All patients underwent magnetic resonance imaging examinations at the subacute (1-3 weeks) and late (6 months) phases after injury. Group-wise differences in functional brain networks were analyzed using graph theory measures. Patterns of long-range functional networks alterations were found in all mild traumatic brain injury patients. Mild traumatic brain injury patients with post-concussion syndrome had greater alterations than patients without post-concussion syndrome. In patients with post-concussion syndrome, changes specifically affected temporal and thalamic regions predominantly at the subacute stage and frontal regions at the late phase. Our results suggest that the post-concussion syndrome is associated with specific abnormalities in functional brain network that may contribute to explain deficits typically observed in PCS patients.
| S-EPMC3675039 | biostudies-literature
Project description:Despite an apparently silent imaging, some patients with mild traumatic brain injury (TBI) experience cognitive dysfunctions, which may persist chronically. Brain changes responsible for these dysfunctions are unclear and commonly overlooked. It is thus crucial to increase our understanding of the mechanisms linking the initial event to the functional deficits, and to provide objective evidence of brain tissue alterations underpinning these deficits. We first set up a murine model of closed-head controlled cortical impact, which provoked persistent cognitive and sensorimotor deficits, despite no evidence of brain contusion or bleeding on MRI, thus recapitulating features of mild TBI. Molecular MRI for P-selectin, a key adhesion molecule, detected no sign of cerebrovascular inflammation after mild TBI, as confirmed by immunostainings. By contrast, in vivo PET imaging with the TSPO ligand [18F]DPA-714 demonstrated persisting signs of neuroinflammation in the ipsilateral cortex and hippocampus after mild TBI. Interestingly, immunohistochemical analyses confirmed these spatio-temporal profiles, showing a robust parenchymal astrogliosis and microgliosis, at least up to 3 weeks post-injury in both the cortex and hippocampus. In conclusion, we show that even one single mild TBI induces long-term behavioural deficits, associated with a persistent neuro-inflammatory status that can be detected by PET imaging.
| S-EPMC9670002 | biostudies-literature
Project description:BackgroundAccurate data on the types of healthcare people seek in the early stages following mild traumatic brain injury (mTBI) in Australia is lacking. We sought to investigate the types of healthcare people seek following mTBI, including seeking no care at all; ascertain the demographic, pre- and peri-injury factors, and symptom characteristics associated with the care that people access; and examine whether choice of care is associated with symptomatic recovery and quality of life.MethodsAn online retrospective survey of Australians aged 18 to 65 years who had experienced a self-reported 'concussion' (mTBI) within the previous 18 months. Types of healthcare accessed were investigated, as well as those who did not seek any care. Data were analysed using frequency and percentages, chi-squared tests and logistic regression models.ResultsA total of 201 respondents had experienced a self-reported 'concussion' but 21.4% of the respondents did not seek any care. Of the 183 respondents who sought healthcare, 52.5% attended a hospital Emergency Department, 41.0% attended a general practitioner and 6.6% accessed sports-based care. Compared to their counterparts, those who had a lower level of education (p = 0.001), had experienced previous mTBI (p = 0.045) or previous mental health issues (p = 0.009) were less likely to seek healthcare, whilst those who had experienced loss of consciousness (p = 0.014), anterograde (p = 0.044) or retrograde (p = 0.009) amnesia, and symptoms including drowsiness (p = 0.005), nausea (p = 0.040), and feeling slow (p = 0.031) were more likely to seek care. Those who did not seek care were more likely to recover within one month (AOR 4.90, 95%CI 1.51 - 15.89, p = 0.008), albeit the relatively large 95%CI warrants careful interpretation. Compared to seeking care, not seeking care was not found to be significantly associated with symptom resolution nor quality of life (p > 0.05).ConclusionsThis study provides unique insight into factors associated with healthcare utilisation in the early stages following mTBI, as well as outcomes associated with choice of care, including not seeking care. Delivering targeted community education on the signs and symptoms of mTBI, and the advantages of seeking care following injury is an important step forward in the management of this challenging condition.
| S-EPMC9254542 | biostudies-literature
Project description:Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2-5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8-18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2-5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory.
| S-EPMC5423316 | biostudies-literature