Magnetic resonance spectroscopy (MRS) is a non-invasive technique used to study metabolites in the brain. MRS findings in traumatic brain injury (TBI) and subconcussive hit literature have been ...mixed. The most common observation is a decrease in
-acetyl-aspartate (NAA), traditionally considered a marker of neuronal integrity. Other metabolites, however, such as creatine (Cr), choline (Cho), glutamate+glutamine (Glx) and
-inositol (mI) have shown inconsistent changes in these populations. The objective of this systematic review and meta-analysis was to synthesize MRS literature in brain injury and explore factors (biological factors such as brain region, injury severity, time since injury, demographics and technical methodological factors such as field strength, acquisition parameters, analysis approach) that may contribute to differential findings. One hundred and thirty-eight studies met inclusion criteria for the systematic review and of those, 62 NAA, 24 Cr, 49 Cho, 18 Glx, and 21 mI studies met inclusion criteria for meta-analysis. A random effects model was used for meta-analyses with brain region as a subgroup for each of the five metabolites studied. Meta-regression was used to examine the influence of potential moderators including injury severity, time since injury, age, sex, tissue composition, and methodological factors. In this analysis of 1428 unique brain-injured subjects and 1132 controls, the corpus callosum was identified as a brain region highly susceptible to metabolite alteration. NAA was consistently decreased in TBI of all severities, but not in subconcussive hits. Cho and mI were found to be increased in moderate-to-severe TBI but not in mild TBI. Glx and Cr were largely unaffected, but did show alterations in certain conditions.
The effects caused by differences in data acquisition can be substantial and may impact data interpretation in multi-site/scanner studies using magnetic resonance spectroscopy (MRS). Given the ...increasing use of multi-site studies, a better understanding of how to account for different scanners is needed. Using data from a concussion population, we compare ComBat harmonization with different statistical methods in controlling for site, vendor, and scanner as covariates to determine how to best control for multi-site data.
The data for the current study included 545 MRS datasets to measure tNAA, tCr, tCho, Glx, and mI to study the pediatric concussion acquired across five sites, six scanners, and two different MRI vendors. For each metabolite, the site and vendor were accounted for in seven different models of general linear models (GLM) or mixed-effects models while testing for group differences between the concussion and orthopedic injury. Models 1 and 2 controlled for vendor and site. Models 3 and 4 controlled for scanner. Models 5 and 6 controlled for site applied to data harmonized by vendor using ComBat. Model 7 controlled for scanner applied to data harmonized by scanner using ComBat. All the models controlled for age and sex as covariates.
Models 1 and 2, controlling for site and vendor, showed no significant group effect in any metabolites, but the vendor and site were significant factors in the GLM. Model 3, which included a scanner, showed a significant group effect for tNAA and tCho, and the scanner was a significant factor. Model 4, controlling for the scanner, did not show a group effect in the mixed model. The data harmonized by the vendor using ComBat (Models 5 and 6) had no significant group effect in both the GLM and mixed models. Lastly, the data harmonized by the scanner using ComBat (Model 7) showed no significant group effect. The individual site data suggest there were no group differences.
Using data from a large clinical concussion population, different analysis techniques to control for site, vendor, and scanner in MRS data yielded different results. The findings support the use of ComBat harmonization for clinical MRS data, as it removes the site and vendor effects.
Increasing rates of sport-related concussion (SRC) in youth impose a significant burden on public health systems and the lives of young athletes. Accurate prediction for those likely to develop ...persistent post-concussion symptomology (PPCS) using a fluid biomarker, reflecting both acute injury and recovery processes, would provide the opportunity for early intervention. Cortisol, a stress hormone released through the hypothalamic-pituitary-adrenal (HPA) axis following injury, may provide a missing physiological link to clinical recovery. This cohort study investigated the change in saliva cortisol following SRC and the association between cortisol and symptom burden in pediatric ice hockey players. Further, the association between cortisol levels and medical clearance to return to play was explored. In total, cortisol samples from 233 players were included; 165 athletes (23.6% female) provided pre-injury saliva and 68 athletes (19.1% female) provided post-SRC saliva samples for cortisol analysis. Quantile (median) regressions were used to compare cortisol between pre-injury and post-SRC groups, and the association between total symptoms (/22) and symptom severity scores (/132) reported on the Sport Concussion Assessment Tool (SCAT)3/SCAT5 and post-SRC cortisol (adjusting for age, sex, history of concussion, and time from injury to sample collection). Results demonstrated significantly lower saliva cortisol in post-SRC athletes compared with the pre-injury group (β = -0.62, 95% confidence interval CI; -1.08, -0.16,
= 0.009). Post-SRC cortisol was not significantly associated with the SCAT3/SCAT5 symptom totals or symptom severity scores; however, females were found to report more symptoms (β = 6.95, 95% CI 0.35, 13.55,
= 0.040) and greater symptom severity (β = 23.87, 95% CI 9.58, 38.15,
= 0.002) compared with males. Exploratory time-to-event analysis revealed a point estimate suggesting a potential association between low cortisol levels and days to medical clearance to return to play. Although preliminary, these findings suggest that the HPA axis may be dysregulated post-SRC. Further, our exploratory analysis and case presentation of post-injury outliers highlight the need to further research cortisol as a prognostic biomarker to inform individualized sex-specific care after SRC.
Climate warming is strongly altering the timing of season initiation and season length in the Arctic. Phenological activities are among the most sensitive plant responses to climate change and have ...important effects at all levels within the ecosystem. We tested the effects of two experimental treatments, extended growing season via snow removal and extended growing season combined with soil warming, on plant phenology in tussock tundra in Alaska from 1995 through 2003. We specifically monitored the responses of eight species, representing four growth forms: (i) graminoids (Carex bigellowii and Eriophorum vaginatum); (ii) evergreen shrubs (Ledum palustre, Cassiope tetragona, and Vaccinium vitis‐idaea); (iii) deciduous shrubs (Betula nana and Salix pulchra); and (iv) forbs (Polygonum bistorta). Our study answered three questions: (i) Do experimental treatments affect the timing of leaf bud break, flowering, and leaf senescence? (ii) Are responses to treatments species‐specific and growth form‐specific? and (iii) Which environmental factors best predict timing of phenophases? Treatment significantly affected the timing of all three phenophases, although the two experimental treatments did not differ from each other. While phenological events began earlier in the experimental plots relative to the controls, duration of phenophases did not increase. The evergreen shrub, Cassiope tetragona, did not respond to either experimental treatment. While the other species did respond to experimental treatments, the total active period for these species did not increase relative to the control. Air temperature was consistently the best predictor of phenology. Our results imply that some evergreen shrubs (i.e., C. tetragona) will not capitalize on earlier favorable growing conditions, putting them at a competitive disadvantage relative to phenotypically plastic deciduous shrubs. Our findings also suggest that an early onset of the growing season as a result of decreased snow cover will not necessarily result in greater tundra productivity.
Concussion is commonly characterized by a cascade of neurometabolic changes following injury. Magnetic Resonance Spectroscopy (MRS) can be used to quantify neurometabolites non-invasively. ...Longitudinal changes in neurometabolites have rarely been studied in pediatric concussion, and fewer studies consider symptoms. This study examines longitudinal changes of neurometabolites in pediatric concussion and associations between neurometabolites and symptom burden. Participants who presented with concussion or orthopedic injury (OI, comparison group) were recruited. The first timepoint for MRS data collection was at a mean of 12 days post-injury (n = 545). Participants were then randomized to 3 (n = 243) or 6 (n = 215) months for MRS follow-up. Parents completed symptom questionnaires to quantify somatic and cognitive symptoms at multiple timepoints following injury. There were no significant changes in neurometabolites over time in the concussion group and neurometabolite trajectories did not differ between asymptomatic concussion, symptomatic concussion, and OI groups. Cross-sectionally, Choline was significantly lower in those with persistent somatic symptoms compared to OI controls at 3 months post-injury. Lower Choline was also significantly associated with higher somatic symptoms. Although overall neurometabolites do not change over time, choline differences that appear at 3 months and is related to somatic symptoms.
Millions of children sustain a concussion annually. Concussion disrupts cellular signaling and neural pathways within the brain but the resulting metabolic disruptions are not well characterized. ...Magnetic resonance spectroscopy (MRS) can examine key brain metabolites (e.g., N‐acetyl Aspartate (tNAA), glutamate (Glx), creatine (tCr), choline (tCho), and myo‐Inositol (mI)) to better understand these disruptions. In this study, we used MRS to examine differences in brain metabolites between children and adolescents with concussion versus orthopedic injury. Children and adolescents with concussion (n = 361) or orthopedic injury (OI) (n = 184) aged 8 to 17 years were recruited from five emergency departments across Canada. MRS data were collected from the left dorsolateral prefrontal cortex (L‐DLPFC) using point resolved spectroscopy (PRESS) at 3 T at a mean of 12 days post‐injury (median 10 days post‐injury, range 2–33 days). Univariate analyses for each metabolite found no statistically significant metabolite differences between groups. Within each analysis, several covariates were statistically significant. Follow‐up analyses designed to account for possible confounding factors including age, site, scanner, vendor, time since injury, and tissue type (and interactions as appropriate) did not find any metabolite group differences. In the largest sample of pediatric concussion studied with MRS to date, we found no metabolite differences between concussion and OI groups in the L‐DLPFC. We suggest that at 2 weeks post‐injury in a general pediatric concussion population, brain metabolites in the L‐DLPFC are not specifically affected by brain injury.
In the largest pediatric concussion in MRS data set to date, we found no differences in brain metabolites between concussion and orthopedic injury in the first two weeks of injury in the L‐DLPFC. This indicates that in a general pediatric concussion population, brain metabolites are either unaffected or recovered.
BACKGROUND AND PURPOSE Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing ...PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3‐cyclopentyloxy‐4‐methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR‐7b, on memory performance, nausea, hippocampal cAMP and amyloid‐β (Aβ) levels.
EXPERIMENTAL APPROACH To measure memory performance, we performed object recognition tests on rats and mice treated with GEBR‐7b or rolipram. The emetic potential of the drug, again compared with rolipram, was evaluated in rats using the taste reactivity test and in mice using the xylazine/ketamine anaesthesia test. Extracellular hippocampal cAMP was evaluated by intracerebral microdialysis in freely moving rats. Levels of soluble Aβ peptides were measured in hippocampal tissues and cultured N2a cells by elisa.
KEY RESULTS GEBR‐7b increased hippocampal cAMP, did not influence Aβ levels and improved spatial, as well as object memory performance in the object recognition tests. The effect of GEBR‐7b on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents.
CONCLUSION AND IMPLICATIONS Our results demonstrate that GEBR‐7b enhances memory functions at doses that do not cause emesis‐like behaviour in rodents, thus offering a promising pharmacological perspective for the treatment of memory impairment.
•Regional Glu reduction found in adults with persistent post-concussive symptoms.•Higher GSH associated with greater functional impact of headache.•Enhanced GSH synthesis and energy shortage may ...contribute to Glu deficit.•Higher GABA linked to history of previous mTBI.
Persistent post-concussive symptoms (PPCS) are debilitating and endure beyond the usual recovery period after mild traumatic brain injury (mTBI). Altered neurotransmission, impaired energy metabolism and oxidative stress have been examined acutely post-injury but have not been explored extensively in those with persistent symptoms. Specifically, the antioxidant glutathione (GSH) and the excitatory and inhibitory metabolites, glutamate (Glu) and γ-aminobutyric acid (GABA), are seldom studied together in the clinical mTBI literature. While Glu can be measured using conventional magnetic resonance spectroscopy (MRS) methods at 3 Tesla, GABA and GSH require the use of advanced MRS methods. Here, we used the recently established Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) to simultaneously measure GSH and GABA and short-echo time point resolved spectroscopy (PRESS) to measure Glu to gain new insight into the pathophysiology of PPCS. Twenty-nine adults with PPCS (mean age: 45.69 years, s.d.: 10.73, 22 females, 7 males) and 29 age- and sex-matched controls (mean age: 43.69 years, s.d.: 11.00) completed magnetic resonance spectroscopy scans with voxels placed in the anterior cingulate and right sensorimotor cortex. Relative to controls, anterior cingulate Glu was significantly reduced in PPCS. Higher anterior cingulate GABA was significantly associated with a higher number of lifetime mTBIs, suggesting GABA may be upregulated with repeated incidence of mTBI. Furthermore, GSH in both regions of interest was positively associated with symptoms of sleepiness and headache burden. Collectively, our findings suggest that the antioxidant defense system is active in participants with PPCS, however this may be at the expense of other glutamatergic functions such as cortical excitation and energy metabolism.
Background and Purpose
To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)‐induced conditioned gaping reactions (nausea‐induced ...behaviour) in rats and to determine if these low systemic doses of CBDA (5–0.1 μg·kg−1) relative to those of CBD could potentiate the anti‐nausea effects of the classic 5‐hydroxytryptamine 3 (5‐HT3) receptor antagonist, ondansetron (OND).
Experimental Approach
We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl‐paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea‐induced conditioned gaping by OND were then determined.
Key Results
CBDA (at doses as low as 0.5 μg·kg−1) suppressed nausea‐induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg−1) alone reduced nausea‐induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg−1) there was an enhancement in the suppression of LiCl‐induced conditioned gaping.
Conclusions and Implications
CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti‐nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients.
Following one or more chemotherapy treatments, many patients report that they experience anticipatory nausea. This phase of nausea has been interpreted as a classically conditioned response where a ...conditional association develops between the contextual clinic cues and the nausea and/or vomiting that developed following treatment. Although rats do not vomit, they display a distinctive gaping reaction when exposed a flavored solution previously paired with a toxin. Here we report that, even in the absence of a flavored solution, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium (Experiment 1 with a distinctive odor and Experiment 3 without a distinctive odor), a low dose of lithium (Experiment 2) or provocative vestibular stimulation (Experiment 2). These results suggest that the conditioned gaping reaction in rats is selectively elicited by nausea-paired contextual stimuli, as well as flavors. This rat model of anticipatory nausea may serve as a valuable preclinical tool to evaluate the effectiveness of anti-nausea treatments and the side effect of nausea produced by newly developed pharmaceutical compounds intended for other clinical treatments.
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