Amy K. Wagner

Concussion in Sports: Postconcussive Activity Levels, Symptoms, and Neurocognitive Performance

CONTEXT Evidence suggests that athletes engaging in high-intensity activities after concussion have more difficulties with cognitive recovery. OBJECTIVE To examine the role postinjury activity level plays in postconcussive symptoms and performance on neurocognitive tests in a population of student-athletes. DESIGN Retrospective cohort study with repeated measures of neurocognitive performance and symptom reporting. SETTING University-based sports concussion clinic. PATIENTS OR OTHER PARTICIPANTS Ninety-five student-athletes (80 males, 15 females: age = 15.88 +/- 1.35 years) were retrospectively assigned to 1 of 5 groups based on a postinjury activity intensity scale. MAIN OUTCOME MEASURE(S) We employed a regression analysis for repeated measures to evaluate the relationship of activity intensity to symptoms and neurocognitive outcome up to 33 days after concussion. Postconcussion symptom scores and neurocognitive (verbal memory, visual memory, visual motor speed, and reaction time) scores served as the primary outcome measures. RESULTS Level of exertion was significantly related to all outcome variables (P < .02 for all comparisons). With multivariate analysis, activity intensity remained significant with respect to visual memory (P = .003) and reaction time (P < .001). CONCLUSIONS Activity level after concussion affected symptoms and neurocognitive recovery. Athletes engaging in high levels of activity after concussion demonstrated worse neurocognitive performance. For these tasks, those engaging in moderate levels of activity demonstrated the best performance.

Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making.

Purpose of reviewEmerging data suggest that biomarkers of brain injury have potential utility as diagnostic, prognostic, and therapeutic adjuncts in the setting of traumatic and ischemic brain injury. Two approaches are being used, namely, assessing markers of structural damage and quantifying mediators of the cellular, biochemical, or molecular cascades in secondary injury or repair. Novel proteomic, multiplex, and lipidomic methods are also being applied. Recent findingsBiochemical markers of neuronal, glial, and axonal damage such as neuron-specific enolase, S100B, and myelin basic protein, respectively, are readily detectable in biological samples such as serum or cerebrospinal fluid and are being studied in patients with ischemic and traumatic brain injury. In addition, a number of studies have demonstrated that novel tools to assess simultaneously multiple biomarkers can provide unique insight such as details on specific molecular participants in cell death cascades, inflammation, or oxidative stress. SummaryMultifaceted cellular, biochemical, and molecular monitoring of proteins and lipids is logical as an adjunct to guiding therapies and improving outcomes in traumatic and ischemic brain injury and we appear to be on the verge of a breakthrough with the use of these markers as diagnostic, prognostic, and monitoring adjuncts, in neurointensive care.

Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis.

Traumatic brain injury (TBI) represents a significant cause of death and disability in industrialized countries. Of particular importance to patients the chronic effect that TBI has on cognitive function. Therapeutic strategies have been difficult to evaluate because of the complexity of injuries and variety of patient presentations within a TBI population. However, pharmacotherapies targeting dopamine (DA) have consistently shown benefits in attention, behavioral outcome, executive function, and memory. Still it remains unclear what aspect of TBI pathology is targeted by DA therapies and what time-course of treatment is most beneficial for patient outcomes. Fortunately, ongoing research in animal models has begun to elucidate the pathophysiology of DA alterations after TBI. The purpose of this review is to discuss clinical and experimental research examining DAergic therapies after TBI, which will in turn elucidate the importance of DA for cognitive function/dysfunction after TBI as well as highlight the areas that require further study.

Relationships between cerebrospinal fluid markers of excitotoxicity, ischemia, and oxidative damage after severe TBI: The impact of gender, age, and hypothermia

Excitotoxicity and ischemia can result in oxidative stress after TBI. Female sex hormones are hypothesized to be neuroprotective after TBI by affecting multiple mechanisms of secondary injury, including oxidative damage, excitotoxicity and ischemia. Ca2+ mediated oxidative stress increases with age, and hypothermia is known to attenuate secondary injury. The purpose of this study was to determine if the relationship between cerebral spinal fluid (CSF) markers of excitotoxicity, ischemia, and oxidative damage are gender and age specific and the role of hypothermia in affecting these relationships. F2-isoprostane, glutamate, and lactate/pyruvate, were assessed in CSF from adults (n = 68) with severe TBI (Glasgow coma scale [GCS] score </= 8) using ventricular CSF samples (n = 207) collected on days 1, 2, and 3 post-injury. F2-isoprostane/glutamate and F2-isoprostane/lactate/pyruvate ratios were determined for patients at each time point. Six-month Glasgow Outcome Scores (GOS) were also obtained. Repeated measures multivariate analysis showed a significant gender effect (p < 0.002) and gender*time interaction (p = 0.012) on F2-isoprostane/glutamate ratios. A significant gender effect (p = 0.050) and gender*time interaction (p = 0.049) was also seen with F2-isoprostane/lactate/pyruvate. Hypothermia (p = 0.001) and age (p = 0.026) significantly increased F2-isoprostane/glutamate ratios. Females had a significant inverse relationship between day 1 F2-isoprostane/glutamate ratios and GOS scores (r =- 0.43; p = 0.05) as well as day 1 F2-isoprostane/lactate/pyruvate ratio (r =- 0.46; p = 0.04) and GOS scores. These results indicate that females have smaller oxidative damage loads than males for a given excitotoxic or ischemic insult and female gonadal hormones may play a role in mediating this neuroprotective effect. These results also suggest that susceptibility to glutamate mediated oxidative damage increases with age and that hypothermia differentially attenuates CSF glutamate versus F2-isoprostane production. Gender and age differences in TBI pathophysiology should be considered when conducting clinical trials in TBI.

Controlled cortical impact injury affects dopaminergic transmission in the rat striatum

The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post‐TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d‐amphetamine‐induced rotational behavior. Adult male Sprague–Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine‐induced rotational behavior was assessed 10 days post‐CCI. Fourteen days post‐CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in Vmax (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury‐related changes in vesicular monoamine transporter or D2 receptor expression (DRD2) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.

Acute treatment with the 5-HT1A receptor agonist 8-OH-DPAT and chronic environmental enrichment confer neurobehavioral benefit after experimental brain trauma

Acute treatment with the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or chronic environmental enrichment (EE) hasten behavioral recovery after experimental traumatic brain injury (TBI). The aim of this study was to determine if combining these interventions would confer additional benefit. Anesthetized adult male rats received either a cortical impact or sham injury followed 15min later by a single intraperitoneal injection of 8-OH-DPAT (0.5mg/kg) or saline vehicle (1.0mL/kg) and then randomly assigned to either enriched or standard (STD) housing. Behavioral assessments were conducted utilizing established motor and cognitive tests on post-injury days 1-5 and 14-18, respectively. Hippocampal CA(1)/CA(3) neurons were quantified at 3 weeks. Both 8-OH-DPAT and EE attenuated CA(3) cell loss. 8-OH-DPAT enhanced spatial learning in a Morris water maze (MWM) as revealed by differences between the TBI+8-OH-DPAT+STD and TBI+VEHICLE+STD groups (P=0.0014). EE improved motor function as demonstrated by reduced time to traverse an elevated narrow beam in both the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups versus the TBI+VEHICLE+STD group (P=0.0007 and 0.0016, respectively). EE also facilitated MWM learning as evidenced by both the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups locating the escape platform quicker than the TBI+VEHICLE+STD group (Ps<0.0001). MWM differences were also observed between the TBI+8-OH-DPAT+EE and TBI+8-OH-DPAT+STD groups (P=0.0004) suggesting that EE enhanced the effect of 8-OH-DPAT. However, there was no difference between the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups. These data replicate previous results from our laboratory showing that both a single systemic administration of 8-OH-DPAT and EE improve recovery after TBI and extend those findings by elucidating that the combination of treatments in this particular paradigm did not confer additional benefit. One explanation for the lack of an additive effect is that EE is a very effective treatment and thus there is very little room for 8-OH-DPAT to confer additional statistically significant improvement.

Evaluation of estrous cycle stage and gender on behavioral outcome after experimental traumatic brain injury.

Female sex hormones are acutely neuroprotective in experimental models of traumatic brain injury (TBI). Because hormonal profiles are known to vary with estrous cycle stage, the purpose of this study was to evaluate how pre-injury estrous stage affects motor and cognitive performance after experimental TBI. We also sought to compare post-injury behavioral performance in males vs. females. Under anesthesia, male (n=18) and female (n=35) Sprague-Dawley rats underwent either controlled cortical impact (CCI) injury (2.7 mm; 4 m/s) or sham operations. Females were grouped according to estrous stage (proestrous or non-proestrous) at the time of surgery. Motor function was assessed pre-injury and for the first 5 days after surgery using beam balance and walking tasks. Spatial memory was assessed beginning 14 days post-injury utilizing the Morris water maze (MWM) task. No significant differences were found on any task between injured females regardless of estrous cycle stage. Females performed significantly better than males on both motor tasks, but gender did not influence MWM performance. Mixed effects multivariate analysis corroborated these results by showing that pre-injury serum hormone levels had little affect on behavioral performance. The results suggest that the presence of endogenous circulating hormones, rather than hormonal status at time of injury, may confer early neuroprotection in females after TBI. The impact of early neuroprotection on later behavioral outcome and the anatomic structural specificity of hormonal neuroprotection require further study.

Intervention with environmental enrichment after experimental brain trauma enhances cognitive recovery in male but not female rats

Environmental enrichment (EE) has been repeatedly shown to affect multiple aspects of brain function, and is known to enhance cognitive recovery after experimental traumatic brain injury (TBI) in males. However, the impact of gender on how EE affects behavioral performance after experimental TBI have not been studied. Male and normally cycling female Sprague-Dawley rats underwent controlled cortical impact injury or sham surgery and then were placed in either a standard or enriched housing environment. Motor function was assessed both pre-injury and for the first 5 days after injury. Spatial memory was assessed beginning 14 days after injury. Placement in an EE after TBI enhanced spatial memory performance in male but not female rats. EE did not impact motor performance in this setting. These findings have gender specific implications for how to approach and evaluate treatments and interventions after TBI.

Use of injury severity variables in determining disability and community integration after traumatic brain injury.

BACKGROUND Long-term outcome is important in managing traumatic brain injury (TBI), an epidemic in the United States. Many injury severity variables have been shown to predict major morbidity and mortality. Less is known about their relationship with specific long-term outcomes. METHODS Glasgow Coma Scale, Revised Trauma Score, Injury Severity Score, and Trauma and Injury Severity Score, along with other demographic and premorbid values, were obtained for 378 consecutive patients hospitalized after TBI at a Level I trauma center between September 1997 and May 1998. Of this cohort, 120 patients were contacted for 1-year follow-up assessment with the Disability Rating Scale, Community Integration Questionnaire, and employment data. RESULTS Univariate analyses showed these to be significant single predictors of 1-year outcome. Multivariate analyses revealed that the Revised Trauma Score and Glasgow Coma Scale had significant additive value in predicting injury variables Disability Rating Scale scores when combined with other demographic and premorbid variables studied. Predictive models of 1-year outcome were developed. CONCLUSION Injury severity variables are significant single outcome predictors and, in combination with premorbid and demographic variables, help predict long-term disability and community integration for individuals hospitalized with TBI.

Acute Serum Hormone Levels: Characterization and Prognosis after Severe Traumatic Brain Injury

Experimental traumatic brain injury (TBI) studies report the neuroprotective effects of female sex steroids on multiple mechanisms of injury, with the clinical assumption that women have hormonally mediated neuroprotection because of the endogenous presence of these hormones. Other literature indicates that testosterone may exacerbate injury. Further, stress hormone abnormalities that accompany critical illness may both amplify or blunt sex steroid levels. To better understand the role of sex steroid exposure in mediating TBI, we 1) characterized temporal profiles of serum gonadal and stress hormones in a population with severe TBI during the acute phases of their injury; and 2) used a biological systems approach to evaluate these hormones as biomarkers predicting global outcome. The study population was 117 adults (28 women; 89 men) with severe TBI. Serum samples (n=536) were collected for 7 days post-TBI for cortisol, progesterone, testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Hormone data were linked with clinical data, including acute care mortality and Glasgow Outcome Scale (GOS) scores at 6 months. Hormone levels after TBI were compared to those in healthy controls (n=14). Group based trajectory analysis (TRAJ) was used to develop temporal hormone profiles that delineate distinct subpopulations in the cohort. Structural equations models were used to determine inter-relationships between hormones and outcomes within a multivariate model. Compared to controls, acute serum hormone levels were significantly altered after severe TBI. Changes in the post-TBI adrenal response and peripheral aromatization influenced hormone TRAJ profiles and contributed to the abnormalities, including increased estradiol in men and increased testosterone in women. In addition to older age and greater injury severity, increased estradiol and testosterone levels over time were associated with increased mortality and worse global outcome for both men and women. These findings represent a paradigm shift when thinking about the role of sex steroids in neuroprotection clinically after TBI.