SCAT5 baseline values, test-retest reliability, and reliable change metrics in high school athletes.

OBJECTIVE: In the United States, more than 1 million sport-related concussions afflict children annually, with many cases undetected or unreported. The Sport Concussion Assessment Tool (SCAT) is widely used to detect concussions in high school, collegiate, and professional sports. The objective of this study was to establish baseline values for the SCAT version 5 (SCAT5) in high school athletes. METHODS: Baseline SCAT5 evaluations were conducted in students (ages 14-19 years) from 19 high schools in central Illinois who were participating in various school-sponsored sports. The SCAT5 evaluations were retrospectively extracted from the electronic medical record system for analysis. Statistical analyses included the Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables, considering significance at p < 0.05. Test-retest reliability at < 6 months, 10-14 months, and 16-20 months was computed using intraclass correlation and Spearman's rho (ρ). Reliable change indices are provided using the Iverson formula. RESULTS: A total of 2833 unique athletes were included, and the average age was 15.5 ± 1.14 (SD) years. There were 721 female (25.5%) and 2112 male (74.5%) athletes. Students ≥ 15 years old had more prior concussions (p < 0.001), and male athletes were more frequently hospitalized for head injury (p = 0.013). Female athletes exhibited a significantly higher prevalence of mood disorders (14.7% vs 4.6%, p < 0.001), whereas attention-deficit/hyperactivity disorder was more common in male athletes (5.2% vs 13.2%, p < 0.001). Symptom number and severity were significantly greater in female athletes (3.17 ± 4.39 vs 2.08 ± 3.49, p < 0.001; 5.47 ± 9.21 vs 3.52 ± 7.26, p < 0.001, respectively), with mood-related symptoms representing the largest differences. Female athletes and students ≥ 15 years old performed better on most cognitive assessments. Female athletes and students < 15 years old performed better on the modified Balance Error Scoring System (p < 0.001). Test-retest reliability was poor to moderate for most assessment components. Reliable change index cutoff values differed slightly by sex, with female athletes often having a greater cutoff value. CONCLUSIONS: This study underscores the variability of SCAT5 baseline values influenced by age, sex, and medical history among adolescent athletes. It provides a robust dataset, delineating baseline values stratified by sex and age within this demographic. Additionally, the results provide enhanced guidance to clinicians for interpretation of change and reliability of baselines.

Pharmacological inhibition of STriatal-Enriched protein tyrosine Phosphatase by TC-2153 reduces hippocampal excitability and seizure propensity.

OBJECTIVE: STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific tyrosine phosphatase. Membrane-bound STEP61 is the only isoform expressed in hippocampus and cortex. Genetic deletion of STEP enhances excitatory synaptic currents and long-term potentiation in the hippocampus. However, whether STEP61 affects seizure susceptibility is unclear. Here we investigated the effects of STEP inhibitor TC-2153 on seizure propensity in a murine model displaying kainic acid (KA)-induced status epilepticus and its effect on hippocampal excitability. METHODS: Adult male and female C57BL/6J mice received intraperitoneal injection of either vehicle (2.8% dimethylsulfoxide [DMSO] in saline) or TC-2153 (10 mg/kg) and then either saline or KA (30 mg/kg) 3 h later before being monitored for behavioral seizures. A subset of female mice was ovariectomized (OVX). Acute hippocampal slices from Thy1-GCaMP6s mice were treated with either DMSO or TC-2153 (10 µM) for 1 h, and then incubated in artificial cerebrospinal fluid (ACSF) and potassium chloride (15 mM) for 2 min prior to live calcium imaging. Pyramidal neurons in dissociated rat hippocampal culture (DIV 8-10) were pre-treated with DMSO or TC-2153 (10 µM) for 1 h before whole-cell patch-clamp recording. RESULTS: TC-2153 treatment significantly reduced KA-induced seizure severity, with greater trend seen in female mice. OVX abolished this TC-2153-induced decrease in seizure severity in female mice. TC-2153 application significantly decreased overall excitability of acute hippocampal slices from both sexes. Surprisingly, TC-2153 treatment hyperpolarized resting membrane potential and decreased firing rate, sag voltage, and hyperpolarization-induced current (Ih ) of cultured hippocampal pyramidal neurons. SIGNIFICANCE: This study is the first to demonstrate that pharmacological inhibition of STEP with TC-2153 decreases seizure severity and hippocampal activity in both sexes, and dampens hippocampal neuronal excitability and Ih . We propose that the antiseizure effects of TC-2153 are mediated by its unexpected action on suppressing neuronal intrinsic excitability.

Standard-space atlas of the viscoelastic properties of the human brain.

Standard anatomical atlases are common in neuroimaging because they facilitate data analyses and comparisons across subjects and studies. The purpose of this study was to develop a standardized human brain atlas based on the physical mechanical properties (i.e., tissue viscoelasticity) of brain tissue using magnetic resonance elastography (MRE). MRE is a phase contrast-based MRI method that quantifies tissue viscoelasticity noninvasively and in vivo thus providing a macroscopic representation of the microstructural constituents of soft biological tissue. The development of standardized brain MRE atlases are therefore beneficial for comparing neural tissue integrity across populations. Data from a large number of healthy, young adults from multiple studies collected using common MRE acquisition and analysis protocols were assembled (N = 134; 78F/ 56 M; 18-35 years). Nonlinear image registration methods were applied to normalize viscoelastic property maps (shear stiffness, µ, and damping ratio, ξ) to the MNI152 standard structural template within the spatial coordinates of the ICBM-152. We find that average MRE brain templates contain emerging and symmetrized anatomical detail. Leveraging the substantial amount of data assembled, we illustrate that subcortical gray matter structures, white matter tracts, and regions of the cerebral cortex exhibit differing mechanical characteristics. Moreover, we report sex differences in viscoelasticity for specific neuroanatomical structures, which has implications for understanding patterns of individual differences in health and disease. These atlases provide reference values for clinical investigations as well as novel biophysical signatures of neuroanatomy. The templates are made openly available (github.com/mechneurolab/mre134) to foster collaboration across research institutions and to support robust cross-center comparisons.

Viscoelasticity of subcortical gray matter structures.

Viscoelastic mechanical properties of the brain assessed with magnetic resonance elastography (MRE) are sensitive measures of microstructural tissue health in neurodegenerative conditions. Recent efforts have targeted measurements localized to specific neuroanatomical regions differentially affected in disease. In this work, we present a method for measuring the viscoelasticity in subcortical gray matter (SGM) structures, including the amygdala, hippocampus, caudate, putamen, pallidum, and thalamus. The method is based on incorporating high spatial resolution MRE imaging (1.6 mm isotropic voxels) with a mechanical inversion scheme designed to improve local measures in pre-defined regions (soft prior regularization [SPR]). We find that in 21 healthy, young volunteers SGM structures differ from each other in viscoelasticity, quantified as the shear stiffness and damping ratio, but also differ from the global viscoelasticity of the cerebrum. Through repeated examinations on a single volunteer, we estimate the uncertainty to be between 3 and 7% for each SGM measure. Furthermore, we demonstrate that the use of specific methodological considerations-higher spatial resolution and SPR-both decrease uncertainty and increase sensitivity of the SGM measures. The proposed method allows for reliable MRE measures of SGM viscoelasticity for future studies of neurodegenerative conditions. Hum Brain Mapp 37:4221-4233, 2016. © 2016 Wiley Periodicals, Inc.

Multi-Parametric Molecular Imaging of the Brain Using Optimized Multi-TE Subspace MRSI.

OBJECTIVE: To develop a novel multi-TE MR spectroscopic imaging (MRSI) approach to enable label-free, simultaneous, high-resolution mapping of several molecules and their biophysical parameters in the brain. METHODS: The proposed method uniquely integrated an augmented molecular-component-specific subspace model for multi-TE 1H-MRSI signals, an estimation-theoretic experiment optimization (nonuniform TE selection) for molecule separation and parameter estimation, a physics-driven subspace learning strategy for spatiospectral reconstruction and molecular quantification, and a new accelerated multi-TE MRSI acquisition for generating high-resolution data in clinically relevant times. Numerical studies, phantom and in vivo experiments were conducted to validate the optimized experiment design and demonstrate the imaging capability offered by the proposed method. RESULTS: The proposed TE optimization improved estimation of metabolites, neurotransmitters and their T2's over conventional TE choices, e.g., reducing variances of neurotransmitter concentration by  âˆ¼  40% and metabolite T2 by  âˆ¼  60%. Simultaneous metabolite and neurotransmitter mapping of the brain can be achieved at a nominal resolution of 3.4 × 3.4 × 6.4 mm 3. High-resolution, 3D metabolite T2 mapping was made possible for the first time. The translational potential of the proposed method was demonstrated by mapping biochemical abnormality in a post-traumatic epilepsy (PTE) patient. CONCLUSION: The feasibility for high-resolution mapping of metabolites/neurotransmitters and metabolite T2's within clinically relevant time was demonstrated. We expect our method to offer richer information for revealing and understanding metabolic alterations in neurological diseases. SIGNIFICANCE: A novel multi-TE MRSI approach was presented that enhanced the technological capability of multi-parametric molecular imaging of the brain. The proposed method presents new technology development and application opportunities for providing richer molecular level information to uncover and comprehend metabolic changes relevant in various neurological applications.

Giant cell arteritis causing symmetric bilateral posterior circulation infarcts.

An 82-year-old woman presented with bilateral, symmetric posterior circulation infarctions secondary to giant cell arteritis (GCA). Her atypical clinical presentation included a lack of headache and fever, but she exhibited signs of systemic illness including generalized weakness, cachexia, apathy, and anemia. Laboratory testing revealed a markedly elevated erythrocyte sedimentation rate, but only a borderline elevated C-reactive protein. Head and neck vascular imaging demonstrated a pattern of vertebral arterial narrowing consistent with GCA-a diagnosis confirmed by temporal artery biopsy. Her unusual symptomatic, laboratory, and imaging presentation highlights the importance of considering GCA in the differential diagnosis of unusual bilateral stroke syndromes, where early treatment decreases morbid outcomes.

Refractory seizures secondary to radiation-induced focal cortical dysplasia/neuronal gigantism: illustrative case.

BACKGROUND: Focal cortical dysplasia is a structural cause of drug-resistant epilepsy commonly identified in childhood. In rare cases, radiation-induced injury has led to radiation-induced cortical dysplasia, also known as "focal neuronal gigantism." OBSERVATIONS: The authors present a 53-year-old woman with recurrent status epilepticus events after she had radiation therapy and surgery for a left frontal meningioma several years prior. Imaging revealed findings consistent with radiation necrosis and possible recurrence. The patient's status epilepticus events required escalating therapies to manage. Scalp electroencephalography indicated that the seizure's origin was in the left hemisphere. A craniotomy was performed to remove the left frontal lesion, and histopathology was consistent with radiation-induced focal cortical dysplasia/neuronal gigantism. The patient's seizures ceased following the surgery, and she remains on maintenance antiseizure medications. LESSONS: Radiation-induced focal cortical dysplasia/neuronal gigantism is an incredibly rare complication of therapy. However, it warrants consideration in the context of radiation necrosis and intractable epilepsy.

PROVE: Retrospective, non-interventional, Phase IV study of perampanel in real-world clinical care of patients with epilepsy.

OBJECTIVE: To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care. METHODS: PROVE was a retrospective, non-interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary efficacy endpoints included median percent changes in seizure frequency per 28 days from baseline, seizure-freedom rate, and overall investigator impression of seizure effect. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs). Efficacy and safety were also assessed according to baseline use of enzyme-inducing antiseizure medications (EIASMs). RESULTS: Overall, 1703 patients were enrolled and included in the Safety Analysis Set (SAS; ≥1 baseline EIASMs, n = 358 [21.0%]; no baseline EIASMs, n = 1345 [79.0%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 17.4 (15.7) months; mean (SD) daily perampanel dose was 5.6 (2.7) mg. The most frequent perampanel titration intervals were weekly (23.4%) and every 2 weeks (24.7%). Across the SAS, 24-month retention rate was 48.1% (n = 501/1042). Based on overall investigator impression at the end of treatment, 51.9%, 35.8%, and 12.3% of patients in the SAS experienced improvement, no change, or worsening of seizures, respectively. TEAEs occurred in 704 (41.3%) patients; 79 (4.6%) had serious TEAEs. The most common TEAE was dizziness (7.3%). There was some variation in efficacy according to EIASM use, while retention rates and safety were generally consistent. SIGNIFICANCE: In this final analysis of >1700 patients with epilepsy receiving perampanel in routine clinical care, favorable retention and sustained efficacy were demonstrated for ≥12 months.

Dynamic role of postsynaptic caspase-3 and BIRC4 in zebra finch song-response habituation.

Activation of the protease caspase-3 is commonly thought to cause apoptotic cell death. Here, we show that caspase-3 activity is regulated at postsynaptic sites in brain following stimuli associated with memory (neural activation and subsequent response habituation) instead of cell death. In the zebra finch auditory forebrain, the concentration of caspase-3 active sites increases briefly within minutes after exposure to tape-recorded birdsong. With confocal and immunoelectron microscopy, we localize the activated enzyme to dendritic spines. The activated caspase-3 protein is present even in unstimulated brain but bound to an endogenous inhibitor, BIRC4 (xIAP), suggesting a mechanism for rapid release and sequestering at specific synaptic sites. Caspase-3 activity is necessary to consolidate a persistent physiological trace of the song stimulus, as demonstrated using pharmacological interference and the zenk gene habituation assay. Thus, the brain appears to have adapted a core component of cell death machinery to serve a unique role in learning and memory.

Hippocampal stiffness in mesial temporal lobe epilepsy measured with MR elastography: Preliminary comparison with healthy participants.

Mesial temporal lobe epilepsy (MTLE) is the most common form of refractory epilepsy. Common imaging biomarkers are often not sensitive enough to identify MTLE sufficiently early to facilitate the greatest benefit from surgical or pharmacological intervention. The objective of this work is to establish hippocampal stiffness measured with magnetic resonance elastography (MRE) as a biomarker for MTLE; we hypothesized that the epileptogenic hippocampus in MTLE is stiffer than the non-epileptogenic hippocampus. MRE was used to measure hippocampal stiffness in a group of patients with unilateral MTLE (n = 12) and a group of healthy comparison participants (n = 13). We calculated the ratio of hippocampal stiffness ipsilateral to epileptogenesis to the contralateral side for both groups. We found a higher hippocampal stiffness ratio in patients with MTLE compared with healthy participants (1.14 v. 0.99; p = 0.004), and that stiffness ratio differentiated MTLE from control groups effectively (AUC = 0.85). Hippocampal stiffness ratio, when added to volume ratio, an established MTLE biomarker, significantly improved the ability to differentiate the two groups (p = 0.038). Stiffness measured with MRE is sensitive to hippocampal pathology in MTLE and the addition of MRE to neuroimaging assessments may improve detection and characterization of the disease.