Olanzapine Liquisolid Tablets Using Kolliphor EL with Improved Flowability and Bioavailability: In vitro and In vivo Characterization.

Objectives: Liquisolid tablets are an innovative approach to enhance the dissolution rate and, thereby, the bioavailability of therapeutic agents with poor aqueous solubility. Materials and Methods: The objective of the current research was to compare the bioavailability of the optimized formulation of the olanzapine (OLZ) liquisolid tablet with that of the marketed tablet (MT) by conducting pharmacokinetic and behavioral assessment studies. Ten formulations were designed using Kolliphor EL as a non-volatile solvent, and the respective tablets were prepared by the direct compression method. Results: Pre-compression studies of powders of all the formulations showed good/excellent flow properties and compressibility. The drug release profiles of liquisolid tablets were determined and compared with those of MT. Based on the in vitro results, K250 was considered as an optimized formulation and selected for further in vivo studies. AUC0-∞ value of K250 formulation was found to be 357.2 ± 35.5 ng.h.mL-1, which was higher than that of the MT (258.4 ± 29.9 ng.h.mL-1). The reduction in locomotor activity was enhanced remarkably in K250 compared with MTs at p < 0.05. The time periods taken to fall in the rotarod test were approximately equal in the experimental groups, which indicated the absence of extrapyramidal side effects. There was a remarkable decrease in the number of boxes covered in the open field test. Conclusion: Kolliphor EL was found to be a potential non-volatile solvent that can be used to produce liquisolid tablets of OLZ with improved flow, compressibility, dissolution, and bioavailability.

Neurobehavioral Abnormalities in Offspring of Young Adult Male Rats With a History of Traumatic Brain Injury.

Children of parents with traumatic brain injury (TBI) are more likely to develop psychiatric disorders. This association is usually attributed to TBI-induced changes in parents' personality and families' social environment. We tested the hypothesis that offspring of young adult male rats with TBI develop neurodevelopmental abnormalities in the absence of direct social contact with sires. Male Sprague-Dawley rats (F0 generation) in the TBI group underwent moderate TBI via a midline fluid percussion injury that involved craniectomy under sevoflurane (SEVO) anesthesia for 40 min on post-natal Day 60 (P60), while F0 rats in the control group were placed in a new cage, one per cage, for the equivalent time duration. A subset of F0 rats was sacrificed on P66 to assess acute changes in hypothalamic-pituitary-adrenal (HPA) axis and inflammation markers. The remaining F0 males were mated with naive females on P90 to generate offspring (F1 generation). The F0 males and F1 males and females were sequentially evaluated in the elevated plus maze, for pre-pulse inhibition of acoustic startle, in the Morris water maze, and for resting and stress levels of serum corticosterone starting on ∼P105 (F0) and ∼P60 (F1), followed by tissue collection for further analyses. Acutely, the F0 TBI males had messenger RNA (mRNA) transcripts altered to support an increased hypothalamic and hippocampal Na+-K+-Cl- (Slc12a2) Cl- importer / K+-2Cl- (Slc12a5) Cl- exporter ratio and decreased hippocampal glucocorticoid receptors (Nr3c1), as well as increased serum levels of corticosterone, interleukin-1ß (IL-1ß), and biomarkers of activated hippocampal microglia and astrocytes. Long-term, F0 TBI rats exhibited increased corticosterone concentrations at rest and under stress, anxiety-like behavior, impaired sensory-motor gating, and impaired spatial memory. These abnormalities were underpinned by reduced mRNA levels of hypothalamic and hippocampal mineralocorticoid receptors (Nr3c2), hippocampal Nr3c1, and hypothalamic brain-derived neurotrophic factor (Bdnf), as well as elevated serum levels of IL-1ß, and biomarkers of activated hippocampal microglia and astrocytes. F1 male offspring of TBI sires exhibited abnormalities in all behavioral tests, while their F1 female counterparts had abnormal pre-pulse inhibition responses only. F1 male offspring of TBI sires also had reduced mRNA levels of hippocampal Nr3c1 and Nr3c2, as well as hypothalamic and hippocampal Bdnf, whereas increases in inflammatory markers were more profound in F1 females. These findings suggest that offspring of sires with a history of a moderate TBI that involved craniectomy under SEVO anesthesia for 40 min, develop sex-dependent neurobehavioral abnormalities in the absence of direct social interaction between the sire and the offspring.

Stumbling Blocks in the Investigation of the Relationship Between Age-Related Hearing Loss and Cognitive Impairment.

The relationship between age-related hearing loss (ARHL) and cognitive impairment (CI) remains intricate. However, there is no robust evidence from experimental or clinical studies to elucidate their relationship. The key unaddressed questions are (a) whether there is a causal effect of ARHL on CI and (b) whether efficacious treatment of ARHL (such as hearing-aid use) ameliorates CI and dementia-related behavioral symptoms. Because of several methodological and systematic flaws/challenges, rigorous verification has not been conducted. Addressing these stumbling blocks is essential to unraveling the relationship between ARHL and CI, which motivated us to undertake this review. Here, we discuss the methodological problems from the perspectives of potential confounding bias, assessments of CI and ARHL, hearing-aid use, functional-imaging studies, and animal models based on the latest information and our experiences. We also identify potential solutions for each problem from the viewpoints of clinical epidemiology. We believe that "objectivity," specifically the use of more objective behavioral assessments and new computerized technologies, may be the key to improving experimental designs for studying the relationship between ARHL and CI.

Canagliflozin Ameliorates Oxidative Stress and Autistic-like Features in Valproic-Acid-Induced Autism in Rats: Comparison with Aripiprazole Action.

Based on their proven anti-inflammatory and antioxidant effects, recent studies have examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in neurodevelopmental disorders such as autism spectrum disorder (ASD). Therefore, the aim of this study is to assess the effects of subchronic systemic treatment with intraperitoneal (i.p.) canagliflozin (20, 50, and 100 mg/kg) compared to aripiprazole (ARP) (3 mg/g, i.p.) in a valproic acid (VPA)-induced rat model of autism. The behavioral characteristics of ASD, oxidative stress, and acetylcholinesterase (AChE) activity in rats with ASD-like behaviors, which were induced by prenatal exposure to VPA, were evaluated. The behavioral assessment methods used for this study were the open field test (OFT), the marble-burying test (MBT), and the nestlet-shredding test (NST) to examine their exploratory, anxiety, and compulsiveness-like actions, while the biochemical assessment used for this study was an ELISA colorimetric assay to measure ASD biomarker activity in the hippocampus, prefrontal cortex, and cerebellum. Rats that were pretreated with 100 mg/kg of canagliflozin displayed a significantly lower percentage of shredding (1.12 ± 0.6%, p < 0.01) compared to the ARP group (3.52 ± 1.6%). Pretreatment with (20 mg/kg, 50 mg/kg, and 100 mg/kg) canagliflozin reversed anxiety levels and hyperactivity and reduced hyper-locomotor activity significantly (161 ± 34.9 s, p < 0.05; 154 ± 44.7 s, p < 0.05; 147 ± 33.6 s, p < 0.05) when compared with the VPA group (303 ± 140 s). Moreover, canagliflozin and ARP mitigated oxidative stress status by restoring levels of glutathione (GSH) and catalase (CAT) and increasing the levels of malondialdehyde (MDA) in all tested brain regions. The observed results propose repurposing of canagliflozin in the therapeutic management of ASD. However, further investigations are still required to verify the clinical relevance of canagliflozin in ASD.

Biobehavioral Assessments in BACPAC: Recommendations, Rationale, and Methods.

The Biobehavioral Working Group of BACPAC was charged to evaluate a range of psychosocial, psychophysical, and behavioral domains relevant to chronic low back pain, and recommend specific assessment tools and procedures to harmonize biobehavioral data collection across the consortium. Primary references and sources for measure selection were the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, the Minimum Data Set from the National Institutes of Health (NIH) Research Task Force on Standards for Chronic Low Back Pain, the Patient-Reported Outcomes Measurement Information System, and NeuroQOL. The questionnaire's recommendations supplemented the NIH HEAL Common Data Elements and BACPAC Minimum Data Set. Five domains were identified for inclusion: Pain Characteristics and Qualities; Pain-Related Psychosocial/Behavioral Factors; General Psychosocial Factors; Lifestyle Choices; and Social Determinants of Health/Social Factors. The Working Group identified best practices for required and optional Quantitative Sensory Testing of psychophysical pain processing for use in BACPAC projects.

Behavioral tests for evaluating the characteristics of brain diseases in rodent models: Optimal choices for improved outcomes (Review).

Behavioral assessment is the dominant approach for evaluating whether animal models of brain diseases can successfully mimic the clinical characteristics of diseases. At present, most research regarding brain diseases involves the use of rodent models. While studies have reported numerous methods of behavioral assessments in rodent models of brain diseases, each with different principles, procedures, and assessment criteria, only few reviews have focused on characterizing and differentiating these methods based on applications for which they are most appropriate. Therefore, in the present review, the representative behavioral tests in rodent models of brain diseases were compared and differentiated, aiming to provide convenience for researchers in selecting the optimal methods for their studies.

Anatomical and behavioral outcomes following a graded hemi-contusive cervical spinal cord injury model in mice.

BACKGROUND: A graded hemi-contusion spinal cord injury produces complex anatomical deformation of the spinal cord parenchyma. The relationship between lesion severity and behavioral consequences in a novel contusion mouse model remains unknown. PURPOSE: We aimed to establish a graded cervical hemi-contusion spinal cord injury model in mice and investigate the correlation between graded anatomical damage to the spinal cord and resulting behavioral impairments. METHODS: Thirty-two mice were divided into groups of 1.2 mm, 1.5 mm and sham. The tip of an impactor with a diameter of 1 mm was utilized to compress the left dorsal cord of C5 by 1.2 mm or 1.5 mm at a speed of 300 mm/s. Forelimb motor function was evaluated using rearing, grooming and grip-strength tests before and after the injuries. Histologically the area of white matter sparing, gray matter sparing and lesion area were quantified at 6-week-post-injury. RESULTS: Behavioral assessments showed a more severe forelimb functional deficit in 1.5 mm contusion displacements relative to 1.2 mm contusion displacements after injury. The 1.2 mm hemi-contusion mainly caused damage to the dorsal fasciculus, ventral and dorsal horn, while the 1.5 mm hemi-contusion lead to additional damage extending to ventral fasciculus. Sparing of the gray and white matter at the epicenter was 36.8 ± 2.4% and 12.4 ± 2.6% in the 1.2 mm group, and 27.6 ± 4.0% and 4.1 ± 2.2% in the 1.5 mm group, respectively. Furthermore, the lesion area was 20.8 ± 3.0% and 36.0 ± 2.1% in the 1.2 mm and 1.5 mm groups, respectively. There was a significant correlation between the performance in the grooming test and white matter sparing, and between grip-test strength and gray matter sparing. CONCLUSION: The present study demonstrates that a hemi-contusion cervical spinal cord injury in mice can be graded by contusion displacement and that there is a correlation between anatomical and behavioral outcomes. This study provides a means for determining the severity of lesions in a contusion mouse model.

Markerless analysis of hindlimb kinematics in spinal cord-injured mice through deep learning.

Rodent models are commonly used to understand the underlying mechanisms of spinal cord injury (SCI). Kinematic analysis, an important technique to measure dysfunction of locomotion after SCI, is generally based on the capture of physical markers placed on bony landmarks. However, marker-based studies face significant experimental hurdles such as labor-intensive manual joint tracking, alteration of natural gait by markers, and skin error from soft tissue movement on the knee joint. Although the pose estimation strategy using deep neural networks can solve some of these issues, it remains unclear whether this method is adaptive to SCI mice with abnormal gait. In the present study, we developed a deep learning based markerless method of 2D kinematic analysis to automatically track joint positions. We found that a relatively small number (< 200) of manually labeled video frames was sufficient to train the network to extract trajectories. The mean test error was on average 3.43 pixels in intact mice and 3.95 pixels in SCI mice, which is comparable to the manual tracking error (3.15 pixels, less than 1 mm). Thereafter, we extracted 30 gait kinematic parameters and found that certain parameters such as step height and maximal hip joint amplitude distinguished intact and SCI locomotion.

Diagnosing Level of Consciousness: The Limits of the Glasgow Coma Scale Total Score.

In nearly all clinical and research contexts, the initial severity of a traumatic brain injury (TBI) is measured using the Glasgow Coma Scale (GCS) total score. The GCS total score however, may not accurately reflect level of consciousness, a critical indicator of injury severity. We investigated the relationship between GCS total scores and level of consciousness in a consecutive sample of 2455 adult subjects assessed with the GCS 69,487 times as part of the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We assigned each GCS subscale score combination a level of consciousness rating based on published criteria for the following disorders of consciousness (DoC) diagnoses: coma, vegetative state/unresponsive wakefulness syndrome, minimally conscious state, and post-traumatic confusional state, and present our findings using summary statistics and four illustrative cases. Participants had the following characteristics: mean (standard deviation) age 41.9 (17.6) years, 69% male, initial GCS 3-8 = 13%; 9-12 = 5%; 13-15 = 82%. All GCS total scores between 4-14 were associated with more than one DoC diagnosis; the greatest variability was observed for scores of 7-11. Further, a wide range of total scores was associated with identical DoC diagnoses. Importantly, a diagnosis of coma was only possible with GCS total scores of 3-6. The GCS total score does not accurately reflect level of consciousness based on published DoC diagnostic criteria. To improve the classification of patients with TBI and to inform the design of future clinical trials, clinicians and investigators should consider individual subscale behaviors and more comprehensive assessments when evaluating TBI severity.

Progressive Cognitive and Post-Traumatic Stress Disorder-Related Behavioral Traits in Rats Exposed to Repetitive Low-Level Blast.

Many military veterans who experienced blast-related traumatic brain injuries (TBI) in the conflicts in Iraq and Afghanistan currently have chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Besides static symptoms, new symptoms may emerge or existing symptoms may worsen. TBI is also a risk factor for later development of neurodegenerative diseases. In rats exposed to repetitive low-level blast overpressure (BOP), robust and enduring cognitive and PTSD-related behavioral traits develop that are present for at least one year after blast exposure. Here we determined the time-course of the appearance of these traits by testing rats in the immediate post-blast period. Three cohorts of rats examined within the first eight weeks exhibited no behavioral phenotype or, in one cohort, features of anxiety. None showed the altered cued fear responses or impaired novel object recognition characteristic of the fully developed phenotype. Two cohorts retested 36 to 42 weeks after blast exposure exhibited the expanded behavioral phenotype including anxiety as well as altered cued fear learning and impaired novel object recognition. Combined with previous work, the chronic behavioral phenotype has been observed in six cohorts of blast-exposed rats studied at 3-4 months or longer after blast injury, and the three cohorts studied here document the progressive nature of the cognitive/behavioral phenotype. These studies suggest the existence of a latent, delayed emerging and progressive blast-induced cognitive and behavioral phenotype. The delayed onset has implications for the evolution of post-blast neurobehavioral syndromes in military veterans and its modeling in experimental animals.

Case report: the use of the AWIN welfare assessment protocol to monitor a group of abandoned donkeys / Estudo de caso: o uso do protocolo AWIN de avaliação de bem-estar para monitorar um grupo de jumentos abandonados

The objective of this study was to reach a diagnosis of the living conditions of abandoned donkeys kept in a restricted farm area through the assessment of their welfare level utilizing the AWIN protocol as a methodological tool. These animals were supposed to be sent to slaughter, but after the activity was temporarily banned, they were abandoned by traders. The protocol of welfare assessment was associated with general environmental and sanitary conditions. Information regarding the mortality rates was also gathered. According to the welfare assessment results, the living conditions of these animals were acceptable in some areas, despite the insufficient shade and shelter, a 3-month food restriction period, and a mortality rate of over 70%. These results demonstrate that welfare assessment protocols must be adapted to crises and databases for welfare indicators in diverse conditions must be created.(AU)

O objetivo deste estudo foi formular um diagnóstico das condições de vida de jumentos abandonados mantidos em uma área restrita de uma propriedade através da avaliação de seu nível de bem-estar, utilizando o protocolo AWIN como ferramenta metodológica. Estes animais seriam destinados ao abate, porém, depois da suspensão temporária da atividade, foram abandonados pelos proprietários. O protocolo de avaliação de bem-estar foi associado às condições ambientais e sanitárias gerais. Informações sobre os índices de mortalidade também foram coletadas. De acordo com os resultados da avaliação de bem-estar, as condições de vida destes animais estavam aceitáveis em algumas áreas, embora não houvesse sombreamento e abrigo suficientes, um período de restrição alimentar de 3 meses e um índice de mortalidade acima de 70%. Estes resultados demonstram que protocolos de avaliação de bem-estar devem ser adaptados a situações de crise, e bancos de dados para indicadores de bem-estar em condições diversas devem ser criados.(AU)

Executive Dysfunction after a Sport-Related Concussion Is Independent of Task-Based Symptom Burden.

A sport-related concussion (SRC) results in short- and long-term deficits in oculomotor control; however, it is unclear whether this change reflects executive dysfunction and/or a performance decrement caused by an increase in task-based symptom burden. Here, individuals with a SRC - and age- and sex-matched controls - completed an antisaccade task (i.e., saccade mirror-symmetrical to a target) during the early (initial assessment ≤12 days) and later (follow-up assessment <30 days) stages of recovery. Antisaccades were used because they require top-down executive control and exhibit performance decrements following an SRC. Reaction time (RT) and directional errors were included with pupillometry, because pupil size in the antisaccade task has been shown to provide a neural proxy for executive control. In addition, the Sport-Concussion Assessment Tool (SCAT-5) symptom checklist was completed prior to and after each oculomotor assessment to identify a possible task-based increase in symptomology. The SRC group yielded longer initial assessment RTs, more directional errors, and larger task-evoked pupil dilations (TEPD) than the control group. At the follow-up assessment, RTs for the SRC and control group did not reliably differ; however, the former demonstrated more directional errors and larger TEPDs. SCAT-5 symptom severity scores did not vary from the pre- to post-oculomotor evaluation for either initial or follow-up assessments. Accordingly, an SRC imparts a persistent executive dysfunction to oculomotor planning independent of a task-based increase in symptom burden. These findings evince that antisaccades serve as an effective tool to identify subtle executive deficits during the early and later stages of SRC recovery.

Transfemoral Approach to Induce Transient Middle Cerebral Artery Occlusion in Rats: The Use of Commercially Available Endovascular Wires.

BACKGROUND: Animal models of stroke play a crucial role in determining the pathophysiology of stroke progression and assessment of any new therapeutic approaches. Transient middle cerebral artery occlusion (tMCAo) in rodent models are the most common site-specific type of ischemia because of their relevance to the clinical setting. Compared with the intraluminal filament technique for inducing tMCAo, the transfemoral approach using endovascular wires is relatively a new technique METHODS: Here we present the use of commercially available wires used for neuro-endovascular surgical procedures to induce tMCAo in rats via a transfemoral approach. We used male Wistar rats in four groups to assess the effect of occlusion time (1 vs. 2 hours) and the wire type (PT2 TM 0.014″ vs. TransendTM EX, 0.014″, Boston Scientific, MA, USA). Infarct volume, edema, neurological deficits, and pro-inflammatory/anti-inflammatory blood biomarkers were used as outcome measures. RESULTS: We observed a significant effect of the wire type on the infarct volume (p value = 0.0096) where infarcts were slightly larger in the PT2 wiregroups. However, the occlusion time had no significant effect on infarct volume, even though the interaction between wire-type * occlusion-time was significant (p value = 0.024). Also, the amount of edema and blood pro-inflammatory/anti-inflammatory biomarkers were not statistically different among the wire-type and occlusion-time groups. CONCLUSIONS: The choice of appropriate endovascular wire should probably be the focus of the study design instead of the occlusion time when planning an experiment. The transfemoral approach using endovascular wires for inducing tMCAo in rats provides a more consistent outcome with fewer complications compared with suture filament models.

Can the Latest Computerized Technologies Revolutionize Conventional Assessment Tools and Therapies for a Neurological Disease? The Example of Parkinson's Disease.

Dramatic breakthroughs in the treatment and assessment of neurological diseases are lacking. We believe that conventional methods have several limitations. Computerized technologies, including virtual reality, augmented reality, and robot assistant systems, are advancing at a rapid pace. In this study, we used Parkinson's disease (PD) as an example to elucidate how the latest computerized technologies can improve the diagnosis and treatment of neurological diseases. Dopaminergic medication and deep brain stimulation remain the most effective interventions for treating PD. Subjective scales, such as the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr stage, are still the most widely used assessments. Wearable sensors, virtual reality, augmented reality, and robot assistant systems are increasingly being used for evaluation of patients with PD. The use of such computerized technologies can result in safe, objective, real-time behavioral assessments. Our experiences and understanding of PD have led us to believe that such technologies can provide real-time assessment, which will revolutionize the traditional assessment and treatment of PD. New technologies are desired that can revolutionize PD treatment and facilitate real-time adjustment of treatment based on motor fluctuations, such as telediagnosis systems and "smart treatment systems." The use of these technologies will substantially improve both the assessment and the treatment of neurological diseases before next-generation treatments, such as stem cell and genetic therapy, and next-generation assessments, can be clinically practiced, although the current level of artificial intelligence cannot replace the role of clinicians.

Oculomotor Executive Dysfunction during the Early and Later Stages of Sport-Related Concussion Recovery.

Executive dysfunction represents the most persistent sequela of mild traumatic brain injury. It is, however, largely unclear whether a sport-related concussion similarly contributes to a persistent executive dysfunction even when an athlete has been cleared medically for return to play. Here, individuals with a diagnosis of a sport-related concussion-and their age- and sex-matched controls-completed an oculomotor assessment during the acute and later stages of injury recovery. Prosaccades (i.e., saccade to a target) and executive-related antisaccades (i.e., saccade mirror-symmetrical to a target) were completed: (1) 2-6 days after a concussive event (initial assessment), and (2) 14-20 days after the initial oculomotor assessment when individuals were cleared for return to play (follow-up assessment). At the initial assessment, the concussed group produced antisaccade reaction times (RT) that were 93 ms longer than the control group (p < 0.001), whereas prosaccade RTs did not differ between groups (p = 0.25). At the follow-up assessment, concussed and control groups produced comparable pro- and antisaccade RTs (ps >0.31); however, the former group exhibited a continued increase in directional errors (p < 0.05). That initial assessment antisaccades-but not prosaccades-differed between groups indicates that the acute recovery of a concussion is associated with a selective executive-related oculomotor deficit, and the continued increase in directional errors at the follow-up assessment suggests that such a deficit persists even when an athlete has been cleared medically for return to play. The antisaccade task may therefore serve to assess subtle executive deficits and determine when an athlete may return to play safely.

Current behavioral assessments of movement disorders in children.

Pediatric movement disorders (PMDs) are common and have recently received increasing attention. As these disorders have special clinical features, the selection of appropriate behavioral assessment tools that can clearly distinguish movement disorders from other diseases (eg, epilepsy and neuromuscular disorders) is crucial for achieving an accurate diagnosis and treatment. However, few studies have focused on behavioral assessments in children. The present report attempts to provide a critical review of the available subjective and objective assessment tests for common PMDs. We believe that the principles of objectification, multi-purpose use, and simplification are also applicable to the selection and development of satisfactory pediatric behavioral assessment tools. We expect that the development of wearable sensors, virtual reality, and augmented reality will lead to the establishment of more reliable and simple tests. In addition, more rigorous randomized controlled trials that have been specifically designed to evaluate behavioral testing in children are also expected in the future.

Longitudinal Magnetic Resonance Imaging Analysis and Histological Characterization after Spinal Cord Injury in Two Mouse Strains with Different Functional Recovery: Gliosis as a Key Factor.

Spinal cord injuries (SCI) are disastrous neuropathologies causing permanent disabilities. The availability of different strains of mice is valuable for studying the pathophysiological mechanisms involved in SCI. However, strain differences have a profound effect on spontaneous functional recovery after SCI. CX3CR1+/eGFP and Aldh1l1-EGFP mice that express green fluorescent protein in microglia/monocytes and astrocytes, respectively, are particularly useful to study glial reactivity. Whereas CX3CR1+/eGFP mice have C57BL/6 background, Aldh1l1-EGFP are in Swiss Webster background. We first assessed spontaneous functional recovery in CX3CR1+/eGFP and Aldh1l1-EGFP mice over 6 weeks after lateral spinal cord hemisection. Second, we carried out a longitudinal follow-up of lesion evolution using in vivo T2-weighted magnetic resonance imaging (MRI). Finally, we performed in-depth analysis of the spinal cord tissue using ex vivo T2-weighted MRI as well as detailed histology. We demonstrate that CX3CR1+/eGFP mice have improved functional recovery and reduced anxiety after SCI compared with Aldh1l1-EGFP mice. We also found a strong correlation between in vivo MRI, ex vivo MRI, and histological analyses of the injured spinal cord in both strain of mice. All three modalities revealed no difference in lesion extension and volume between the two strains of mice. Importantly, histopathological analysis identified decreased gliosis and increased serotonergic axons in CX3CR1+/eGFP compared with Aldh1l1-EGFP mice following SCI. These results thus suggest that the strain-dependent improved functional recovery after SCI may be linked with reduced gliosis and increased serotonergic innervation.

Longitudinal electrophysiological changes after cervical hemi-contusion spinal cord injury in rats.

OBJECTIVE: To evaluate the longitudinal somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) characterization from acute to chronic injury following cervical hemi-contusion spinal cord injury (SCI) in rats, and correlate the MEPs & SEPs to the behavioral outcomes. METHODS: Fifteen adult male Sprague-Dawley rats were subjected to the hemi-contusion spinal cord injury at C5. Forelimb MEPs & SEPs were applied to 5 animals before injury and 3h, 1d, 3d, 1w, 2w, 4w and 8w after injury respectively. Forelimb functional assessments, including Montoya staircase task and cylinder rearing test, were conducted on another 10 animals before injury and at 2w, 4w and 8w after injury respectively, as well as histological analysis of the cord at 8w after injury. A group correlation was performed between the MEPs & SEPs and behavioral outcomes. RESULTS: The hemi-contusion injury resulted in unilateral tissue damage at the epicenter with loss of the ventral horns and lateral funiculus. Both ipsilateral and contralateral forelimb MEPs showed latency prolongation and amplitude reduction at 3h after injury. The MEPs amplitude increased with time after injury, but the ipsilateral amplitude was persistently lower than the contralateral amplitude. The ipsilateral MEPs latency increased with time after injury and was significantly longer than the contralateral MEPs latency. The ipsilateral SEPs amplitude dropped after injury and stayed at a lower level up to 8 weeks. There was no difference in the SEPs latency among time points and between sides. At 8 weeks after injury, the ipsilateral forelimb grasped 30% pellets while the contralateral forelimb close to 81%. An obvious decreased usage of the ipsilateral paw and increased usage of the contralateral paw were observed in rearing test after injury. The MEPs latency and amplitude correlated significantly with the forelimb motor function. CONCLUSION: Cervical hemi-contusion SCI led to persistent changes in MEPs & SEPs of the ipsilateral forelimb, ipsilateral impairment in motor function and unilateral cord tissue damage. Reliable electrophysiology assessment was obtained in chronic phase due to unstable MEPs & SEPs of bilateral forelimb immediately after injury, which might reflect the underlying pathological processes. The present study further confirmed the link of the MEPs to the behavioral outcomes, supporting the longitudinal electrophysiology assessment for neurological impairment after SCI.

Neurocognitive and Fine Motor Deficits in Asymptomatic Adolescents during the Subacute Period after Concussion.

Adolescents are at high risk for sustaining concussions. There is considerable controversy regarding the sensitivity of neurocognitive tests to detect and track dysfunction in the aftermath of concussion. Two neurocognitive test batteries were compared during the subacute phase of recovery from concussion to determine sensitivity to concussion. Adolescents (ages 11-17 years) with a concussion diagnosis (eight males, seven females, 9-69 days after injury) were recruited through a concussion clinic and compared with community nonconcussed volunteers (11 males, three females). Adolescents completed the online version of the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) on a desktop computer and the Defense Automated Neurobehavioral Assessment (DANA) on a handheld device, as well as the Grooved Pegboard Test, which assessed manual dexterity and motor speed. There were no differences in self-reported symptoms on the Post-Concussion Symptom Scale comparing concussed and nonconcussed adolescents. No significant between-groups differences were observed in ImPACT performance. Performance deficits were apparent for the DANA assessment, reflecting lower throughput scores for simple reaction time and response inhibition parameters in those with concussion. Concussed adolescents also had slower Grooved Pegboard Test performance when using the nondominant hand. Both the DANA test battery and the Grooved Pegboard Test appear to have promise as tools to detect persistent cognitive and motor dysfunction in the subacute period after concussion.

Validating Multidimensional Outcome Assessment Using the TBI Common Data Elements: An Analysis of the TRACK-TBI Pilot Sample.

The Glasgow Outcome Scale-Extended (GOSE) is often the primary outcome measure in clinical trials for traumatic brain injury (TBI). Although the GOSE's capture of global function outcome has several strengths, concerns have been raised about its limited ability to identify mild disability and failure to capture the full scope of problems patients exhibit after TBI. This analysis examined the convergence of disability ratings across a multidimensional set of outcome domains in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot study. The study collected measures recommended by the TBI Common Data Elements (CDE) Workgroup. Patients presenting to 3 emergency departments with a TBI of any severity enrolled in TRACK-TBI prospectively after injury; outcome measures were collected at 3 and six months postinjury. Analyses examined frequency of impairment and overlap between impairment status across the CDE outcome domains of Global Level of Functioning (GOSE), Neuropsychological (cognitive) Impairment, Psychological Status, TBI Symptoms, and Quality of Life. GOSE score correlated in the expected direction with other outcomes (M Spearman's rho = .21 and .49 with neurocognitive and self-report outcomes, respectively). The subsample in the Upper Good Recovery (GOSE 8) category appeared quite healthy across most other outcomes, although 19.0% had impaired executive functioning (Trail Making Test Part B). A significant minority of participants in the Lower Good Recovery subgroup (GOSE 7) met criteria for impairment across numerous other outcome measures. The findings highlight the multidimensional nature of TBI recovery and the limitations of applying only a single outcome measure.