Increased sleep need and daytime sleepiness 6 months after traumatic brain injury: a prospective controlled clinical trial.

Post-traumatic sleep-wake disturbances are common after acute traumatic brain injury. Increased sleep need per 24 h and excessive daytime sleepiness are among the most prevalent post-traumatic sleep disorders and impair quality of life of trauma patients. Nevertheless, the relation between traumatic brain injury and sleep outcome, but also the link between post-traumatic sleep problems and clinical measures in the acute phase after traumatic brain injury has so far not been addressed in a controlled and prospective approach. We therefore performed a prospective controlled clinical study to examine (i) sleep-wake outcome after traumatic brain injury; and (ii) to screen for clinical and laboratory predictors of poor sleep-wake outcome after acute traumatic brain injury. Forty-two of 60 included patients with first-ever traumatic brain injury were available for follow-up examinations. Six months after trauma, the average sleep need per 24 h as assessed by actigraphy was markedly increased in patients as compared to controls (8.3 ± 1.1 h versus 7.1 ± 0.8 h, P < 0.0001). Objective daytime sleepiness was found in 57% of trauma patients and 19% of healthy subjects, and the average sleep latency in patients was reduced to 8.7 ± 4.6 min (12.1 ± 4.7 min in controls, P = 0.0009). Patients, but not controls, markedly underestimated both excessive sleep need and excessive daytime sleepiness when assessed only by subjective means, emphasizing the unreliability of self-assessment of increased sleep propensity in traumatic brain injury patients. At polysomnography, slow wave sleep after traumatic brain injury was more consolidated. The most important risk factor for developing increased sleep need after traumatic brain injury was the presence of an intracranial haemorrhage. In conclusion, we provide controlled and objective evidence for a direct relation between sleep-wake disturbances and traumatic brain injury, and for clinically significant underestimation of post-traumatic sleep-wake disturbances by trauma patients.

Acute S100B in serum is associated with cognitive symptoms and memory performance 4 months after paediatric mild traumatic brain injury

OBJECTIVE This study explored whether acute serum marker S100B is related with post-concussive symptoms (PCS) and neuropsychological performance 4 months after paediatric mild traumatic brain injury (mTBI). RESEARCH DESIGN AND METHODS This prospective short-term longitudinal study investigated children (aged 6-16 years) with mTBI (n = 36, 16 males) and children with orthopaedic injuries (OI, n = 27, 18 males) as a control group. S100B in serum was measured during the acute phase and was correlated with parent-rated PCS and neuropsychological performance 4 months after the injury. MAIN OUTCOMES AND RESULTS The results revealed no between-group difference regarding acute S100B serum concentration. In children after mTBI, group-specific significant Spearman correlations were found between S100B and post-acute cognitive PCS (r = 0.54, p = 0.001) as well as S100B and verbal memory performance (r = -0.47, p = 0.006). In children after OI, there were insignificant positive relations between S100B and post-acute somatic PCS. In addition, insignificant positive correlations were found between neuropsychological outcome and S100B in children after OI. CONCLUSIONS S100B was not specific for mild brain injuries and may also be elevated after OI. The group-specific association between S100B and ongoing cognitive PCS in children after mTBI should motivate to examine further the role of S100B as a diagnostic biomarker in paediatric mTBI.

Exploring the Impact of Decreased AMPK Pathway Activity on Brain Injury Outcome

Each year, 150 million people sustain a Traumatic Brain Injury (TBI). TBI results in life-long cognitive impairments for many survivors. One observed pathological alteration following TBI are changes in glucose metabolism. Altered glucose uptake occurs in the periphery as well as in the nervous system, with an acute increase in glucose uptake, followed by a prolonged metabolic suppression. Chronic, persistent suppression of brain glucose uptake occurs in TBI patients experiencing memory loss. Abberant post-injury activation of energy-sensing signaling cascades could result in perturbed cellular metabolism. AMP-activated kinase (AMPK) is a kinase that senses low ATP levels, and promotes efficient cell energy usage. AMPK promotes energy production through increasing glucose uptake via glucose transporter 4 (GLUT4). When AMPK is activated, it phosphorylates Akt Substrate of 160 kDa (AS160), a Rab GTPase activating protein that controls Glut4 translocation. Additionally, AMPK negatively regulates energy-consumption by inhibiting protein synthesis via the mechanistic Target of Rapamycin (mTOR) pathway. Given that metabolic suppression has been observed post-injury, we hypothesized that activity of the AMPK pathway is transiently decreased. As AMPK activation increases energy efficiency of the cell, we proposed that increasing AMPK activity to combat the post-injury energy crisis would improve cognitive outcome. Additionally, we expected that inhibiting AMPK targets would be detrimental. We first investigated the role of an existing state of hyperglycemia on TBI outcome, as hyperglycemia correlates with increased mortality and decreased cognitive outcome in clinical studies. Inducing hyperglycemia had no effect on outcome; however, we discovered that AMPK and AS160 phosphorylation were altered post-injury. We conducted vii work to characterize this period of AMPK suppression and found that AMPK phosphorylation was significantly decreased in the hippocampus and cortex between 24 hours and 3 days post-injury, and phosphorylation of its downstream targets was consistently altered. Based on this period of observed decreased AMPK activity, we administered an AMPK activator post-injury, and this improved cognitive outcome. Finally, to examine whether AMPK-regulated target Glut4 is involved in post-injury glucose metabolism, we applied an inhibitor and found this treatment impaired post-injury cognitive function. This work is significant, as AMPK activation may represent a new TBI therapeutic target.

Automated detection and classification of brain injury lesions on structural magnetic resonance imaging

El daño cerebral adquirido (DCA) es un problema social y sanitario grave, de magnitud creciente y de una gran complejidad diagnóstica y terapéutica. Su elevada incidencia, junto con el aumento de la supervivencia de los pacientes, una vez superada la fase aguda, lo convierten también en un problema de alta prevalencia. En concreto, según la Organización Mundial de la Salud (OMS) el DCA estará entre las 10 causas más comunes de discapacidad en el año 2020. La neurorrehabilitación permite mejorar el déficit tanto cognitivo como funcional y aumentar la autonomía de las personas con DCA. Con la incorporación de nuevas soluciones tecnológicas al proceso de neurorrehabilitación se pretende alcanzar un nuevo paradigma donde se puedan diseñar tratamientos que sean intensivos, personalizados, monitorizados y basados en la evidencia. Ya que son estas cuatro características las que aseguran que los tratamientos son eficaces. A diferencia de la mayor parte de las disciplinas médicas, no existen asociaciones de síntomas y signos de la alteración cognitiva que faciliten la orientación terapéutica. Actualmente, los tratamientos de neurorrehabilitación se diseñan en base a los resultados obtenidos en una batería de evaluación neuropsicológica que evalúa el nivel de afectación de cada una de las funciones cognitivas (memoria, atención, funciones ejecutivas, etc.). La línea de investigación en la que se enmarca este trabajo de investigación pretende diseñar y desarrollar un perfil cognitivo basado no sólo en el resultado obtenido en esa batería de test, sino también en información teórica que engloba tanto estructuras anatómicas como relaciones funcionales e información anatómica obtenida de los estudios de imagen. De esta forma, el perfil cognitivo utilizado para diseñar los tratamientos integra información personalizada y basada en la evidencia. Las técnicas de neuroimagen representan una herramienta fundamental en la identificación de lesiones para la generación de estos perfiles cognitivos. La aproximación clásica utilizada en la identificación de lesiones consiste en delinear manualmente regiones anatómicas cerebrales. Esta aproximación presenta diversos problemas relacionados con inconsistencias de criterio entre distintos clínicos, reproducibilidad y tiempo. Por tanto, la automatización de este procedimiento es fundamental para asegurar una extracción objetiva de información. La delineación automática de regiones anatómicas se realiza mediante el registro tanto contra atlas como contra otros estudios de imagen de distintos sujetos. Sin embargo, los cambios patológicos asociados al DCA están siempre asociados a anormalidades de intensidad y/o cambios en la localización de las estructuras. Este hecho provoca que los algoritmos de registro tradicionales basados en intensidad no funcionen correctamente y requieran la intervención del clínico para seleccionar ciertos puntos (que en esta tesis hemos denominado puntos singulares). Además estos algoritmos tampoco permiten que se produzcan deformaciones grandes deslocalizadas. Hecho que también puede ocurrir ante la presencia de lesiones provocadas por un accidente cerebrovascular (ACV) o un traumatismo craneoencefálico (TCE). Esta tesis se centra en el diseño, desarrollo e implementación de una metodología para la detección automática de estructuras lesionadas que integra algoritmos cuyo objetivo principal es generar resultados que puedan ser reproducibles y objetivos. Esta metodología se divide en cuatro etapas: pre-procesado, identificación de puntos singulares, registro y detección de lesiones. Los trabajos y resultados alcanzados en esta tesis son los siguientes: Pre-procesado. En esta primera etapa el objetivo es homogeneizar todos los datos de entrada con el objetivo de poder extraer conclusiones válidas de los resultados obtenidos. Esta etapa, por tanto, tiene un gran impacto en los resultados finales. Se compone de tres operaciones: eliminación del cráneo, normalización en intensidad y normalización espacial. Identificación de puntos singulares. El objetivo de esta etapa es automatizar la identificación de puntos anatómicos (puntos singulares). Esta etapa equivale a la identificación manual de puntos anatómicos por parte del clínico, permitiendo: identificar un mayor número de puntos lo que se traduce en mayor información; eliminar el factor asociado a la variabilidad inter-sujeto, por tanto, los resultados son reproducibles y objetivos; y elimina el tiempo invertido en el marcado manual de puntos. Este trabajo de investigación propone un algoritmo de identificación de puntos singulares (descriptor) basado en una solución multi-detector y que contiene información multi-paramétrica: espacial y asociada a la intensidad. Este algoritmo ha sido contrastado con otros algoritmos similares encontrados en el estado del arte. Registro. En esta etapa se pretenden poner en concordancia espacial dos estudios de imagen de sujetos/pacientes distintos. El algoritmo propuesto en este trabajo de investigación está basado en descriptores y su principal objetivo es el cálculo de un campo vectorial que permita introducir deformaciones deslocalizadas en la imagen (en distintas regiones de la imagen) y tan grandes como indique el vector de deformación asociado. El algoritmo propuesto ha sido comparado con otros algoritmos de registro utilizados en aplicaciones de neuroimagen que se utilizan con estudios de sujetos control. Los resultados obtenidos son prometedores y representan un nuevo contexto para la identificación automática de estructuras. Identificación de lesiones. En esta última etapa se identifican aquellas estructuras cuyas características asociadas a la localización espacial y al área o volumen han sido modificadas con respecto a una situación de normalidad. Para ello se realiza un estudio estadístico del atlas que se vaya a utilizar y se establecen los parámetros estadísticos de normalidad asociados a la localización y al área. En función de las estructuras delineadas en el atlas, se podrán identificar más o menos estructuras anatómicas, siendo nuestra metodología independiente del atlas seleccionado. En general, esta tesis doctoral corrobora las hipótesis de investigación postuladas relativas a la identificación automática de lesiones utilizando estudios de imagen médica estructural, concretamente estudios de resonancia magnética. Basándose en estos cimientos, se han abrir nuevos campos de investigación que contribuyan a la mejora en la detección de lesiones. ABSTRACT Brain injury constitutes a serious social and health problem of increasing magnitude and of great diagnostic and therapeutic complexity. Its high incidence and survival rate, after the initial critical phases, makes it a prevalent problem that needs to be addressed. In particular, according to the World Health Organization (WHO), brain injury will be among the 10 most common causes of disability by 2020. Neurorehabilitation improves both cognitive and functional deficits and increases the autonomy of brain injury patients. The incorporation of new technologies to the neurorehabilitation tries to reach a new paradigm focused on designing intensive, personalized, monitored and evidence-based treatments. Since these four characteristics ensure the effectivity of treatments. Contrary to most medical disciplines, it is not possible to link symptoms and cognitive disorder syndromes, to assist the therapist. Currently, neurorehabilitation treatments are planned considering the results obtained from a neuropsychological assessment battery, which evaluates the functional impairment of each cognitive function (memory, attention, executive functions, etc.). The research line, on which this PhD falls under, aims to design and develop a cognitive profile based not only on the results obtained in the assessment battery, but also on theoretical information that includes both anatomical structures and functional relationships and anatomical information obtained from medical imaging studies, such as magnetic resonance. Therefore, the cognitive profile used to design these treatments integrates information personalized and evidence-based. Neuroimaging techniques represent an essential tool to identify lesions and generate this type of cognitive dysfunctional profiles. Manual delineation of brain anatomical regions is the classical approach to identify brain anatomical regions. Manual approaches present several problems related to inconsistencies across different clinicians, time and repeatability. Automated delineation is done by registering brains to one another or to a template. However, when imaging studies contain lesions, there are several intensity abnormalities and location alterations that reduce the performance of most of the registration algorithms based on intensity parameters. Thus, specialists may have to manually interact with imaging studies to select landmarks (called singular points in this PhD) or identify regions of interest. These two solutions have the same inconvenient than manual approaches, mentioned before. Moreover, these registration algorithms do not allow large and distributed deformations. This type of deformations may also appear when a stroke or a traumatic brain injury (TBI) occur. This PhD is focused on the design, development and implementation of a new methodology to automatically identify lesions in anatomical structures. This methodology integrates algorithms whose main objective is to generate objective and reproducible results. It is divided into four stages: pre-processing, singular points identification, registration and lesion detection. Pre-processing stage. In this first stage, the aim is to standardize all input data in order to be able to draw valid conclusions from the results. Therefore, this stage has a direct impact on the final results. It consists of three steps: skull-stripping, spatial and intensity normalization. Singular points identification. This stage aims to automatize the identification of anatomical points (singular points). It involves the manual identification of anatomical points by the clinician. This automatic identification allows to identify a greater number of points which results in more information; to remove the factor associated to inter-subject variability and thus, the results are reproducible and objective; and to eliminate the time spent on manual marking. This PhD proposed an algorithm to automatically identify singular points (descriptor) based on a multi-detector approach. This algorithm contains multi-parametric (spatial and intensity) information. This algorithm has been compared with other similar algorithms found on the state of the art. Registration. The goal of this stage is to put in spatial correspondence two imaging studies of different subjects/patients. The algorithm proposed in this PhD is based on descriptors. Its main objective is to compute a vector field to introduce distributed deformations (changes in different imaging regions), as large as the deformation vector indicates. The proposed algorithm has been compared with other registration algorithms used on different neuroimaging applications which are used with control subjects. The obtained results are promising and they represent a new context for the automatic identification of anatomical structures. Lesion identification. This final stage aims to identify those anatomical structures whose characteristics associated to spatial location and area or volume has been modified with respect to a normal state. A statistical study of the atlas to be used is performed to establish which are the statistical parameters associated to the normal state. The anatomical structures that may be identified depend on the selected anatomical structures identified on the atlas. The proposed methodology is independent from the selected atlas. Overall, this PhD corroborates the investigated research hypotheses regarding the automatic identification of lesions based on structural medical imaging studies (resonance magnetic studies). Based on these foundations, new research fields to improve the automatic identification of lesions in brain injury can be proposed.

The Utility of the CVLT-C as an Embedded Validity Indicator After Pediatric Mild Traumatic Brain Injury.

Results of neuropsychological examinations depend on valid data. Whereas clinicians previously believed that clinical skill was sufficient to identify non-credible performance by examinees on standard tests, research demonstrates otherwise. Consequently, studies on measures to detect suspect effort in adults have received tremendous attention in the previous twenty years, and incorporation of validity indicators into neuropsychological examinations is now seen as integral. Few studies exist that validate methods appropriate for the measurement of effort in pediatric populations. Of extant studies, most evaluate standalone measures originally developed for use with adults. The present study examined the utility of indices from the California Verbal Learning Test – Children's Version (CVLT-C) as embedded validity indicators in a pediatric sample. Participants were 225 outpatients aged 8 to 16 years old referred for clinical assessment after mild traumatic brain injury (mTBI). Non-credible performance (n = 39) was defined as failure of the Medical Symptom Validity Test (MSVT). Logistic regression demonstrated that only the Recognition Discriminability index was predictive of MSVT failure (OR = 2.88, p < .001). A cutoff of z ≤ -1.0 was associated with sensitivity of 51% and specificity of 91%. In the current study, CVLT-C Recognition Discriminability was useful in the identification of non-credible performance in a sample of relatively high-functioning pediatric outpatients with mTBI. Thus, this index can be added to the short list of embedded validity indicators appropriate for pediatric neuropsychological assessment.

The Role of Hope in Rehabilitation and Long-term Outcomes among patients with Comorbid Spinal Cord and Traumatic Brain Injuries.

Spinal cord injury (SCI) and traumatic brain injury (TBI) are two potentially devastating conditions alone; when they co-occur in an individual they can be doubly so. The role of hope in rehabilitating oneself and recovering emotionally is examined in this paper. More specifically, Snyder's Model of Hope (1991) is examined as a tool that can aid in the rehabilitative process and help treatment providers, their patients, and the families of patients keep hope alive during a time of physical and emotional upheaval. This paper further examines the roles of hope in a rehabilitation program at Craig Hospital, a private, non-profit hospital dedicated exclusively to the rehabilitation of SCIs and TBIs and designated as a TBI and SCI Model Systems Center.

Sleep-wake disorders persist 18 months after traumatic brain injury but remain underrecognized

OBJECTIVE This study is a prospective, controlled clinical and electrophysiologic trial examining the chronic course of posttraumatic sleep-wake disturbances (SWD). METHODS We screened 140 patients with acute, first-ever traumatic brain injury of any severity and included 60 patients for prospective follow-up examinations. Patients with prior brain trauma, other neurologic or systemic disease, drug abuse, or psychiatric comorbidities were excluded. Eighteen months after trauma, we performed detailed sleep assessment in 31 participants. As a control group, we enrolled healthy individuals without prior brain trauma matched for age, sex, and sleep satiation. RESULTS In the chronic state after traumatic brain injury, sleep need per 24 hours was persistently increased in trauma patients (8.1 ± 0.5 hours) as compared to healthy controls (7.1 ± 0.7 hours). The prevalence of chronic objective excessive daytime sleepiness was 67% in patients with brain trauma compared to 19% in controls. Patients significantly underestimated excessive daytime sleepiness and sleep need, emphasizing the unreliability of self-assessments on SWD in trauma patients. CONCLUSIONS This study provides prospective, controlled, and objective evidence for chronic persistence of posttraumatic SWD, which remain underestimated by patients. These results have clinical and medicolegal implications given that SWD can exacerbate other outcomes of traumatic brain injury, impair quality of life, and are associated with public safety hazards.

Verbal recall after mild traumatic brain injury: Sensitivity of the rapid screen of concussion

The present study aimed to determine whether including a sensitive test of immediate and delayed recall would improve the diagnostic validity of the Rapid Screen of Concussion (RSC) in mild Traumatic Brain Injury (mTBI) versus orthopaedic clinical samples. Two studies were undertaken. In Study 1, the performance of 156 mTBI and 145 orthopaedic participants was analysed to identify the number of individuals who performed at ceiling on the verbal memory subtest of the RSC, as this test required immediate and delayed recall of only five words. A second aim was to determine the sensitivity and specificity levels of the RSC. Study 2 aimed to examine whether replacement of the verbal memory subtest with the 12-word Hopkins Verbal Learning Test (HVLT) could improve the sensitivity of the RSC in a new sample of 26 mTBI and 30 orthopaedic participants. Both studies showed that orthopaedic participants outperformed mTBI participants on each of the selected measures. Study 1 showed that 14% of mTBI participants performed at ceiling on the immediate and 21.2% on delayed recall test. Performance on the original battery yielded a sensitivity of 82%, specificity of 80% and overall correct classification of 81.5% participants. In Study 2, inclusion of the HVLT improved sensitivity to a level of 88.5%, decreased specificity to a level of 70% and resulted in an overall classification rate of 80%. It was concluded that although inclusion of the five-word subtest in the RSC can successfully distinguish concussed from non-concussed individuals, use of the HVLT in this protocol yields a more sensitive measure of subtle cognitive deficits following mTBI.

Stakeholder opinion of functional communication activities following traumatic brain injury

Primary objective : To establish a process whereby assessment of functional communication reflects the authentic communication of the target population. The major functional communication assessments available from the USA may not be as relevant to those who reside elsewhere, nor assessments developed primarily for persons who have had a stroke as relevant for traumatic brain injury rehabilitation. Research design : The investigation used the Nominal Group Technique to elicit free opinion and support individuals who have compromised communication ability. A survey mailed out sampled a larger number of stakeholders to test out differences among groups. Methods and procedures : Five stakeholder groups generated items and the survey determined relative 'importance'. The stakeholder groups in both studies comprised individuals with traumatic brain injury and their families, health professionals, third-party payers, employers, and Maori, the indigenous population of New Zealand. Main outcomes and results : There was no statistically significant difference found between groups for 19 of the 31 items. Only half of the items explicitly appear on a well-known USA functional communication assessment. Conclusions : The present study has implications for whether functional communication assessments are valid across cultures and the type of impairment.