Structural And Functional Connectivity Alterations And Their Relationship With Cognitive Impairment In Traumatic Brain Injury

Abstract

Traumatic Brain Injury (TBI) can be defined as an alteration in brain function or evidence of brain pathology caused by an external force. In this thesis the focus of attention is on brain diffuse axonal injury (DAI). DAI is widespread damage to axons throughout the white matter in the brain, caused by sustained acceleration and deceleration forces at the moment of injury (Adams, 1982). Is characterised by the presence of microhaemorrhages mainly in the cerebral hemispheres, corpus callosum, and brainstem. However, other regions such as the thalamus, basal ganglia and fornices are also susceptible (Adams, 1989). Diffuse damage makes the main contribution to neurological dysfunction in TBI patients and typically associated with poor prognosis (Smith and Meaney, 2000). In the absence of significant focal contusions, diffuse brain damage may be not detected on neuroimaging MRI initial scans and macroscopical brain examination. However, microscopic primary damage can be appreciated. In a first stage, primary damage, which is the direct consequence of the direct impact either by mechanical or external forces, produces tissue segmentation. Secondary damage then occurs. This includes a cascade of biological reactions which provokes cytoskeletal disorganization, protein accumulation, metabolic, hypoxic and microvascular damage, and excitotoxicity. As DAI is an evolving process, thus traumatic axonal injury (TAI) has more recently been suggested as a more appropriate term for describing diffuse axonal damage. These secondary processes can result in injury or complete disruption of critical white matter pathways between the cortex and deep grey matter structures (Buki & Povlishock, 2006). Taking into account that this disruption of white matter pathways may be causing cognitive deficits, the main hypothesis of this thesis is that white matter damage is responsible for the alterations in connectivity making the main contribution to cognitive deficits after diffuse, chronic and severe TBI. Moreover, the main objective to identify possible structural and functional connectivity alterations in the brains of patients suffering from diffuse axonal injury and to relate them with cognitive impairment by applying neuropsychological assessment and magnetic resonance imaging techniques. To investigate the connectivity alteration and their relationship with cognitive impairment after chronic TBI, we performed four studies. The first study aimed to investigate the role of white matter damage in declarative and working memory deficits after diffuse TBI focusing on the main associative fasciculi. Given that memory impairment is one of the most common deficits of patients with severe TBI, and taking into account the white matter alterations resulting from the first study, we performed this second study with the aim of assessing structural brain damage in subjects with diffuse and chronic severe TBI and to study its relationship with declarative memory impairment. The third study was the first multimodal approach study in TBI to explore the functional and structural patterns of connectivity underlying working memory impairment after severe traumatic axonal injury. And finally, in the fourth study, we wanted to take advantage of the analysis of resting state fMRI and aimed to explore abnormalities in brain activity and connectivity during the resting state in patients with chronic traumatic axonal injury and examine the relationship of these abnormalities with deficits in structural connectivity and global cognitive outcome. The general conclusion extracted from the results of the studies performed here is that, although after TAI there are clear widespread patterns of white matter damage and cortical atrophy, the results of these studies seem to suggest that long-term cognitive sequelae after diffuse TBI follows a predominant frontal pattern of alteration. Disrupted frontal white matter structural connectivity and the basal activity of the frontal lobe at rest are the main alterations explaining cognitive outcome after diffuse and chronic TBI.

INTRODUCCIÓN: El daño axonal difuso que se sufre después de un traumatismo craneoencefálico, produce alteraciones cerebrales estructurales y funcionales que se pueden visualizar y analizar mediante imágenes por resonancia magnética (IRM). Estas alteraciones pueden explicar los déficits cognitivos. OBJETIVO: Identificar las posibles alteraciones funcionales y estructurales cerebrales en pacientes con daño axonal difuso y su relación con sus déficits cognitivos mediante la aplicación de pruebas neuropsicológicas y IRM MÉTODOS/ESTUDIOS: La tesis incluye cuatro artículos de investigación en los que se combinan técnicas por tensor de difusión, resonancia magnética funcional, estudio de grosor cortical y volumetría junto con tests neuropsicológicos. La batería de test escogida incluye diferentes pruebas para la evaluación de los dominios cognitivos más frecuentemente alterados en estos pacientes: funciones ejecutivas, aprendizaje y memoria, atención y velocidad de procesamiento mental. Los pacientes incluidos en los estudios se caracterizan principalmente por ser pacientes adultos jóvenes (20-45 años) con TCE grave (GCS≤8) en estado crónico (≤2años desde el traumatismo craneo-encefálico), con evidencia de patología cerebral difusa en la IRM clínica, Los pacientes se han emparejado con un grupo control de acuerdo con las variables edad, escolaridad y dominancia manual. RESULTADOS: 1) El decremento de anisotropía fraccional (AF) en fascículos largos asociativos explica los déficits de memoria de trabajo mientras que una disrupción más local se relaciona más con déficits de memoria declarativa; 2) a pesar de una afectación general de sustancia blanca en todos los tractos cerebrales evidenciado por una reducción de AF y una reducción generalizada cortical, los déficits de memoria declarativa se explican por una alteración cortico-subcortical de sustancia blanca y por la reducción cortical en el área del precuneus; 3) La alteración de la conectividad estructural explica las alteraciones cerebrales de activación funcional y explica los déficits de memoria de trabajo; 4) El incremento de actividad funcional del lóbulo frontal en estado de reposo está asociado a un mejor rendimiento cognitivo. CONCLUSIÓN: La alteración de la conectividad estructural, especialmente la alteración de conexiones con el lóbulo frontal, junto con la alteración de la actividad funcional basal medida en estado de reposo, son las alteraciones principales causantes de las alteraciones cognitivas después de un traumatismo craneo-encefálico de carácter difuso.