Brain healing

Abstract: Traumatic brain injury is a leading killer of children and is a major public health problem around the world. Using general principles of neurocritical care, various treatment strategies have been developed to attempt to restore homeostasis to the brain and allow brain healing, including mechanical factors, cerebrospinal fluid diversion, hyperventilation, hyperosmolar therapies, barbiturates and hypothermia. Careful application of these therapies, normally in a step-wise fashion as intracranial injuries evolve, is necessary in order to attain maximal neurological outcome for these children. It is hopeful that new therapies, such as early hypothermia or others currently in preclinical trials, will ultimately improve outcome and quality of life for children after traumatic brain injury.

Abstract: Research reported by Posner & Raichle may be usefully applied to the rehabilitation of persons with brain damage. Their findings are related to the “dual premotorsystems hypothesis” that reciprocally interactive medial and lateral brain systems are involved in attention and learning. Recent studies show that “brain healing” occurs through dynamic reorganization involving attentional networks postulated by Posner & Raichle.

Abstract: The extent of effective regeneration in the adult mammalian brain following structural injury has been an issue of contention for the last several decades. Historical views proposed that the adult brain was set in a state of stasis, preventing effective regenerative alterations and functional recovery following brain trauma. The irreversible loss of function following injury to the adult mammalian brain has been attributed to an intrinsic inability of damaged neurons to re-initiate growth following injury, which is further compounded by a non-facilitative environment. However, accumulating evidence, based on diverse models of experimental neuronal and brain lesion, have challenged two major dogmas in neuro-repair research, namely, that neurons from the adult mammalian brain are incapable of intrinsically driven regeneration, and that neurogenesis is strictly restricted to developmental periods. Collectively, these studies have provided compelling evidence indicating that the adult brain may possess a vast intrinsic capacity for repair following injury. Furthermore, strategies aimed at facilitating neuronal replacement or re-establishing lost neuronal connections have made remarkable inroads into understanding the potential for injury-induced plasticity in the adult brain. Despite these advances, however, no effective treatment currently exists to target the full repertoire of pathological alterations that contribute to permanent loss of function following acquired brain injury. A broader understanding of the specific molecular and cellular events responsible for the limit in brain repair is still required, particularly for therapeutic interventions to effectively complement and enhance endogenous brain repair mechanisms. This thesis, therefore, sought to address three specific aspects associated with the intrinsic capacity for brain and neuronal repair following structural injury. Initially, the neurogenic potential of the injured adult brain was evaluated in an experimental model of structural brain injury by examining populations of proliferating and progenitor cells, to determine whether these cell populations have the capacity to undergo neuronal differentiation and contribute to neuronal replacement in injured brain tissue. Secondly, the reactive and regenerative alterations associated with the neural response to structural brain injury vol investigated in a range of neuronal and glial cell populations to determine particular alterations that may be indicative of neuronal regeneration and brain healing. Finally, utilising an in vitro model of axonal injury in which neurons can be studied in relative isolation, free of compounding glial responses, the intrinsic regenerative potential of individual mature brain neurons was determined and the mechanisms underlying this response were characterised through comparison with developing neurons and application of agents that specifically disrupt the cytoskeleton. Results from this study highlighted several important aspects of the neural response to injury indicating that, rather than responding passively, the adult brain mounts an adaptive repair process. These alterations involved the coordinated activation of both neuronal and glial cell populations, which ultimately resulted in the restoration of relatively normal cytoarchitecture. Specifically, adaptive injury-induced alterations included the activation of various cell populations, particularly neural progenitor cells, astrocytes and microglia, which may contribute to brain healing; evidence of re-vascularisation surrounding the lesion site; and regenerative neuronal changes, such as a profuse axonal sprouting response and an up-regulation of regeneration-associated genes. In summary these findings indicate that the adult mammalian brain possesses a remarkable intrinsic capacity for repair following injury and highlight several aspects of this response that may be therapeutically targeted to enhance brain repair following injury.