Development Of Executive Functions In Children With Frontal Lobe Lesions
Funder
National Health and Medical Research Council
Funding Amount
$160,379.00
Summary
Executive functions (EF), refer to the ability to problem solve, think flexibly and in abstract terms and pay attention. EFs are essential for managing daily life activities. The frontal lobes of the brain are believed be important in coordinating EFs. In childhood, frontal areas are developing rapidly and damage may affect ongoing development due to impairments in a child's capacity to function normally within their environment, interfering with adaptive functions such as new learning and reaso ....Executive functions (EF), refer to the ability to problem solve, think flexibly and in abstract terms and pay attention. EFs are essential for managing daily life activities. The frontal lobes of the brain are believed be important in coordinating EFs. In childhood, frontal areas are developing rapidly and damage may affect ongoing development due to impairments in a child's capacity to function normally within their environment, interfering with adaptive functions such as new learning and reasoning. Executive dysfunction in children manifests as disorganisation, impulsivity, inattention and inappropriate behaviour. Such problems are often masked in early chilhood, due to highly structured environments and support of parents and care-givers in day-to-day activities. However, as children mature, expectations of indepence increase and executive deficits become more apparent (ie. child 'grows into' these problems). Appropriate treatment and management is dependent on (i) improvement in early identification of patients at risk for such sequelae; (ii) establishing long-term consequences of executive deficits to ongoing development. This research aims to advance our understanding of EFs and their development through childhood, both in healthy children and children with cerebral lesions to regions believed to subsume EFs(ie the frontal lobes). While anecdotal case data is available, to our knowledge, no other study has attempted to do this using a longitudinal group design. Specific predictions include; (i) Children with frontal lobe damage will perform more poorly on EF measures, in comparison to children with damage to other cerebral areas and healthy children; (ii) Children with frontal lobe damage will show increasing deficits on EF tasks over time, reflecting an inability to acquire executive skills in the expected time frame, when compared with children with localised damage to cerebral areas excluding the frontal lobes, and healthy children.Read moreRead less
Using Astrocytes To Protect The Brain From Injury: Investigating Mechanisms And Therapeutic Strategies.
Funder
National Health and Medical Research Council
Funding Amount
$374,310.00
Summary
Brain damage caused by hypoxia (lack of oxygen) is a common problem in babies and can lead to outcomes ranging from cerebral palsy to death. We have a limited understanding of the mechanisms that cause damage, and thus very limited treatments. This project will investigate the role of cells called astrocytes in brain injury and identify novel therapeutic strategies to prevent or reverse brain damage. The outcomes of this research will ultimately lead to new treatments for hypoxic brain injury.
Molecular Cell Biology Of HNP22: Role In Alcohol Dependence
Funder
National Health and Medical Research Council
Funding Amount
$346,320.00
Summary
We used a differential screening procedure to detect changes in gene expression in the human alcoholic brain and described a novel gene, which we named hNP22, with increased expression in the superior frontal cortex of the alcoholic cases. This is the first report of a novel alcohol-responsive gene isolated from the human brain. We now propose to further explore the hNP22 gene, its product and its regulation in human brain tissue, and in a variety of experimental systems. We will determine how p ....We used a differential screening procedure to detect changes in gene expression in the human alcoholic brain and described a novel gene, which we named hNP22, with increased expression in the superior frontal cortex of the alcoholic cases. This is the first report of a novel alcohol-responsive gene isolated from the human brain. We now propose to further explore the hNP22 gene, its product and its regulation in human brain tissue, and in a variety of experimental systems. We will determine how protein expression correlates with the level of alcohol consumption. We will use animal and cell culture models to determine the response of the gene to various stimuli. We will express the recombinant protein to determine its function. It is likely that the gene product may be a component in an important signal pathway within neuronal cells and thus may represent a novel target for therapeutic intervention.Read moreRead less
Role Of Kynurenine Metabolites In Causing And Preventing Excitotoxic Brain Damage In The Fetus.
Funder
National Health and Medical Research Council
Funding Amount
$92,815.00
Summary
Brain damage is present in some babies at birth, and recent epidemiological and clinical studies strongly suggest that this either occurs some time during the pregnancy, or the conditions are such that the fetal brain is particularly vulnerable to the stresses that are present during labor and birth. In this project we propose that hypoxic (low oxygen) conditions in the womb, either alone or in combination with substances released because of maternal infection, cause accumulation of a neurotoxic ....Brain damage is present in some babies at birth, and recent epidemiological and clinical studies strongly suggest that this either occurs some time during the pregnancy, or the conditions are such that the fetal brain is particularly vulnerable to the stresses that are present during labor and birth. In this project we propose that hypoxic (low oxygen) conditions in the womb, either alone or in combination with substances released because of maternal infection, cause accumulation of a neurotoxic substance - QUINOLINIC ACID - in the fetal brain and circulation. The increased production of QUINOLINIC ACID occurs because certain cells react to the low oxygen and infectious conditions - these cells include MICROGLIA, a cell type in the brain. Little is currently known about MICROGLIA in the developing brain. We will therefore study the effects of hypoxia and infection in fetal sheep, and we will determine how these conditions affect MICROGLIA and the synthesis of QUINOLINIC ACID in the fetal brain. The capacity of the brain to produce QUINOLINIC ACID is closely related to the dietary intake of the essential amino acid TRYPTOPHAN, and it is decreased when synthetic analogues of tryptophan are infused. Therefore, we have devised a treatment regime using these tryptophan analogues to prevent increases of QUINOLINIC ACID concnetrations in the fetal brain, and we propose that a simple treament is at hand to reduce the incidence of perinatal brain damage in human pregnancies.Read moreRead less
Mechanisms Of Cell Death In Focal Cerebral Ischaemia
Funder
National Health and Medical Research Council
Funding Amount
$229,624.00
Summary
Stroke most commonly results from interruption to a major artery in the brain. If not rapidly reversed the reduction in blood flow leads to the death of many cells in the brain tissue. There is currently considerable interest in developing treatments to be used in the early stages of stroke that can reduce cell death. As the extent of cell death is the major determinant of the long-term disabilities from stroke, such treatments are likely to provide considerable benenfits for affected individual ....Stroke most commonly results from interruption to a major artery in the brain. If not rapidly reversed the reduction in blood flow leads to the death of many cells in the brain tissue. There is currently considerable interest in developing treatments to be used in the early stages of stroke that can reduce cell death. As the extent of cell death is the major determinant of the long-term disabilities from stroke, such treatments are likely to provide considerable benenfits for affected individuals. Our study will investigate mechanisms underlying the death of brain cells in an animal model of stroke and in cells treated in culture. These studies will specifically focus on the role in cell death of alterations in mitochondria, a part of the cell that provides the energy needed for their normal function. The proposed investigations will identify molecular events that contribute to the mitochondrial dysfunction and examine the importance of these changes in brain tissue damage. The findings should contribute to the identication of new therapeutic approaches aimed at ameliorating the consequences of stroke.Read moreRead less
The Use Of Soluble Antagonists Of EphA4 In Spinal Cord Injuries
Funder
National Health and Medical Research Council
Funding Amount
$622,361.00
Summary
Permanent and limited recovery of function following spinal cord injury is a direct result of the lack of nerve regrowth through the injury. Our preliminary data suggest that antagonising the effects of EphA4, a protein involved in brain development, leads to substantial functional recovery simultaneous with nerve regrowth. In addition to designing new, more effective blockers of EphA4, we will study the signalling pathways that EphA4 activates to inhibit nerve regrowth.
Characterisation Of Substance P Antagonists As A Novel Therapeutic Intervention For Use In Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
Traumatic brain injury (TBI) is responsible for more deaths in Australians under 45 years of age than any other cause. The economic and social cost of head injury to the community is enormous with billions of dollars spent each year on the management and rehabilitation of trauma patients. Despite the enormity of this public health problem, no effective treatment currently exists. A number of studies have demonstrated that much of the morbidity following TBI is associated with the development of ....Traumatic brain injury (TBI) is responsible for more deaths in Australians under 45 years of age than any other cause. The economic and social cost of head injury to the community is enormous with billions of dollars spent each year on the management and rehabilitation of trauma patients. Despite the enormity of this public health problem, no effective treatment currently exists. A number of studies have demonstrated that much of the morbidity following TBI is associated with the development of a secondary injury process that occurs between hours to days after the insult. This delayed progression of injury suggests that appropriate pharmacologic intervention can prevent, or at least attenuate, this secondary injury process with a resultant improvement in outcome. Over the past 15 years, a number of groups, including ours, have been investigating the secondary mechanisms associated with the development of functional deficits after TBI. Our previous studies have demonstrated that decline in brain free magnesium is associated with functional deficits after experimental brain injury, and that magnesium administration after injury can improve outcome. Magnesium is now on clinical trial as a pharmacologic intervention. Recent studies have suggested that magnesium decline facilitates neurogenic inflammation, which has been associated with oedema formation, oxidative damage and cell death. Although a number of neuropeptides have been implicated in this process, it is thought that substance P release is closely associated with these pathophysiological processes. Therefore, inhibiting neuropeptide release, or inhibiting substance P binding, may offer a novel therapeutic approach for the attenuation of oedema and development of neurologic deficits after TBI. This proposal will use a combined biochemical, pharmacologic and behavioural approach to characterise the role of neuropeptides in brain trauma, and attempt to develop a novel therapy for use in clinical trauma.Read moreRead less
Insult, Injury And Recovery In Brain Disease: From Molecules To Therapeutic Outcome
Funder
National Health and Medical Research Council
Funding Amount
$8,215,611.00
Summary
When nerve cells are damaged, destroyed or injured, through disease or trauma, common pathological processes are set in train. Even though there are many factors that might trigger disease, these inevitably lead to common processes that end in cell death or initiate protective processes. One theme involves the factors that surround these responses to nerve injury and stress, and the consequent protective and regenerative responses that ensue. Another theme, closely integrates with the first, is ....When nerve cells are damaged, destroyed or injured, through disease or trauma, common pathological processes are set in train. Even though there are many factors that might trigger disease, these inevitably lead to common processes that end in cell death or initiate protective processes. One theme involves the factors that surround these responses to nerve injury and stress, and the consequent protective and regenerative responses that ensue. Another theme, closely integrates with the first, is to exploit basic biological mechanisms with the aim of identifying and developing therapeutic targets for the management of a wider range of neurological conditions.Read moreRead less
Representation Of Spatial Coordinate Systems Within Posterior Parietal Cortex And Hippocampus
Funder
National Health and Medical Research Council
Funding Amount
$43,759.00
Summary
To accurately reach for an object or walk from one room to another, our brains need to be able to locate objects around us and detect obstacles in our path. Our amazing ability to make an accurate eye movement directly towards an object such as a cup of tea and move our hand smoothly and directly to the cup is something we all take for granted. However, this ability requires enormous computational complexity which our brains have evolved to handle with ease. We plan to determine the parts of the ....To accurately reach for an object or walk from one room to another, our brains need to be able to locate objects around us and detect obstacles in our path. Our amazing ability to make an accurate eye movement directly towards an object such as a cup of tea and move our hand smoothly and directly to the cup is something we all take for granted. However, this ability requires enormous computational complexity which our brains have evolved to handle with ease. We plan to determine the parts of the brain that perform these computations by using a relatively new technique called functional magnetic resonance imaging or fMRI. This is a non-invasive technique that requires a person to lie in an MRI scanner and perform simple eye movement tasks while the scanner takes images of the brain. With this technology we are able to determine which regions of the brain are most active during the performance of each task, thereby giving us an insight into how the brain works. An area of the brain called the parietal lobe is thought to be involved in the localization of objects, such as reaching for a cup of tea. We will study this area using fMRI to determine how a map of space is represented within the parietal lobe. This region of the brain communicates with another region, the hippocampus which is thought to be involved in navigation, such as walking about the house or driving in the city. Functional MRI will be used to study the hippocampus of our subjects while they perform simple navigational tasks through a maze which is simulated on a computer screen. This will reveal the role hippocampus plays in navigation and the relationship between the parietal lobe and hippocampus. We hope that the greater understanding of hippocampus that will arise from this study will enable us to devise a robust method for imaging hippocampal function with fMRI. We expect that these techniques will aid in the diagnosis of hippocampal abnormalities in patients with temporal lobe epilepsy.Read moreRead less