Does Caffeine Affect The Development Of The Very Immature Brain: Dose Response Relationship?
Funder
National Health and Medical Research Council
Funding Amount
$668,386.00
Summary
Premature birth is a major health problem worldwide. Preterm babies often develop apnoea of prematurity (AOP), which is commonly treated with caffeine. Trials indicate that preterm babies treated with low dose caffeine have less neurodevelopmental disabilities at 18 months. Higher doses of caffeine are often needed to reduce AOP but the risk of this is unknown. We will study the short and long-term effects of increasing doses of caffeine on the developing brain in a long-gestation species.
Contribution Of Disturbed Blood Flow And Cerebral Metabolism To White Matter Damage In The Perinatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$369,375.00
Summary
It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral ....It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral palsy. Such outcomes are often associated with the presence of asphyxia and infection during pregnancy, leading to the belief that the damage first arises while the baby is still in utero. In this application we suggest that asphyxia and-or infection during pregnancy cause prolonged disturbances in the regulation of blood flow and integrity of the blood-brain barrier in the developing brain, together with changes in metabolism that result in accumulation of prostaglandins and the toxic hydroxyl radical, leading irreversibly to cell death. If this series of events proves to be true, we have suggested and will test several protocols for protecting the fetal brain, which should be readily translatable to clinical practice.Read moreRead less
Neuroactive Steroids In The Developing Brain: Potential For Preventing Perinatal Brain Damage
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown tha ....Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown that protective neuroactive steroids are present in very large amounts in the fetal brain. Steroids produced by the placenta are converted to these neuroactive products by enzymes in the brain leading to the high levels that are seen during fetal life. Certain adverse conditions during pregnancy as well as preterm birth may cause marked changes in the balance of steroids that could increase susceptibility to brain injury. We have found that areas of the brain, where damage most often occurs, normally contain the highest amount of protective steroids, but only in late pregnancy. This suggests that disturbances that lower steroid production in these areas could contribute to the death of cells, particularly in mid-pregnancy and after premature birth. In the proposed studies, we will examine whether a toxic balance of steroids develops following adverse events in pregnancy as well as the areas of the brain where this is most pronounced. We will examine the changes in the expression of enzymes that can potentially cause the accumulation of protective steroids in the brain. We will then examine treatments that can raise the concentration of steroids and determine which combination of steroids best reduces cell death and brain injury following complications during pregnancy. The findings of this work will indicate the best therapeutic approach that may be adopted to modify the concentration of certain steroids so as to reduce the risk of brain damage in the fetus and neonate.Read moreRead less
Neurosteroid Mediated Protection After Birth: Approaches For Maximising Protective Steroid Levels In The Neonatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$450,703.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the ....Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the fetal brain and levels rise further in response to fetal stress. The placenta contributes steroid precursors that help maintain these high neurosteroid levels. This placenta-fetal brain interaction comprises an internal mechanism that protects the fetal brain from adverse events during pregnancy. At birth, however, there is a dramatic decline in neurosteroid concentrations in the brain after the loss of the placental precursor supply. The fall in concentrations is even greater in animals that are born growth restricted. This suggests that newborns, particularly those from compromised pregnancies, are at increased risk of brain damage due to low neurosteroid levels. We believe that certain commonly used steroid therapies may also lower steroid levels in the brain and result in increased vulnerability to brain damage during birth or in the early neonatal period. Alternatively, we propose that replacement of neurosteroid precursors in the newborn may raise brain neurosteroid levels and protect against brain damage. In the proposed studies we will evaluate treatments that can raise the concentration of steroids and determine the best strategy for reducing brain injury following complications during pregnancy, at birth and during the early newborn period. This work will determine the best therapeutic approaches for maximising neurosteroid-induced brain protection and for reducing the risk of brain damage.Read moreRead less
Why Does Early Life Stress Aggravate Limbic Epileptogenesis?
Funder
National Health and Medical Research Council
Funding Amount
$540,116.00
Summary
High rates of anxiety and depression occur in individuals with temporal lobe epilepsy (TLE), the most common form of focal epilepsy in adults. Rats that have experienced early life stress show increased anxiety, decreased seizure thresholds and accelerated epilepsy as adults. We have important leads to mechanisms. The proposed study will better understand the mechanisms connecting early life stress and psychiatric disease to adult TLE, and to test interventions that may counteract these effects.
RISK AND PROTECTION FACTORS FOR NORMAL AND ABNORMAL BRAIN AGEING: A LONGITUDINAL EPIDEMIOLOGICAL MRI STUDY
Funder
National Health and Medical Research Council
Funding Amount
$153,020.00
Summary
Brain is considered the last frontier of medicine, and ageing the major challenge to health care in the 21st century. In this proposal, we bring these two challenges together in a major new longitudinal study of ageing in Canberra that has recently been initiated. This is a longitudinal study of a random community sample covering 3 age groups - 20-24 years, 40-44 years and 60-64 years, with at least 2000 participants in each age group - who are being assessed in 1999-2001, and will be followed u ....Brain is considered the last frontier of medicine, and ageing the major challenge to health care in the 21st century. In this proposal, we bring these two challenges together in a major new longitudinal study of ageing in Canberra that has recently been initiated. This is a longitudinal study of a random community sample covering 3 age groups - 20-24 years, 40-44 years and 60-64 years, with at least 2000 participants in each age group - who are being assessed in 1999-2001, and will be followed up at 4-yearly intervals for 20 years. The focus of the study is on neuropsychiatric disorders (anxiety, depression, substance use and cognitive disorders). In this application, we propose to perform MRI scans and blood tests on a quarter (n-500) of the 60-64 sample to obtain an epidemiological sample for brain morphology. Not only will we be able to study changes in brain morphology over time, and relate it with cognitive function and psychiatric disorder, we will also be able to assess the role of risk and protection factors. We are particularly interested in brain reserve, dietary factors (anti-oxidants, omega 3, wine and folate) and drugs (anti-inflammatory drugs, hormone replacement and vitamin supplements) as protection factors, and hypertension, homocysteine levels, white matter lesions on MRI and low hippocampal volumes as risk factors for cognitive impairment and dementia. We also want to study the brain morphological correlates of Depression in a community sample. The study will enhance our understanding of the ageing brain, both in health and disease, and identify factors that increase or decrease the risk of cognitive impairment and psychiatric disorder in old age.Read moreRead less
Multicentre Trial Of Calcium Channel Blocker Versus Calcium Channel Blocker Plus Cox2 Inhibitor In Preterm Labour
Funder
National Health and Medical Research Council
Funding Amount
$644,130.00
Summary
Preterm birth is a major problem in our society, and has enormous consequences for parents and children. It also has a major impact on scarce financial resources. When women present in preterm labor, current therapies have only limited success in stopping contractions and postponing birth. They have not been shown to reduce the rates of the serious neonatal problems associated with prematurity. This project will be coordinated in Newcastle, N.S.W., and will involve major perinatal centres throug ....Preterm birth is a major problem in our society, and has enormous consequences for parents and children. It also has a major impact on scarce financial resources. When women present in preterm labor, current therapies have only limited success in stopping contractions and postponing birth. They have not been shown to reduce the rates of the serious neonatal problems associated with prematurity. This project will be coordinated in Newcastle, N.S.W., and will involve major perinatal centres throughout Australia, along with overseas centres. It will test a new combination of drugs for their ability to postpone delivery in women presenting with preterm labour. It is postulated that the combination of drugs will be more effective than existing therapies. The drugs used in the trial are Nifedipine and Rofecoxib. Complications of prematurity include neonatal death, cerebral palsy, visual and hearing impairment, and chronic lung disease. These complications are most significant in extremely premature infants - in particular, those under 28 weeks gestation at the time of their delivery. For this reason, the study will focus only on women presenting in labour below 28 weeks. The ability to stop labour is important, but the main aim of any treatment for preterm labour is to reduce the rates of neonatal death and handicap. Babies born to women enrolled in this study will be followed for a period of one year after birth to assess their outcomes. It is our hypothesis that the combination of Rofecoxib and Nifedipine will result in lower rates of death and handicap in babies than Nifedipine alone. In addition, we will examine the rates of side effects in women receiving therapy. Currently used therapies, including intravenous ventolin, have high rates of maternal side effects. Nifedipine and Rofecoxib have both been shown to have low rates of maternal side effects.Read moreRead less