Delineating The Anatomical Correlates Of Neurocognitive And Psychomotor Dysfunction In Depression By FMRI
Funder
National Health and Medical Research Council
Funding Amount
$388,340.00
Summary
Severe depression is characterised by slowing of mental and motor abilities. Previous research by our group indicates the role of small frontal and basal brain regions in the regulation of these abilities. This research will extend our previous studies by providing new information detailing the underlying physiology of behavioural and structural abnormalities in patients with severe depression. Emerging research by our group and others suggest that some types of severe depression in later life a ....Severe depression is characterised by slowing of mental and motor abilities. Previous research by our group indicates the role of small frontal and basal brain regions in the regulation of these abilities. This research will extend our previous studies by providing new information detailing the underlying physiology of behavioural and structural abnormalities in patients with severe depression. Emerging research by our group and others suggest that some types of severe depression in later life are due to undetected forms of cerebrovascular disease. If we are able to demonstrate that the key features of severe depression of this type (psychomotor, attentional, memory and executive disturbance and global disability) are related to such brain changes this may lead to a major breakthrough in the prevention and treatment of these disorders. A new type of brain imaging technology called 'functional Magnetic Resonance Imaging' (fMRI) permits simultaneous investigation of the structure and function of small areas of the brain. As the technique does not use radiation and can be performed while the patient is completing mental tasks, it can be used in repeated experiments. Consequently, it permits description of brain changes (areas of activation) that occur during specific mental tasks. Therefore, if we are now able to use this technique to extend our previous clinical and imaging studies we will be able to test whether some forms of late-life depression are due to undetected brain changes.Read moreRead less
THE NATURAL HISTORY OF COGNITIVE IMPAIRMENT AND DEMENTIA IN A STROKE COHORT
Funder
National Health and Medical Research Council
Funding Amount
$290,747.00
Summary
In a current NHMRC-funded study, we have examined 200 stroke patients (and 100 control subjects) at 3 months after a stroke and one year later, and identified those who have impairment in memory and other cognitive functions. We have also studied these subjects in detail from a psychiatric perspective and performed brain scans on them using magentic resonance imaging. We find that many stroke patients have problems with their cognitive functioning which has a major impact on their lives. A large ....In a current NHMRC-funded study, we have examined 200 stroke patients (and 100 control subjects) at 3 months after a stroke and one year later, and identified those who have impairment in memory and other cognitive functions. We have also studied these subjects in detail from a psychiatric perspective and performed brain scans on them using magentic resonance imaging. We find that many stroke patients have problems with their cognitive functioning which has a major impact on their lives. A large number also become depressed. These consequences of stroke are not given sufficient importance by clinicians. The fact that stroke is a common problem in the elderly, and our society is aging, makes this a problem of major public health significance. In the new proposal, we plan to study these subjects up to 3 years with repeat neuropsychiatric assessments and brain scans to investigate the natural history of stroke-related cognitive impairment. We will determine whether further new cases of dementia develop in the period 1-3 years, what happens to the brain lesions picked up on brain scans, and how these deficiencies affect the patients' living status and their longevity. We will be able to determine the factors that lead to a good outcome, and suggest strategies that may be applicable to improve the functioning of these individuals.Read moreRead less
Early Events In Arteriolar Remodeling: Adaptation To Prolonged Vasoconstriction
Funder
National Health and Medical Research Council
Funding Amount
$415,750.00
Summary
Small arteries, while acutely responding to their environment with changes in diameter to regulate local blood flow and pressure, also undergo structural adaptation or remodelling. These events occur over a range of time-frames and involve both non-genetically and genetically regulated events. Thus a contractile event, while initially decreasing vessel diameter, also activates longer time frame processes which can span from rearrangment of cellular junctions-contacts to overt structural changes ....Small arteries, while acutely responding to their environment with changes in diameter to regulate local blood flow and pressure, also undergo structural adaptation or remodelling. These events occur over a range of time-frames and involve both non-genetically and genetically regulated events. Thus a contractile event, while initially decreasing vessel diameter, also activates longer time frame processes which can span from rearrangment of cellular junctions-contacts to overt structural changes within the vessel wall (for example thickening of the muscle layer). These adaptive processes may enable the forces of contraction to be maintained without continued energy expenditure and damage to the vessel per se. However, they can also contribute to long-term alterations in the control of blood pressure and perhaps contribute to states of hypertension as well as other common vascular diseases. For these studies we will use arterioles, isolated by microsurgical techniques, together with sophisticated computer and video-based approaches. These techniques allow arterioles to be studied under controlled conditions and relevant biochemical measurements performed. We will also use a cell model where cultured cells will be studied after defined periods of mechanical stimulation (for example stretch). Cells will be probed using a novel microscopic technique (atomic force microscopy) which enables the cell membrane to be studied with respect to changes in composition as well as physical characteristics (for example stiffness). The studies are relevant to our understanding of the normal adaptive processes occurring within blood vessels to control blood flow and pressure. The studies are also of direct relevance to our understanding of common vascular disease states including hypertension, complications of diabetes and chronic inflammatory disorders.Read moreRead less
Trajectories Between Childhood Internalising Behaviour Problems And Adolescent Depressive Symptoms
Funder
National Health and Medical Research Council
Funding Amount
$55,000.00
Summary
Depressive symptoms are known to escalate sharply through the adolescent years. Adolescents who experience an episode of depression are very likely to experience further mental illness as adults. Efforts to prevent depressive illness may be advanced by research delineating the factors and processes implicated in the early emergence of depressive symptoms. To advance such an understanding this project will analyse data collected, in part, through NHMRC support to Australian Temperament Project (A ....Depressive symptoms are known to escalate sharply through the adolescent years. Adolescents who experience an episode of depression are very likely to experience further mental illness as adults. Efforts to prevent depressive illness may be advanced by research delineating the factors and processes implicated in the early emergence of depressive symptoms. To advance such an understanding this project will analyse data collected, in part, through NHMRC support to Australian Temperament Project (ATP) researchers. The ATP data will be used to examine factors associated with the development and progression of depressive symptoms from childhood to adolescence. The ATP data set includes detailed longitudinal data collected from multiple sources (parents, teachers and youth) concerning child and adolescent temperament, behavioural problems, mother-child relations, health, depressive symptoms, school achievement, school adjustment, social skills, peer relationships, parenting practices, stressful life events, and sociodemographic factors. Of an original sample of 2443 enrolled in the cohort in 1983 (aged 4-8 months) a subsample of 1,350 adolescents should complete the data collection due in 2000 (age 17-18). Through the analysis of ATP data proposed in this application, models will be developed to explain the risk and resiliency processes in childhood and early adolescence influencing the development and course of adolescent depression, for different subgroups of adolescents. To achieve this objective, analyses will: 1. identify groups who have differing trajectories from childhood internalising behaviour problems to adolescent depressive symptoms; 2. compare groups to identify factors that contribute to the progression from internalising behaviour problems to depressive symptoms, while also identifying factors which appear to impede such progression and; 3. compare groups to identify factors associated with transient versus persistent depressive symptoms in adolescence.Read moreRead less
How Does Activated Protein C Create Intact, Non-leaky, Stable Blood Vessels?
Funder
National Health and Medical Research Council
Funding Amount
$564,644.00
Summary
Vascular dysfunction is a common feature of many diseases, including sepsis, diabetes, atherosclerosis, tumours and asthma. These vessels have compromised structural and functional integrity, leading to leakage of blood components and causing inflammation in tissues. Based on our recent findings, this project aims to discover how activated protein C creates normal, healthy non-leaky blood vessels and prevents vascular dysfunction in disease.
Understanding The Role Of Muscarinic Receptors In The Pathophysiology Of Depression And Bipolar Disorder
Funder
National Health and Medical Research Council
Funding Amount
$480,074.00
Summary
The causes of bipolar disorder and major depressive disorder, which effect many Australians, remain unknown. We have recently shown decreases in muscarinic receptors in the brain of people with bipolar disorder and major depressive disorder. Muscarinic receptors are important in maintaining the functions of the brain that seem to be affected in people with bipolar disorder and major depressive disorder. Here we seek to understand how changes in muscarinic receptors occur in both disorders.
Local Microvascular Regulatory Mechanisms In Diabetes: Relevance To Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
In diabetes mellitus, the excessive levels of sugar in the blood may cause changes in metabolic processes within cells that lead to disturbances in the function of the circulatory and nervous systems. Such disturbances have been shown to occur in the early stages of diabetes and ultimately lead to longterm consequences including poor wound healing (often culminating in limb amputations), increased risk of blindness, kidney disease and heart failure. At present it is not possible to restore norma ....In diabetes mellitus, the excessive levels of sugar in the blood may cause changes in metabolic processes within cells that lead to disturbances in the function of the circulatory and nervous systems. Such disturbances have been shown to occur in the early stages of diabetes and ultimately lead to longterm consequences including poor wound healing (often culminating in limb amputations), increased risk of blindness, kidney disease and heart failure. At present it is not possible to restore normal metabolism, leaving patients at risk of developing complications involving the circulatory and nervous systems. An understanding of the processes involved in the development of such complications would allow alternate treatment strategies to be devised in order to improve the quality of life and life expectancy of diabetic patients. The events leading to abnormalities in the function of the circulatory and nervous systems are uncertain, however, studies have demonstrated that in diabetes there may be an insufficient blood supply to nerves and this would be expected to cause nerve damage. At present, our understanding of the factors involved in regulating blood flow to nerves is limited. The studies described in this proposal are aimed at testing the hypothesis that nerve blood vessels are themselves involved in the regulation of flow through an intrinsic ability to change their diameter in response to tissue demands and that in diabetes alterations in the capacity of nerve blood vessels to constrict or dilate compromises their role in the control of nerve blood flow . Information obtained from these studies will improve our understanding of the early disturbances in the function of circulatory and nervous systems leading to alterations in blood flow which precede the development of overt changes characteristic of the complications associated with diabetes. This will provide insight into developing new treatment strategies for diabetic patients.Read moreRead less
A Double-blind Sham Controlled Trial Of RTMS In Treatment Resistant Major Depression
Funder
National Health and Medical Research Council
Funding Amount
$371,491.00
Summary
Treatment Resistant Depression is clearly a major health issue - depression is common, results in marked morbidity and mortality and a large percentage of patients do not respond to, or cannot tolerate standard treatment. The development of new treatments for this condition is undoubtedly required. International efforts are underway to try and establish the efficacy of high frequency left Transcranial Magnetic Stimulation (HFL-TMS) to the point where the technique may be approved by regulatory a ....Treatment Resistant Depression is clearly a major health issue - depression is common, results in marked morbidity and mortality and a large percentage of patients do not respond to, or cannot tolerate standard treatment. The development of new treatments for this condition is undoubtedly required. International efforts are underway to try and establish the efficacy of high frequency left Transcranial Magnetic Stimulation (HFL-TMS) to the point where the technique may be approved by regulatory authorities and clinically introduced. However, clearly the response rate to HFL-TMS is suboptimal for its widespread use. The overall goal of this research program is to develop repetitive TMS (rTMS) methods to the point at which they are highly relevant and applicable to clinical practice. None of the substantial international studies is focusing on novel applications such as sequential bilateral rTMS (SBrTMS). The planned outcome of this study is that it may change the focus of rTMS application and practice nationally and internationally. If we can follow our well received initial study of this technique with a substantial comparative trial as planned here, it will provide enough evidence for the more widespread adoption and testing of SBrTMS as a viable alternative to HFL-TMS. Ultimately, this or a modification of it, may become the rTMS administration method of choice. Additionally, we will have a sufficient sample size to start to explore meaningful predictors of clinical response including biological, psychosocial-personality variable predictors.Read moreRead less
Antioxidant Glutathione Peroxidase (GPx) Mimetics And Atherosclerosis: A Role For Targeted Antioxidant Therapy.
Funder
National Health and Medical Research Council
Funding Amount
$358,319.00
Summary
This proposal investigates the use of antioxidant therapy, targeted at increasing the function of the body's important antioxidant enzyme GPx1, to reduce atherosclerosis both in a non-diabetic and diabetic setting. Strong clinical evidence and our recently published data support an important role for GPx1 in limiting atherosclerosis. We will now investigate the molecular mechanisms involved in mediating these effects and whether compounds that mimic GPx1 function reduce atherosclerosis.
Vascular And Neuro-glial Dysfunction In Diabetic Retinopathy
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
The retina is responsible for sight. Vision occurs by interactions between blood vessels, neurons (cells that transmit electrical signals for vision) and glia (cells that support the retina). In diabetes, high amounts of glucose in blood increases certain factors within retinal cells. These factors slowly cause damage, such that after 15 years of diabetes all patients will have some retinal disease and many will loose sight. Indeed, diabetes is the leading cause of blindness in working people. T ....The retina is responsible for sight. Vision occurs by interactions between blood vessels, neurons (cells that transmit electrical signals for vision) and glia (cells that support the retina). In diabetes, high amounts of glucose in blood increases certain factors within retinal cells. These factors slowly cause damage, such that after 15 years of diabetes all patients will have some retinal disease and many will loose sight. Indeed, diabetes is the leading cause of blindness in working people. The main treatment for diabetic retinal disease is to burn away damaged blood vessels, however, this treatment has problems. Firstly, the burns destroy healthy retina and the disease continues, secondly, the treatment is performed late in the disease and therefore does not prevent the early changes in retinal cells, and thirdly, changes in neurons and glia are often not considered. Therefore, there is an urgent need to understand how blood vessels, neurons and glia interact with each other to threaten vision in diabetes, with the intention of developing safer and more effective treatments. This will be the focus of the current project. Currently, there are no studies that have examined the sequential changes in retinal blood vessels, neurons and glia in diabetes. This is mainly due to the lack of an experimental rodent model that progresses from mild to severe diabetic retinal disease. In 2003, we established such a model in the diabetic Ren-2 rat. In this project the diabetic Ren-2 rat will be used to study retinal cell changes and also to identify the factors that damage these cells. We suggest that angiotensin, bradykinin and VEGF are involved. These factors are present in the normal retina and are increased in diabetes. We will block these factors with specific drugs with the intention of understanding how these factors affect retinal cells in diabetes, and also to develop new drug therapies for the treatment of both early and late diabetic retinal disease.Read moreRead less