Dr Teresa Lee was awarded the 2013 UNSW Rising Star Award.
Healthy brain functioning is an important part of healthy ageing. Several brain features have shown links with healthy ageing; including brain size, brain white matter hyperintensity (WMH) and brain metabolites. Age-related changes are influenced by both genetic and environmental factors, and this study looked at how they influence the structure and biochemistry of the brain. Participants were recruited from the OATS Study (average age 72 years). Firstly structural equation modeling was performed to compare MRI brain scan data from identical and fraternal twins. The influences of age and sex on the heritability of these parameters were examined, as well as identifying any common genetic factors. Estimations showed significant heritability of the brain size, WMH volume and brain biochemistry in the elderly. Brain size heritability decreased with age, but WMH volume heritability increased. There were no significant differences between males and females in the heritability of brain metabolites and WMH volumes, but the heritability of brain size was higher in males. Also, common genetic factors were observed between the volumes and WMHs of different brain regions and also between the brain metabolites. The results showed that the human brain is largely influenced by genetic factors in later life, but that this influence may diminish with increasing age, particularly for brain size. As environmental factors may become more important in later life, it is suggested that healthy ageing may be optimized by enrichment of environmental conditions.
The World Health Organisation has in recent years declared depression as the number one cause of disability in the world. Treatment options include pharmacotherapy, cognitive behavior therapy and supportive counseling. The adverse effects of pharmacotherapy (a major deterrent to patient compliance) and recent literature reporting only 6-7% of depressed patients remit on pharmacotherapy are of concern. Many patients suffering from depression turn to Complementary Medicine, including acupuncture for answers. Empirically acupuncture has been helpful in treating depression, however, due to the heretogeneity of acupuncture in depression studies, results have been inconclusive. Acupuncture’s adverse effects profile is minimal and it is well tolerated. This project is a comprehensive investigation on the use of low intensity laser acupuncture (LA) in the treatment of depression based on the highly significant pilot study using LR14, CV14, HT7, LR8 acupoints. The significant brain effects of these acupoints under LA in healthy and depressed subjects are identified and evaluated. Default mode network (DMN) modulation by LA and its relevance to depression is explored. The pilot clinical study was repeated with both clinician and self-reporting measures. An attempt is also made to identify the components of depression that improved with LA. The final experiment was to test the differential brain activation between LA and NA on the most significant acupoint within the treatment regime. The replication of the positive findings of the anti-depressant regime using LA has been further clarified by the fMRI studies: LA modulates the brain regions important in depression, including the DMN. There are wider brain regions stimulated with LA in depressed subjects (DS). Its stimulation of brain regions important in wellbeing and sense of self (identity) in healthy subjects (HS) does suggest maintenance LA may be helpful. Acupoint specificity was identified. Somatisation effects were significantly improved in the clinical study delivering a better quality of life. Transient fatigue was the only adverse effect reported. Further work on acupoint specificity in actual treatment regimes for different conditions is necessary. LA and NA both have commonality and specificity in their brain effects that need further exploration.
Im has just returned from the Neuroscience Research Institute at Gachon University, Incheon, Korea, where she is collaborating with Prof. Zhang Hee Cho and Dr. Richard Niemztow on the US Govt. $5.4M grant on the fMRI evidence for Battlefield Acupuncture’s brain effects in pain modulation.
Alzheimer's Disease (AD) is a devastating and costly disorder that will become more common with the ageing of society. Accordingly, the delay, prevention and treatment of AD has risen as a top priority worldwide. Several lines of evidence suggest delay and prevention of AD may be possible through non-pharmacological lifestyle interventions.
This thesis has an interest in cognitive lifestyle, defined as lifelong habits of complex mental activity, and lifestyle-related physical activity, and their interventional counterparts, cognitive training and physical exercise. Extensive epidemiological research links these lifestyle factors with decreased dementia incidence and decreased cognitive impairment. Also, clinical trials evidence suggests that cognitive training and physical exercise can be effective at improving cognitive outcomes in healthy individuals as well as those with Mild Cognitive Impairment (MCI). However, the mechanisms by which these lifestyle factors or interventions lead to positive cognitive outcomes are largely unknown (systematically reviewed in Chapter 2).
This thesis therefore aimed at addressing these knowledge gaps using multimodal MRI. Three studies are presented, organized around two main themes. Firstly, potential neuroplastic mechanisms linked to cognitive lifestyle are investigated in Chapters 3 and 4. Secondly, the longitudinal effects of cognitive and physical training on brain structure, function and cognition in MCI is assessed in Chapter 5, in the setting of the Study of Mental Activity and Regular Training (SMART) Trial.
In Chapter 3, midlife managerial experience was revealed to be the key part of cognitive lifestyle linked to protection from hippocampal atrophy in late life. In Chapter 4, we extend this to MCI, finding that managerial experience is also linked to hippocampal morphometry, hippocampal functional networks, memory performance and subjective memory concerns. In Chapter 5 we found that cognitive training and physical resistance training stimulate distinct mechanisms: resting state hippocampal functional connectivity and posterior cingulate cortical thickness, respectively. Furthermore, these different types of brain plasticity were associated with different training-related therapeutic cognitive outcomes. Finally, in Chapter 6 we integrate these findings with the literature in terms of both long-term and short-term brain plasticity, discuss the limitations of current longitudinal MRI processing methods, and make recommendations about future research directions.
Major Depressive Disorder (MDD) is a debilitating and pervasive illness with a lifetime prevalence of between 10-15% of the world’s population. The prevailing hypothesis of depression is the stress neurotrophic hypothesis, and is characterised by excessive levels of stress and glucocorticoids. Excessive stress and glucocorticoids result in detrimental changes to the structure and functioning of the brain, including effects upon neuroplasticity. Neuroplasticity allows the brain to differentially respond to stimuli, and adapt to changes in the environment. Impaired neuroplasticity is linked to a number of symptoms in depression. The thesis aims were to find a means to objectively test neuroplasticity in subjects suffering MDD, and to compare neuroplasticity with matched controls. A secondary aim was to discover if neuroplasticity changed with treatment for depression. To achieve these aims, three separate experiments were carried out. The aim of the first study was to find a conditioning protocol that induced robust and consistent increases in motor cortical excitability, thus providing a means of measuring neuroplasticity, in healthy subjects. The selected conditioning protocol would be used for measurement of neuroplasticity in healthy and depressed populations in two subsequent studies. Using the paired associative stimulation (PAS) protocol selected from study 1, the aim for study 2 was to compare neuroplasticity in depressed subjects with that of age and gender matched controls. By measuring motor cortical plasticity before and after PAS conditioning, this study provided one of the first objective demonstrations of impaired neuroplasticity in individuals with MDD that is not confounded by subject effort or motivation. In study 3, PAS-induced neuroplasticity was measured twice in the same subjects. The first measure was taken while subjects were depressed, the second, after a treatment course of transcranial direct current stimulation. This study showed a significant improvement in neuroplasticity and mood state after treatment, though change in mood did not correlate with change in neuroplasticity. This research supports a hypothesis of impaired neuroplasticity in depression. Thesis findings provide evidence of improved neuroplasticity and depressive symptoms after treatment, and thus provide important information about the pathophysiology and treatment of MDD.
Parkinson’s disease (PD) is a neurodegenerative disease which is caused by many factors including progressive degeneration of dopamine (DA)-secreting neurons which reside in the midbrain substantia nigra (SN). Currently, there is no cure for treating PD and therefore, alternative treatment such as cell replacement therapy using human embryonic stem cells is required. A specific investigation on the derivation of DA neurons was carried out by using a three-dimensional (3D) environment via encapsulation. A detailed gene and protein expression analysis during neuronal differentiation showed earlier onset of midbrain DA (mdDA) neuronal markers and secreted higher DA level than the cells differentiated under conventional two-dimensional (2D) culture system. This data corresponds to the microarray data which revealed up-regulation of mRNA expressions that are involved in neuronal developments such as Wnt, hedgehog and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, a hESC reporter cell line which has been stably integrated with a plasmid vector that contains a human TH promoter tagged with an enhanced green fluorescent protein (eGFP) marker with no abnormal karyotype. Results from this study displayed a more effective differentiation towards neuroectoderm and DA neurons when differentiated under 3D environment. It is a very useful model to study the proliferation and directed differentiation of hESC to various lineages. This 3D system also allows the separation of feeder cells from hESC during the process of differentiation and also has potential for immune-isolation during transplantation studies. The derivation of hESC reporter cell line containing TH-tagged eGFP could be further utilised to isolate homogeneous population of DA neurons for possible transplantation studies or developmental pathway analysis in the future.