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PROJECTS COMPLETED FOR THE YEAR 2014/2015


ANXIETY DISORDERS

The role of controlled and automatic processes in Generalised Anxiety Disorder aimed at

improving the treatment of chronic anxiety. The researcher attempted to direct attention away from worry, and to modify mental habits that focus on the negative. It was found that a habit to attend to threat very quickly cannot be influenced by deliberate efforts to direct attention. However, efforts to replace verbal worry with other forms of thinking can not only be implemented successfully following training, but all methods lead to reductions in negative thoughts. Furthermore, replacing worry with any form of positive mentation for a week reduced negative thought intrusions, trait worry and anxiety in people with a diagnosis of generalised anxiety disorder.


Investigating the neurocognitive regulation of anxiety states using suggestions and fMRI

looked at ways to help those with anxiety disorders. This project extends prior studies using hypnosis in combination with magnetic resonance neuroimaging techniques to investigate brain systems involved in the regulation of anxiety and calmness. The project showed that hypnotic suggestions effectively elicit states of anxiety as well as calmness. It was found that the middle frontal gyrus as a key node involved in the experience and regulation of anxiety. The brain systems involved in affect regulation identified by this study are already informing a project using real time fMRI biofeedback to train participants to control their own brain activity, specifically targeting via mental strategies circuits known to be involved in the regulation and re-appraisal of anxiety. These methods promise to provide a safe, effective alternative or adjunct to medication and/or cognitive behavioural therapy in the treatment of anxiety disorders.


DEPERSONALISATION DISORDERS

Clinical Studies and Neuromodulation in Depersonalisation Disorder

studied patients with depersonalisation. The project aimed to improve our clinical understanding of depersonalisation and develop more effective treatments via two routes: brain imaging and stimulation studies. A case series of seven patients with depersonalization were involved in a trial of repetitive Transcranial Magnetic Stimulation (where parts of the brain are temporarily ‘deactivated’). This research showed promising results and suggest that a larger scale trial is warranted. Two pieces of research have been published: the first compared profiles of anxiety symptoms between large samples of people with anxiety disorders and those with Depersonalisation. Both groups were similar in their thoughts about anxiety symptoms but differed in the physical experience. The second paper looked at the relationship between the concept of being mindful and depersonalization in a sample of 22 patients. As predicted, the depersonalization patients showed significant impairment in their ability to be mindful.


DEPRESSION

Modelling Synaptic Connectivity in Depression studied patients with depression.
Dendritic spines are small membrane protrusions on the neuron where synapses occur. Further to this altered or mutant genes, such as DISC1, have been shown to increase the susceptibility of individuals to depression and coinciding loss of dendritic spines signifying a loss of synapses. The aim of the project was to investigate whether pairing estrogen with antidepressants is able to rescue the loss of synapses on neurons caused by the presence of mutated MDD susceptibility genes. Previous work has demonstrated that estrogen – a steroid hormone – has a powerful effect on synaptic connectivity and communication, through the increase number of dendritic spines on a neuron leading to an increase in the number of synapses. This project has shown that estrogens are able to rescue the dendritic spine number in the presence of a mutation in a susceptibility gene for MDD. This provides preliminary data that estrogen treatment could in conjunction with antidepressants provide potential treatments for patients with depression.


Impact of Nutrition on Adult Neurogenesis and Depression

studied the impact of nutrition on adult neurogenesis and depression. This project studied the effect of nutrients present in our every-day diet that have been shown in epidemiological studies to have a positive effect on depressive symptoms. We suspect they are having this behavioural effect by increasing neurogenesis. Using a human hippocampal cell line and developing an in vitro model of stress by exposing the cells to cortisol (i.e. Anacker et al., 2011), our studies showed that omega-3 fatty acids have the capability to prevent the effects of cortisol by increasing the percentage of diving cells and neurogenesis while decreasing apoptosis mainly by promoting survival.


EATING DISORDERS

An fMRI pilot study of the effects of meal support in Eating Disorder

compared patients with anorexia nervosa with normal controls. It was demonstrated that a series of sessions aimed at decreasing anxiety associated with eating were effective not only in reducing the patient’s symptoms, but this change is reflected in changes in brain activation. Brain scans indicated that after the intervention and compared to controls, patients displayed decreased brain responses to food stimuli in a midline fronto-parietal network. mThis suggests that after repeated exposure to food stimuli patients might have learned strategies to reduce negative responses to food.


MOTOR NEURON DISEASE

Analysis of pathways leading to clearance of TDP-43

reported that in the majority of patients with motor neuron disease (MND) and frontotemporal dementia (FTD), a specific protein called TDP-43 is directly toxic to neurons. Research had previously shown that mutations in the gene controlling this protein causes MND and FTD in rare cases (1-2%), although it accumulates in over 90% of all MND and in about 60% of FTD cases. Thus the majority of people are accumulating this protein without mutation. At the time the project started little was known about how this protein came to aggregate and how these aggregates were cleared from cells. The project explored the involvement of this protein in initiating toxicity using neuronal cell lines and transgenic mice and successfully introduced the aggregates of the protein into neuroblastoma cells and measured the propensity for the protein to aggregate under normal and stressful conditions. Cells were assayed for the signature features of TDP-43 toxicity (including phosphorylation, ubiquitination, P62 recruitment), and by immunocytochemistry. The research was able to show in detail how this gene operates and suggests that in addition to the normal impairment of the ubiquitin proteasome system that occurs with age, a second hit in these pathways occurs in patients with MND and FTD, which drives the accumulation and aggregation of this gene (TDP-43). Her data suggest that therapies targeted to clearing excess TDP 43 in these patients should not be limited to one or other of these pathways but rather a combination of the two. Impairment of the autophagy pathway is increasingly recognised to be important in the pathogenesis of many neurodegenerative disorders. This study has provided important insights into the handling of TDP-43 in neurons in the healthy physiological setting but also when it begins to accumulate as seen in disease. She has gone on to use these discoveries to inform analysis of more complex modules of TDP-43 mediated disease in Drosophila and mice. Based on this work it has also established collaborations with several Pharmaceutical companies who wish to utilise the cellular and animal models we have developed to screen for compounds from their libraries that might have efficacy in MND an FTD.


Analysing a TDP-43 transgenic mouse model of MND

studied effects of TDP-43 on MND & FTD. The project sought to establish a mouse model that more closely resembled the human disease. It was possible to produce a transgenic mouse and undertake long term monitoring of welfare and weight of these mice as well as their ability to stay on a slowly accelerating rotating cylinder, a test known as the ‘rotarod’, which measures the ability of the mouse to balance on the rod. Also studied were the brain, spinal cord, peripheral nerves and muscles of the mice to look at the effects of overexpression of this protein in terms of neuronal damage (neuronal loss, inflammation, motor nerve loss from peripheral nerves and loss of neuro-muscular junctions and muscle atrophy). It was found that mice overexpressing one human wild type gene (TDP-43WT) develop no overt physical or pathological phenotype, while those overexpressing another (TDP-43Q331K) develop an age-dependent mild motor and pathological phenotype. Mice that possess both these genes develop marked tremor at 3 weeks and a rapidly progressive paralysis requiring euthanasia by 8-10 weeks. Such mice demonstrate major neuronal loss, robust astroglial and microglial reactivity, increased cytoplasmic TDP-43 accumulation and detergent resistant TDP-43. The motor axons in the lumbar nerve root were significantly reduced as were their neuromuscular junction number and muscles, which showed marked denervation. It was proposed that mislocalisation and aggregation of the mutant protein seeds the rapid recruitment of wild-type TDP-43 to the aggregates that in turn greatly accelerates the disease processes. This study has provided important insights into the nature of toxicity produced by this gene (TDP-43) in mammals. The progressive paralyzing phenotype in the double transgenic mouse closely resembles the clinical features of MND patients. The pathological features of TDP-43 aggregation, neuronal loss and denervation of muscles also is similar to the pathology of the human disease. Having a mouse model will allow us to map the temporal course of disease in a way that is not possible form human post-mortem tissues. This basis of this work has also established collaborations with several Pharmaceutical companies who wish to utilise these cellular and animal models developed to screen for compounds from their libraries that might have efficacy in MND an FTD.

Charity No 284286



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