Neuropsychiatry and Stress Biology
Developmental Psychobiology @ The Florey below
The worldwide ENIGMA MDD consortium: detecting robus imaging markers of depression - also offered as MBiomedSc
Supervisors: Dr. Lianne Schmaal and Dr. Chris Davey
Project Site: Orygen the National Centre of Excellence in Youth Mental Health, University of Melbourne
Contact: Dr. Lianne Schmaal, T: 0393422886 E: lianne.schmaal@unimelb.edu.au
Project description: Major depressive disorder (MDD) is a highly debilitating disorder that has an enormous detrimental impact on patient's life and a high social and economic burden. Many studies have identified structural and functional brain alterations in MDD. However, to date, volumetric and functional brain differences have not always been consistent, which may in part be explained by small sample sizes and differences in methodological and clinical characteristics between studies. To address the limited statistical power of prior studies, the MDD working group within the “Enhancing NeuroImaging Genetics through Meta-Analysis”, or ENIGMA, was initiated a few years ago, see
http://enigma.ini.usc.edu/ongoing/enigma-mdd-working-group/
The overall aims of the ENIGMA MDD consortium are to 1) identify robust imaging markers of MDD, 2) establish the neurobiological correlates underlying variation in disease profile and disease course, and 3) identify the genetic factors affecting neurobiological alterations in MDD using available genome-wide data, and relate the genetic risk profile to the implicated brain circuits. Currently, 31 research sites from around the world are participating in ENIGMA MDD and sharing neuroimaging data.
The student will support ongoing ENIGMA MDD work, which includes development and execution of data processing, quality assurance and statistical analyses protocols for neuroimaging (structural MRI, resting state fMRI and DTI) and genetic data, organising and harmonising databases, communicating with members of the consortium, writing scientific papers on the above topics, and incorporating the research into a PhD thesis. Candidates with an interest in psychology, biological psychiatry and imaging neuroscience are encouraged to apply. Having prior experience with neuroimaging analyses and having strong statistical and computer programming skills is desirable. Further detail about this project is available upon request.
Understanding the heterogeneity of youth depressin using machine learning methods - also offered as MBiomedSc
Supervisors: Dr. Lianne Schmaal and Dr. Chris Davey
Project Site: Orygen the National Centre of Excellence in Youth Mental Health, University of Melbourne
Contact: Dr. Lianne Schmaal, T: 0393422886 E: lianne.schmaal@unimelb.edu.au
Project description: The conventional approach to diagnosing MDD does not reflect the complexity and heterogeneity of the disorder, and consequently, reproducible neurobiological and genetic studies remain elusive. Depression is a complex heterogeneous disorder and the diagnostic label of MDD based on the classificatory systems of the DSM and ICD is likely to encompass biologically distinct phenotypes with different aetiologies and different optimal treatment strategies. This project aims to disentangle phenotypic heterogeneity of youth depression by integrating neurobiological information with clinical and behavioural data using machine learning techniques.
This project (or potentially PhD project) will use functional magnetic resonance imaging (fMRI) and data on symptom dimensions. The student will be involved in the acquisition of the neuroimaging and clinical data, processing of neuroimaging data and using machine learning methods to stratify the patients. Patients will be recruited from Orygen Youth Health and headspace centres. Candidates with an interest in psychology, biological psychiatry and imaging neuroscience are encouraged to apply. Having prior experience with neuroimaging analyses and having strong statistical and computer programming skills is desirable. Further detail about this project is available upon request.
The relationship between dietary quality, nutrient biomarkers, and major depressive disorder - also offered as MBiomedSc
Supervisors: Dr Jerome Sarris
Project Site: The Melbourne Clinic (Richmond)
Contact: Dr Jerome Sarris jsarris@unimelb.edu.au
Project description: Emerging data is showing there is a relationship between mental health and a person’s dietary quality and nutrient status. We have novel data assessing dietary quality, in addition to serum levels of essential fatty acids, zinc, folate, and B12, in a sample of adults with current major depressive episode (n=150). This sub-project (from an NHMRC-funded study) will explore the relationships between these factors to determine any meaningful associations. Matched control data will be collected by the successful research student, to determine any differences between depressed and healthy people in respect to their dietary quality and nutrient status
Mapping the Human Schizophrenia Connectome - also offered as MBiomedSc
Supervisors: Dr Andrew Zalesky (Melbourne Neuropsychiatry Centre), Dr Alex Fornito (Monash Biomedical Imaging), Dr Luca Cocchi (Queensland Brain Institute), Professor Christos Pantelis (Melbourne Neuropsychiatry Centre)
Project Site: Melbourne Neuropsychiatry Centre
Contact: Dr Andrew Zalesky: azalesky@unimelb.edu.au
Project description: This project aims to comprehensively map the entire human connectome in schizophrenia. The student will complete one of the largest clinical connectome mapping studies undertaken in the world by analysing high-quality brain imagin
g data in more than 330 individuals with schizophrenia provided by the Australian Schizophrenia Research Bank (ASRB). The ASRB is the largest brain research project ever undertaken in Australia. This project will apply advanced fibre tracking algorithms to the diffusion-MRI brain imaging data acquired in each patient, with the goal of comprehensively mapping all disrupted connections comprising the entire schizophrenia connectome. VLSCI computational resources may be utilised for this purpose.
Figure: Disruptions to functional brain connectivity in schizophrenia.
Human Connectome Bioinformatics - also offered as MBiomedSc
Supervisors: Dr Andrew Zalesky, Professor Christos Pantelis
Project Site: Melbourne Neuropsychiatry Centre
Contact: Dr Andrew Zalesky: azalesky@unimelb.edu.au
Project description: The connectome refers to a comprehensive network description of the brain’s internal wiring. Advances in magnetic resonance imaging (MRI) have enabled reliable mapping of the large-scale connectome in the living human brain. Comparing the human connectome between healthy and diseased brains has identified disease-specific anomalies in brain circuitry that may provide novel therapeutic targets and potential biomarkers to assess risk and predict patient outcomes. Th
is project aims to develop and apply tools that capitalise on these advances.
Figure: The human connectome mapped using diffusion-MRI and tractography
Neuroimaging in schizophrenia spectrum disorders - ONLY offered as MBiomedSc
Supervisors: Dr Vanessa Cropley, Dr Andrew Zalesky, Dr Tamsyn Van Rheenen, Dr Chad Bousman, Professor Christos Pantelis
Project Site: Melbourne Neuropsychiatry Centre, The Alan Gilbert Building, 161 Barry Street, Carlton South
Contact: Dr Vanessa Cropley; T: (03) 8344 1876; E: vcropley@unimelb.edu.au or Dr Tamsyn Van Rheenen E: Tamsyn.van@unimelb.edu.au
Project description: The Melbourne Neuropsychiatry Centre (MNC) is a joint centre of Melbourne Health (North Western Mental Health) and The University of Melbourne (Department of Psychiatry). Research at MNC focuses on improving our understanding of the neurobiological processes involved in disorders of the brain and mind.
Our group has structural Magnetic Resonance Image (MRI) scans previously collected from the Australian Schizophrenia Research Bank (ASRB). The ASRB is an Australian register and storage facility of medical research data that links clinical and neuropsychological information, blood samples and structural MRI scans from people with schizophrenia and healthy non-psychiatric controls. This data is collected across five research sites within Australia, including the MNC. The data is accessible to researchers wanting to undertake research using the resources of the ASRB.
The Psychosis and Developmental Neuropsychiatry Stream of MNC has several projects available that will investigate gene x environment interactions on structural neuroimaging parameters and behaviour in schizophrenia or risk for psychosis. These projects will utilise MRI scans and associated clinical, cognitive and genetic data collected as part of the ASRB. Projects for 2016 include:
Investigating the influence of prefrontal and striatal dopaminergic genes, cannabis exposure and their interaction on cognition and prefrontal-striatal volumes in high and low schizotypy
Examining the interaction between the brain derived neurotrophic factor (BDNF) gene and childhood adversity on hippocampal subfield volume in schizophrenia and healthy controls
Investigating the impact of neurodevelopmental genes (e.g. neuregulin) on neurological soft signs and its association with cortical gyrification, cognition and age of illness onset in schizophrenia
The student will be responsible for pre-processing, tracing (if applicable) and statistical analysis of MRI scans and associated clinical and genetic data. The student will also be trained in the application of imaging analysis in neuropsychiatry.
Effects of oxytocin genetic variants on brain and behavior in schizophrenia - also offered as MBiomedSc
Supervisors: Dr Cali Bartholomeusz (Orygen); Dr Chad Bousman (Melbourne Neuropsychiatry Centre); Prof Cyndi Shannon-Weickert (Neuroscience Research Australia); Prof Christos Pantelis (Melbourne Neuropsychiatry Centre)
Project site: Orygen, The National Centre of Excellence in Youth Mental Health and Centre for Youth Mental Health, 35 Poplar Road, Parkville; and Melbourne Neuropsychiatry Centre, The Alan Gilbert Building, 161 Barry Street, Carlton South.
Contact: Dr Cali Bartholomeusz Email: barc@unimelb.edu.au
Project Description: Oxytocin (OXT), a neurohypophysial hormone and neurotransmitter, is widely recognized as having an important role in human social cognition and prosocial behavior. These domains, which contribute to general social functioning, are significantly impaired in schizophrenia. Variation in OXT single nucleotide polymorphisms (SNPs) and OXT receptor (OXTR) SNPs have been linked to risk for schizophrenia. In addition, several of these SNPs have been associated with the severity of psychopathology, as well as social cognitive impairment in schizophrenia. A number of neuroimaging studies support a link between structural differences in social brain areas and OXTR variants in the healthy population, however no study has yet examined the relationship that these variants have to brain volumes in schizophrenia.
Aims: To examine the relationships between genetic load for previously identified OXT/OXTR SNPs and cognition, symptoms, and social functioning, in Australians with schizophrenia and healthy control participants. We will also investigate whether these relationships are linked to and potentially mediated by, brain volumes, particularly of the amygdala, nucleus accumbens and medial prefrontal/anterior cingulate cortices.
Method: Pre-existing data from the Australian Schizophrenia Research Bank will be utilised for the current study. Correlation statistics, and mediation analyses where appropriate, will be conducted to explore the associations between genetic variants and outcome measures and brain volumes. ANOVAs will also be conducted to explore differences between patients and healthy controls.
Outcome: This project will increase our understanding of how variants in key OXT and OXTR SNPs are related to risk for schizophrenia, symptomatology, cognition and general social functioning in an Australian sample
MRI volumetry and shape analysis in frontotemporal dementia and schizophrenia
Supervisors: Dr Dennis Velakoulis and Dr Mark Walterfang
Project Site: Melbourne Neuropsychiatry Centre, Royal Melbourne Hospital
Contact: Dr Dennis Velakoulis T: 93428750 E: Hdennis.velakoulis@mh.org.au
Project Description: It has been well recognised for over a century that some patients with schizophrenia develop a dementia but the nature of this dementia has remained unclear. Recent clinical, neuropathological and genetic studies have identified a previously unrecognised association between chronic schizophrenia and frontotemporal dementia. This project aims to examine whether the volume and shape changes identified in schizophrenia are quantitatively and qualitatively similar to patients with a frontotemporal dementia. In addition to demographic and diagnostic information a subset of the subjects have neuropsychological and bedside screening cognitive testing which can be correlated with brain structural volumes and shape.
Aims: To estimate and compare brain structure volume and shape in an existing database of MRI images of patients with chronic schizophrenia and frontotemporal dementia compared to control subjects.
Methods: Specific regions of interest to examine would include:
Frontal and temporal lobes
Orbitofrontal / dorsolateral / medial frontal cortex
hippocampus
Insula cortex
Superior temporal gyrus
Depending on the region of interest the project would require the learning of methods for analysing the region and developing a reliable method for this assessment.
Outcome: To assess and compare the nature and pattern of brain changes in chronic schizophrenia and FTD.
Characerisation of physiological stress responses in patients with depression and epilepsy - also offered as MBiomedSc
Supervisors: Dr Dennis Velakoulis, Dr Chris Turnbull and Professor Terry O’Brien
Project Site: Melbourne Neuropsychiatry Centre, Royal Melbourne Hospital and Alan Gilbert Building
Contact: Dr Dennis Velakoulis T: 93428750 E: Hdennis.velakoulis@mh.org.au
Project Description: Depression and epilepsy are disabling disorders that are common in the community. Both disorders have been shown to have effects on the human body’s physiological response to stress. These effects have been identified in both the autonomic nervous system (responsible for immediate responses to stress) and the hypothalamic-pituitary-adrenal axis (which mediates longer-term stress responses). However, it is not known whether these effects occur through similar mechanisms, partly because previous research has not focused extensively on patients with both disorders. This project will broaden our understanding of stress physiology in these disorders by assessing stress physiology in patients who have been admitted to hospital for assessment of seizures and have one or both disorders.
Aims: To compare the effects of depression and epilepsy, particularly temporal lobe epilepsy, human physiological stress responses and to assess whether these effects are additive or have a more complex interaction
Methods: The project will measure parameters of the physiological stress response in patients who have been admitted to investigate their epilepsy. Assessment of the autonomic nervous system will use a variety of measures of heart rate variability, and the HPA axis will be measured by the level of the hormone cortisol in saliva. Clinical data will be obtained by working with the clinical team caring for the patient and involves direct patient contact.
Outcome: To better understand stress physiology in depression (a psychiatric illness) and epilepsy (a neurological disorder) by assessing their interaction.
Functional disconnections and the pathophysiology of psychosis - also offered as MBiomedSc
Supervisors: Dr Nigel Jones and Prof Terence J O’Brien.
Project Site: Department of Medicine (RMH), MBC Neurosciences Building, Parkville
Contact: Dr Nigel Jones T: 9035 6402 E: ncjones@unimelb.edu.au
Project Description: Functional disconnections in cortico‐thalamo‐cortical (CTC) systems, the neuronal circuits of attention, cognition and perception, are thought to underlie dysfunctions of conscious integration such as those seen in schizophrenia. More than 80% of the neurons that make up the CTC systems are glutamatergic. There is considerable evidence to suggest that NMDA‐type glutamate receptors are implicated in the pathophysiology of schizophrenia. Non‐competitive NMDA receptor antagonists (PCP, ketamine, MK‐801), at subanaesthetic doses, induce cognition impairment, schizophreniform psychosis, hallucinations, and exacerbate both positive and negative symptoms in schizophrenic patients. In rodents, ketamine produces a wide spectrum of abnormal behaviour relevant to schizophrenia. The neuronal mechanisms underlying transient disruption in NMDA receptor function remain to be determined. CTC circuits generate coherent synchronized gamma frequency (30‐80 Hz) oscillations during conscious brain operations. Disruption of cognition‐related coherences of gamma oscillations between cortical areas is a major functional abnormality in schizophrenic patients.
This project will explore the hypothesis that aberrant cortical gamma frequency activity induced by ketamine mediates alterations in behavioural activity, thereby linking NMDA-mediated dysfunction of neuronal activity to schizophrenic-like behaviour.
Research plan: Rats are surgically implanted with recording electrodes and connected to a computer facilitating measurement of the EEG and analysis of the effects of drugs on cortical brain rhythms in the gamma frequency. The resultant changes in cortical rhythms will be concurrently measured with either sensorimotor gating or working memory to establish a temporal and magnitudinal association between disruptions to gamma oscillations and behavior.
Skills: small animal surgery, EEG measurement, behavioural analysis.
Antidepressants in epilepsy
Supervisor: Dr Nigel Jones and Dr Sandy Shultz
Project Site: Department of Medicine (RMH), MBC Neurosciences Building, Parkville.
Contact: Nigel Jones E: ncjones@unimelb.edu.au Sandy Shultz E: sandy.shutlz@unimelb.edu.au
Project description: Patients with epilepsy also frequently suffer from psychiatric disorders such as depression. As a consequence, many patients receive antidepressants to mitigate these mood disorders. While these are generally effective, the influence of antidepressants on the severity of the epilepsy in patients, and on the risk of developing epilepsy, has been little studied. Our provocative recent data suggest that antidepressants actually promote the development of epilepsy, which could have major implications for how these drugs are prescribed to patients. Using a range of animal models, including post-traumatic epilepsy, this project seeks to characterise and understand the influence of antidepressants such as Prozac on epilepsy development. Available as Honours, Masters or PhD projects
Skills: Small animal handling; animal models of epilepsy; models of traumatic brain injury; small animal surgery and EEG recording; MRI, animal behaviour and cognition, molecular biology techniques, such as real-time qPCR, Western blotting; histology, including immunocytochemistry
Temporal lobe epilepsy, the HPA axis and depression - also offered as MBiomedSc
Supervisor: Prof Terence O’Brien, Dr Dennis Velakoulis,
Project Site: Department of Psychiatry and Medicine Royal Melbourne Hospital
Contact: Terence O’Brien T: 8344 5490 E: obrientj@unimelb.edu.au, Dennis Velakoulis T: 93428750 E: dennis.velakoulis@mh.org.au
Project description: The key structures involved in mesial temporal lobe epilepsy – the hippocampus and amygdala – are critical components in the central regulation of the HPA axis. The implications of this have hardly been studied at all. Does the HPA axis function normally when someone has mesial temporal sclerosis (the usual pathology underlying TLE)? What happens to HPA axis function when a temporal lobe is excised to treat intractable TLE (temporal lobectomy)? There are good reasons to think the answers to these questions are very important for several reasons, e.g., glucocorticoids and stress have been shown in animal models of this kind of epilepsy to aggravate the disorder, to speed up its rate of development.
Project: We have a small preliminary study in progress, testing HPA function before and after temporal lobectomy. We’re using the dex/CRH test, doing this about 2 weeks before and at 6 and 12 weeks after surgery. We’re doing the same protocol with surgical control patients, having elective brain surgery for nonepilepsy conditions remote from the temporal lobe.
We think temporal lobectomy disinhibits the HPA axis, which may help explain the transient mood disturbance that occurs in temporal lobectomy patients in the early months following surgery.
This study will interest students interested in a topic that involves basic neuroscience and neuroendocrinology but also with a very immediate clinical relevance. It will involve contact with patients – in recruitment, obtaining informed consent, administering questionnaires and helping administer the dex/CRH test (a two hour procedure). It will also involve data analysis and writing-up in the usual way.
Does stress contribute to epilepsy? - also offered as MBiomedSc
Supervisor: Dr Nigel Jones and Prof Terence O’Brien
Project Site: Department of Medicine (RMH), MBC Neurosciences Building, Parkville.
Contact: Dr Nigel Jones T: 9035 6402 E : ncjones@unimelb.edu.au
Project description: Chronic stress is strongly linked to the development of psychiatric disturbances, such as depression and anxiety disorders. Interestingly, these disorders are prevalent in a high proportion of people suffering from epilepsy.
Recent literature suggests that environmental exposures such as stress may also contribute to the development of epilepsy. This project aims to investigate this hypothesis, with a parallel focus on anxiety and depression-like behaviour.
Using rat models, this study will determine whether exposure to repeated stressful situations leads to a vulnerability to limbic epilepsy. It will also study whether psychiatric disturbances are enhanced in subjects who have experienced the stress.
The second stage of the project will investigate molecular and plasticity changes which occur after epilepsy to determine whether the stress can influence such parameters as stress receptor expression and neurogenesis.
Skills: Small animal handling and neurosurgery (electrode implantations), neurobehavioural testing and analysis, post-mortem stereology.
High Frequency Brain Wave Patterns in a Rodent Model of Schizophrenia
Supervisors: Dr Chris French, A/ProfAnthony Hannan, Dr Nigel Jones, Prof Terence O’Brien
Project Site: Department of Medicine RMH, MBC Neurosciences Building, Parkville
Contact: Chris French frenchc@unimelb.edu.au
Project description: High frequency (“gamma”) brain wave activity has been associated with higher cognitive activity in humans and animals, and has shown to be abnormal in psychosis and schizophrenia. Phospholipase C-β1 (PLCβ1) is an enzyme that is altered in human schizophrenia and a PLCβ1 knockout mouse displays deficits (locomotor hyperactivity, sensorimotor gating and cognitive impairment) homologous to those seen in schizophrenia. Remarkably, some of these deficits can be improved with antipsychotic drugs that are efficacious in humans.
The aim of these experiments is to characterize the gamma-frequency brain wave patterns of normal and PLCβ1 knockout mice, and to investigate whether the behavioural effects of antipsychotic drugs can be correlated with brain wave patterns.
These experiments are likely to lead to a better understanding of the functional abnormalities that lead to schizophrenia in humans and to suggest new and better forms of treatment.
Estrogen, antipsychotics and schizophrenia - also offered as MBiomedSc
Supervisors: Dr Andrea Gogos and Dr Snezana Kusljic
Project Site: Hormones in Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental Health
Contact: Dr Andrea Gogos E: andrea.gogos@florey.edu.au and Dr Snezana Kusljic E: skusljic@unimelb.edu.au
Project description: A role for sex hormones in the development of schizophrenia has been hypothesized to explain the observed sex difference in the age-of-onset, with women presenting symptoms on average 3-4 years later than in men. Interestingly, clinical trials have shown that adjunctive estrogen treatment in women with schizophrenia can accelerate the beneficial effect of the antipsychotic treatment. Our laboratory aims to study the role of estradiol, progesterone and testosterone in modulating symptoms of schizophrenia and depression. We currently use both in vivo and in vitro rodent models, as well as post-mortem CNS tissue. This project aims to investigate the expression of estrogen receptors in the brain using one of the approaches commonly-used in our laboratory: radioligand receptor binding, western blot, or in situ hybridization.
Developmental Psychobiology @ The Florey
Early life stress and memory development
Supervisors: Dr Heather Madsen Co-supervisor: Dr Jee Hyun Kim
Project Site: Florey Institute, Parkville
Contact: E: heather.madsen@florey.edu.au
Project description: Early life experiences play a pivotal role in shaping personality and psychosocial functioning into adulthood. For example, early life adversity in humans is associated with increased risk of developing mental illnesses such as depression and anxiety. Given the importance of these first few years of life, it is interesting that most adults fail to recall autobiographical events from their early childhood years. Infantile amnesia is the term used to describe this phenomenon of accelerated forgetting during infancy, and it is not unique to humans. In fact, infantile amnesia has been observed in every altricial species examined; that is, animals that undergo extensive post-gestational development.
Many investigations into infantile amnesia have used Pavlovian fear conditioning in rats as a model of learning and memory. While adult rats exhibit excellent memory retention following just a single conditioning episode, infant rats rapidly forget fear associations over short intervals. Recently it has been shown that exposure to early life stress improves retention of learned fear in infant rats. The aim of this project is to investigate the neurobiological changes that underlie this early transition to adult-like memory.
Regulation of emotional memory across development
Supervisors: Dr Despina Ganella, Co-supervisor: Dr Jee Hyun Kim
Project Site: Florey Institute, Parkville
Contact: E: despina.ganella@florey.edu.au
Project description: Most anxiety disorders emerge during childhood, and individuals with childhood onset express more severe symptoms than do individuals who have adult onset. In fact, there is growing recognition that mental disorders may actually be developmental brain disorders and, as such, treatment strategies should focus on the young population. Currently, the effective treatments for anxiety disorders are cognitive-behavioural therapies that rely on inhibition of emotional memory. This project will examine inhibition of emotional memory throughout development using Pavlovian fear conditioning as a model of anxiety disorders in rats.
Latent inhibition in adolescent rats
Supervisors: Dr Jee Hyun Kim
Project Site: Florey Institute, Parkville
Contact: E: jee.kim@florey.edu.au
Project description: Ever wondered why individual differences exist in developing an anxiety disorder following a similar traumatic experience (e.g., a car accident)? It turns out that having previous related experiences before the traumatic event can play a huge part. For example, a veteran driver with many years of safe driving experience will be less likely to develop an anxiety disorder following a car accident, compared to a novice driver who has not had much prior safe driving. This protection from forming fear memories due to previous safe experiences is called ‘latent inhibition’, and this process shares similar mechanisms to ‘extinction’ that refers to safe experiences following the traumatic event. In the present project, we’d like to investigate latent inhibition in adolescent vs adult rats, as we know that extinction is different across the two ages. Examining latent inhibition in adolescence may help us to understand why adolescence is a particularly vulnerable age to experience anxiety disorders.