NRP's Research Focus

The following is a list of the projects our researchers are currently working on:

STREAM 1 (2007-2010) BASIC SCIENCE GRANTS

Prof Alan Harvey, Prof Donald Robertson, Dr Kathryn Heel
Grant Title: Gene therapy and the treatment of CNS injury.
Trauma to the adult central nervous system (brain and spinal cord) results in disruption of nerve pathways, death of neurons and long-lasting behavioural dysfunction. Gene therapy is a relatively new strategy that attempts to increase the viability and regenerative capacity of injured neurons. This promising approach involves the use of modified viruses to introduce neuroprotective and/or growth-promoting genes into compromised cells. The team has begun to analyse the effects of such genetic modifications on transduced neurons. In this new project Harvey further examines, in retinal neurons (in the visual system), how long-term expression of virally-introduced growth-promoting genes affects neurons and the expression of genes in the host. From a neurological perspective, while gene therapy may eventually be of benefit to injured patients, it is important to know if there are any potential pitfalls in this promising technology.

Dr Giles Plant, Prof Alan Harvey
Grant Title: Are olfactory ensheathing glia a myelinating cell in the central nervous system?
Clinical trials are currently underway in three countries using olfactory ensheathing cells (OEC) to repair the injured spinal cord of humans. OEC have been reported to have a positive effect in the repair of the spinal cord including the restoration of myelin sheaths (insulation) around axons (long nerve fibres) within the spinal cord. A successful cell transplant ideally would, in conjunction with axonal growth, produce mature myelin for the injured axons to work efficiently. This project will look at the capacity of OECs to produce myelin and the mechanisms are involved. The results will help develop protocols to select and grow OEC to carry out specific repair functions. The findings will have important implications for the future use of OEG, not only for spinal cord injury, which has both primary and secondary demyelination events, but also for promoting remyelination in diseases such as multiple sclerosis.

Dr Paul Watt, Prof Adrian West, Dr Bruno Meloni, Dr Nadia Milech
Grant Title: Identification of Phylomer peptides with neuro-protective activity in neurotrauma-related brain injury models.
An important aspect of reducing neurological disabilities associated with trauma is the prevention of secondary neuronal death, known as apoptosis (or 'cell suicide'). A number of protein-derived peptides (Phylomers) have been identified that disrupt a critical control point in the induction of apoptosis. A subset of these Phylomer peptides have been assessed for this form of neuro-protective potential: five have shown strong neuro-protective potential using in vitro models of apoptotic cell death (ie, nerve cells in a petri dish); two of the Phylomers are also neuro-protective in vivo (ie tested within a living animal). The goal of this project is to characterise the remainder of the peptide leads, and thus identify those to use for subsequent preliminary clinical trials in traumatic brain injury and stroke.

Dr Rachel Sherrard, Prof Alan Harvey (now completed)
Grant Title: Neurotrauma therapy and the reformation of ordered, functionally effective connections.
Long-term improvement following neurotrauma requires either re-growth of damaged connections or modifications in those that remain so that neural circuits are rebuilt and function restored. Current experimental treatments aim to promote new connectivity by transplanting growth-promoting cells or viruses that modify tissue to over-produce growth factors and facilitate connectivity. Unfortunately, molecules that aid growth also regulate the direction in which connections grow, so that more new connections may develop at the expense of accuracy. The general aim of this project is to examine whether a continuous source of growth factor disrupts the ability of reinnervating axons to recognise their appropriate targets. The significance is that the knowledge obtained will clarify the usefulness of these new technologies of tissue engineering, which can induce high expression levels of a range of growth promoting agents, for functional repair.

Prof Sarah Dunlop, Dr Lindy Fitzgerald (2007-2009)
Grant Title: Defining mechanisms underlying secondary damage in the CNS.
Following neurotrauma, some nerve cells adjacent to the damaged region remain intact but stop functioning due to a complex process termed secondary degeneration. Cells lose the myelin insulation from their nerve fibres (axons), relocate their terminals to inappropriate sites and may even die. Protecting function in this intact but vulnerable tissue is currently the most feasible approach to optimizing the functional outcome of neurotrauma. This project will determine if, as currently suspected, secondary degeneration is triggered by defective transport of substances along nerve fibres or 'axons' (axonal transport). The team will test whether a new anti-glaucoma drug, protective of axon transport, prevents secondary degeneration. The project is novel since calcium channel blockers are emerging as a promising therapeutic for limiting secondary damage in the CNS. Although not yet examined in visual system models, calcium channel blockers are also known to improve myelination in experimental autoimmune encephalitis and following spinal cord injury. This work will contribute towards determining whether such drugs are appropriate to consider for alleviation of secondary degeneration following neurotrauma.

Dr Giles Plant, Dr Stuart Hodgetts, Dr Paul Simmons, Dr Phil Horner, Dr Drew Sellers
Grant Title: Investigating the Mechanism of Improved Functional Outcome in Spinal Cord Injured Rats after Human Stromal Cell Transplant Therapy.
Using transplanted human bone-marrow-stromal-stem-cells (hBMSCs) as a therapy for spinal cord injury (SCI), Dr Pant has found that highly purified hBMSCs isolated from adult human SCI patients promote a marked improvement in functional recovery in animal models. Anatomically, tissue sparing was observed, as well as the expression of new neuronal proteins. This new project will investigate the mechanism(s) responsible for the enhanced level of functional spinal cord repair in rats subjected to hBMSC therapy. It also seeks to determine whether the donor hBMSCs induce a stem cell response in the host animal and/or are directly involved in the repair of the myelin (insulation layer) around the nerve fibres. hBMSCs represent an attractive alternative source of stem cells for cellular therapies, as they are easily isolated and expanded in culture, have the potential to differentiate into specific cell types, and they can be taken from a patient to be used to repair their own cord, avoiding the likelihood of immunological problems. hBMSCs are also easily transduced with retro- or lentiviral vectors.

STREAM 2 (2008-2010) BASIC SCIENCE GRANTS

Dr J Rodger, Dr R Sherrard
Grant Title: Less inhibition with more stimulation? Promoting recovery after Neurotrauma
Some experimental treatments for neurotrauma aim to promote new nerve cell connections by blocking growth-inhibiting molecules in the brain, however this can happen at the expense of accuracy. This project will test whether an enriched environment and activities that increase sensory feedback to damaged parts of the brain will compensate for this loss of accuracy. Anatomical and functional repair in regions of the brain controlling vision and movement will be assessed.

Dr J Rodger, J Dundas, A/Prof G Thickbroom
Grant Title: A comparison of non-invasive interventions to maximise plasticity in the brain
Following neurotrauma, the brain displays some ability to reorganise itself ('plasticity'), which can sometimes partially restore function. However, such plasticity can also result in inappropriate connections being formed and poor function. This project investigates the impact of three clinically relevant methods that have been shown to increase brain plasticity: environmental enrichment, task-specific training and direct current stimulation. A mouse model of abnormal brain connectivity is used to compare the changes in anatomy and physiology, and consequences for function.

Prof A Harvey, Dr J Rodger
Grant Title: Can gene therapy promote regeneration after distal axonal injury in the brain?
Using combinations of gene therapy and neural transplantation, Harvey and Rodger have successfully induced repair of the optic nerve when the nerve injury was close to the retinal ganglion cells (RGCs) in the eye. However it is important to know whether this approach enhances re-growth after an injury further along the length of the nerve tract, as is commonly the case with spinal cord injury. This project therefore looks at whether genetic manipulation and peripheral nerve grafting stimulates re-growth after an optic nerve injury occurring at a long distance from the eye's RGCs.

Dr S Hodgetts, Dr G Plant, Dr P Simmons
Grant Title: Neuronal regeneration & improved functional outcome after complete transection SCI in rats using combinatorial therapies
Many animal studies in spinal cord regeneration have used an incomplete 'bruise' injury model that leaves some pathways intact, making it difficult to determine whether functional improvements are a result of true regeneration of injured tracts. The improvement may be due to behavioural compensation, re-'insulation' of damaged (but intact) tracts, or sprouting of spared nerve fibres. This project focuses on true nerve regeneration in a model that involves complete transection of the cord (available to few laboratories internationally). Promising strategies to treat spinal cord injury will be investigated, including human and rat bone marrow cell transplantation and anti-scarring agents.

STREAM 1 (2007-2010) CLINICAL RESEARCH GRANTS

Dr Barbara Singer, Dr John Dunne, Prof Kevin Singer
Grant Title: The effect of repeated passive stretching on calf muscle stiffness after acquired brain injury.
Increased calf muscle stiffness is a common consequence of acquired brain injuries, such as traumatic head injury and stroke, in adults. In conjunction with spasticity, this stiffness interferes with functional mobility around the ankle. This makes walking far more difficult and increases the risk of tripping and falling. Prolonged stretching is used to maintain muscle length, but does not address 'through range muscle stiffness' in the calf. This study will examine the effect of a novel approach to reducing calf muscle stiffness, namely cyclic passive stretching. This treatment is expected to reduce stiffness via three mechanisms: 1) improving lubrication between layers of soft tissue, 2) reducing stretch reflex sensitivity (spasticity), and 3) reducing abnormal linkages between the microscopic fibres, called actin and myosin, within the contractile part of the muscle. Continuous passive movement devices (CPM) have long been used to reduce soft tissue and joint stiffness following orthopaedic surgery. Studies have provided preliminary support for the efficacy of cyclic passive stretching with CPM devices in reducing soft tissue and joint stiffness in individuals with spastic hypertonia following stroke. There are no data currently available regarding the therapeutic potential of this intervention, including the duration of the effect or the association between reduced calf muscle stiffness and ease with which functional tasks are able to be performed.

Dr John Beca, Dr Simon Erickson, A/Prof Warwick Butt
Grant Title: Hypothermia in Traumatic Brain Injury (TBI) in Children: a multi-centre prospective RCT of early prolonged hypothermia therapy in children with TBI.
Traumatic brain injury (TBI) is the leading cause of death in childhood and survivors of severe injuries commonly have multiple life long disabilities. Hypothermia or cooling has been shown to protect the brain and reduce damage from a variety of causes. Longer periods of cooling may also be better than shorter periods. Adult TBI studies are inconclusive and the only trial in children has shown no benefit with a short period of cooling (24 hours). Prolonged cooling (72 hours) does reduce brain damage in newborn infants with birth asphyxia. To do a study capable of determining whether prolonged hypothermia is beneficial in children with TBI would require approximately 450 children. The NRP is providing this grant for Dr Beca and his team to conduct a pilot study of 50 children admitted to intensive care with severe TBI in Australia and New Zealand. Neurological outcomes in children who are cooled to 32-33°C for 72 hours following TBI will be compared to those who have their temperature maintained at 36-37°C (all other aspects of care will be managed with a standardised protocol). The purpose of this pilot study is to establish the feasibility of doing a larger study with other international centres. It will also assess the safety of more prolonged cooling and protocol adherence.

A/Prof Gary Thickbroom, Dr Dylan Edwards, Prof Frank Mastaglia (2007)
Grant Title: Using brain stimulation to help recovery after spinal cord injury and stroke.
Brain plasticity is known to contribute to recovery of function after stroke. Professor Thickbroom and his team have previously shown that, following a stroke, adaptive reorganization occurs in the area of the brain's motor cortex that controls the hand. But little is known of how the brain adapts to spinal cord injury (SCI), and whether brain stimulation techniques might be able to facilitate recovery after SCI. The team now aims to explore and enhance activity dependent plasticity with interventional magnetic brain stimulation. The stimulation methods are designed to increase synaptic strength (ie the communication between nerve fibres) in order to promote functional recovery in the presence of structural damage, on the basis that brain plasticity contributes to recovery regardless of where the injury occurs in the central nervous system. In the first part of this new project, changes that occur in the motor area of the brain after SCI will be investigated. In the second part of the project, interventional brain stimulation will be applied over the motor cortex of subjects following SCI and stroke to increase excitability of nerve tracts that extend from the brain, down the spinal cord. The researchers will thereby determine whether stimulation over an area of the cortex can improve voluntary movement and function in the part of the body that area controls. The intervention is painless and the team hopes that the findings will lead to the development of therapies that will enhance brain plasticity and recovery following SCI, stroke and other forms of neurological injury and disease.

Prof Stephan Schug, Ms Patricia Ray, Dr A Browne, Ms Tracy Redwood, Ms Nicky Fortescue, Dr Michelle Byrnes, Mr John Ker
Grant Title: Holistic Multidisciplinary Approach to the Treatment of Pain for Individuals following Spinal Cord Injury Utilizing a Biopsychosocial Model.
Pain following spinal cord injury (SCI) is a significant problem with approximately 80% of patients reporting the presence of pain and 58% of patients rating their pain as severe or excruciating. The aim of this project is to (i) investigate the incidence, prevalence and classification of SCI pain retrospectively; (ii) investigate the natural history of SCI pain using a prospective longitudinal design; (iii) evaluate prospectively the effectiveness of a holistic multidisciplinary Lifestyle, Education and Activation Program (LEAP) implemented in the acute, chronic or long term chronic outpatient phases following SCI; and finally (iv) to identify physical and psychological predictors of treatment response following SCI at various time points. There are currently no treatment guidelines or single treatment that has demonstrated efficacy for treating chronic pain in SCI. There is, however, established efficacy for multidisciplinary pain management approaches. This new project will extend the team's current research into the effectiveness of outpatient LEAP group therapy for patients with chronic non-malignant pain as a primary diagnosis. The multidisciplinary team brings together clinical expertise of state leaders in SCI neurorehabilitation, multidisciplinary pain management, clinical psychology within neurological populations, clinical neuroscience and neuroplasticity.

Clinical A/Prof Jonathan Foster, Clinical A/Prof Neville Knuckey, Prof Ralph Martins
Grant Title: The Role of APOE as a Modulator in Recovery from Traumatic Brain Injury.
Recent evidence suggests that the possession of the Apolipoprotein E (APOE) e4 allele may adversely influence the brain's vulnerability and is associated with a poor outcome after traumatic brain injury (TBI). Moreover, both the possession of the e4 allele and TBI represents significant positive risk factors for the incidence of Alzheimer's disease. Associate Professor Foster and his team aim to resolve some of the discrepancies in this literature in this area by a) conducting prospective comparisons of the effects of TBI on neuropsychological functioning, b) evaluating the relevance of a range of brain-related biomarkers (including APOE status) for recovery from TBI, and c) investigating the impact of a novel exercise regime across TBI patients with different genetic and biological profiles. The aim of this research is to determine whether a 'high risk' biological and genetic profile exists in some individuals who sustain a TBI, conferring an increased risk of neurocognitive deficits and adverse neurological outcomes and possibly impacting upon the outcome of exercise-based rehabilitation protocols.

Prof Sarah Dunlop, Prof Frank Mastaglia, Mr John Ker, Prof Robert Grove, A/Prof John Buchanan, Dr Barbara Singer, Dr David Lloyd, A/Prof Gary Thickbroom, Dr Brendan Lay, Prof Peter Hamer, A/Prof Garry Allison, Dr Romola Bucks
Grant Title: Move Again Program (MAP) - Developing exercise programs for rehabilitation & recovery in individuals with spinal cord injury.
Ultimately, the MAP team aims to deliver the highest international standard of exercise rehabilitation and recovery facilities and programs to Western Australians with neurological injury, in order to significantly improve their physical and mental health and well being. In the first instance, MAP will focus on spinal cord injury (SCI). Information will be gathered on 1) the current exercise levels, attitudes towards and obstacles to exercise within the SCI community; 2) the currently available international and national SCI exercise rehabilitation interventions and their effects; and 3) effective methods of outcome assessment. The MAP team will then develop and assess the benefit of specific research exercise protocols for those with SCI, including those involving electrical stimulation (ES) and transcranial magnetic stimulation (TMS), according to the stage of injury. The findings will help us better understand which types of exercise intervention are beneficial and should be offered to individuals following SCI. Additional information is available on the Move Again Program webpage.

STREAM 2 (2008-2010) CLINICAL RESEARCH GRANTS

Dr T Corcoran, Prof M Paech, Prof S Schug, Dr T Mori, Dr S Honeybul, Dr K Ho
Grant Title: Neuroprostanes reflect ongoing neurological injury
A major limitation to improvement in outcome from traumatic brain injury is the lack of a marker of brain injury that is sensitive and specific enough to be clinically useful. 'Neuroprostanes' are a group of compounds that reflect oxidative stress - a common endpoint of many of the mechanisms that injure the brain. Recent work suggests that they may be reliable indicators of the severity and status of neurological injury. In patients who have suffered a severe brain injury, this team aims to determine whether neuroprostane levels in the blood accurately reflect neurological injury and whether this may guide therapy.

Dr Andrea Loftus, Dr Barbara Singer, Prof Geoff Hammond, Mr Ian Cooper
Grant Title: The impact of NMES based bilateral training program on left neglect, anosognosia & arm function after stroke
Following a stroke, only about 10% of patients regain useful arm function, so many interventions to assist upper limb recovery have been investigated. Two promising strategies are the use of electrical stimulation to assist activation of the muscles of the affected arm and practicing moving both arms together. The latter strategy is suggested to help balance activation of affected and unaffected sides of the brain. This study will investigate the efficacy, and duration of any benefit, of these two strategies, combined or in isolation, to promote functional recovery after a stroke.

A/Prof Garry Allison, A/ Prof John Buchanan
Grant Title: A randomized controlled trial of dynamic neurological rehabilitation for acquired brain injury (running program)
This trial of a dynamic rehabilitation program for individuals with brain injury is being undertaken within Royal Perth Hospital's Physiotherapy Department. From pilot work already undertaken, the investigators have determined that there is some degree of clinical utility in an innovative initiative called the "running" program, which is offered to some individuals attending the Neurological Outpatients clinic. This project involves undertaking a high level assessment of each individual's underlying physical impairments before and after participation to examine functional outcomes and translation of these into activities of daily living. All individuals will be followed up to examine if improvements are maintained over time.

Dr Michelle Byrnes, Dr Janet Beilby, Dr David Blacker
Grant Title: Mindfulness-Based Cognitive Therapy for neurotrauma patients: application of a novel intervention
Many people who experience neurotrauma face not only devastating physical disability, but also significant psycho-social challenges. They are faced with issues affecting quality of life, mood, coping styles, social functioning and community participation. Mindfulness-Based programs, which are proliferating in clinical settings, are used in the treatment of stress, depression, anxiety and chronic pain. The aims of this project are to: i) apply Mindfulness-Based Cognitive Therapy (MBCT) to spinal cord injured and stroke patients; ii) evaluate the effectiveness of a MBCT group program in the chronic phases of the rehabilitation process; and iii) identify psycho-social and behavioral predictors of the therapeutic response. MBCT has the potential to improve an individual's ability to cope with the significant stressors associated with everyday life following neurotrauma.