NRP's Research Highlights (1999-2010)

NRP researchers continue to find answers to important questions regarding neurotrauma - shedding light on how brain and spinal cord tissue reacts when damaged and what is needed to ensure the survival and recovery of the delicate and complex central nervous system.

1. Cell survival and preventing secondary degeneration; investigating mechanisms to "nurse" nerve tissue through periods of trauma

During the early years of the Program NRP scientists established:

• that human brain cells can adapt to reduced oxygen concentrations by "hibernating";
• a reliable brain cell culture model allowing the examination of signaling pathways involved in delayed neuronal death;
• a 'peptide inhibitor' that blocks a key protein responsible for delayed brain cell death and prevents necrotic cell death (usually considered an irreversible process) following injury;
• that applying a combination of magnesium sulfate and mild hypothermia for a specific time period following brain injury significantly reduces neuronal death;
• identified 55 proteins that represent potential therapeutic targets for the development of drugs to reduce brain cell death following brain injury.

Over the last three years NRP scientists Sarah Dunlop and Melinda Fitzgerald have:

• undertaken a comprehensive assessment of the sequence of events contributing to secondary degeneration and demyelination, identifying potential therapeutic targets and demonstrating...
• that the calcium channel blocker lomerizine protects nerve tissue from secondary death and has other beneficial effects, but does not preserve myelination; and
• that in astrocytes vulnerable to secondary degeneration, there is rapid spread of oxidative stress leading to dysfunction of oligodendrocytes (cells that produce myelin);
• explored non-invasive treatment strategies to reduce oxidative stress during secondary degeneration, demonstrating...
• that daily near infrared light treatment immediately following a nerve lesion restores function to normal within days (more effectively than lomerizine) by reducing oxidative stress in astrocytes, leading to preservation of oligodendrocytes, nerve cell axons and therefore function.

2. Studying human spinal cord injury (understanding events at the site of injury)

During the early years of the Program NRP scientists:

• contributed to the understanding of the role of Schwann cells after spinal cord injury;
• discovered that a structure called Clarke's Nucleus survives in spinal cord injury patients, answering a question posed by experimental neurobiologists over many previous years;
• completed a human spinal cord injury atlas, a much needed neuroscience resource as scientists approached human clinical trials of new treatments for spinal cord injury.

3. Central nervous system repair and regeneration

During the early years of the Program NRP scientists:

• successfully transplanted mouse olfactory ensheathing glial (OEG) cells into the injured adult mouse spinal cord, observing strong nerve re-growth into, across and beyond the lesion sites, with good behavioural outcomes;
• developed techniques to deliver DNA into OEG cells, enabling them to produce growth factors that act as 'fertilizers' for injured spinal cord axons;
• developed allograft and reconstructed peripheral nerve graft models in rat for central nervous system repair - a revolutionary approach using donor nerve sheaths and the host's own Schwann cells, obviating the need to harvest the host's own major peripheral nerves;
• discovered ways of massively increasing survival and regeneration of adult retinal ganglion cells using gene therapy and growth factors, as well as agents to block growth-inhibitory molecules that are normally present in the adult brain and spinal cord;
• set up a state of the art live cell-imaging facility (in 1999) that for the first time allowed scientists to visualise re-growing nerve fibres in living spinal cord tissue, providing direct insights into how nerve fibres can be appropriately guided;
• identified a protein called DR6 that is capable of triggering delayed cell death following neural injury - a major obstacle to overcome in the treatment of head and spinal injuries;
• revealed many molecules that may be involved in promoting axonal regeneration following injury (leading to further investigations);
• demonstrated that administration of a small metal-binding protein that occurs naturally in the human body is capable of inducing significant regeneration of injured nerve fibres and offering extensive neuro-protection.

Over the last three years:

• Alan Harvey and his team demonstrated that the dendritic (tree-like) architecture in retinal ganglion cells (in the visual system) is altered when exposed to long-term virally mediated gene therapy. The changes vary depending on the type of transgene introduced. This work has important implications, particularly considering these methods have begun to be clinically tested overseas.
• Giles Plant and Alan Harvey ascertained that specific co-factors are essential for embryonic olfactory ensheathing cells (OECs) to stimulate myelination following spinal cord injury; and that it is unlikely that adult-derived OECs can act as myelination agents in therapeutic use.
• Giles Plant and Stuart Hodgetts found that bone marrow stem cells isolated from human spinal cord injured patients and transplanted into animal models of spinal cord injury (SCI) resulted in significant functional improvements, beyond that achieved through transplantation of other cell types in similar SCI models. The stem cells induced growth in the host tissue (but not myelination); improved gait was observed in both acute and chronic models of injury. The NRP 3-year Review highlighted this research as having considerable potential for translation to clinical trials.

4. Re-establishing orderly projections in target tissue of the brain

During the early years of the Program NRP scientists:

• determined that fibres surviving a partial lesion of the optic nerve positively influence the ability of those that were damaged to find their correct destinations in the brain;
• demonstrated for the first time the expression of a key "map making" molecule, Ephrin A2, during nerve regeneration, vital for restoration of orderly connections in the brain;
• made significant progress in understanding the activity of key map-making molecules (Eph/ephrins and Pax genes) and how these must interact to re-establish order and function in the brain following neurotrauma;
• demonstrated that training during optic nerve regeneration alters gene expression to allow nerve fibres to be guided to their correct locations, converting an animal that would otherwise be blind into one that can see and confirming the importance of physiotherapy post injury;
• created a computerized gait analysis apparatus to qualitatively assess walking recovery in animals following neural injury and with subsequent treatments and training;

Over the last three years NRP scientists:

• Jenny Rodger and Colleagues have used an animal model of brain injury to:
• show that reduced inhibition in the brain encourages repair;
• show that compared to a standard environment, environmental enrichment improves reinnervation and function, but only if the environmental input is relevant to the injured brain structure (for example, light is important for visual function);
• shed light on the mechanism by which transcranial magnetic stimulation, currently used to treat a wide range of neurological conditions, improves brain function without adversely affecting healthy brain tissue.

5. Neural re-organisation, training and therapies promoting physical and psycho-social recovery after neurotrauma

During the early years of the Program NRP scientists:

• demonstrated that brain plasticity and re-organisation can lead to recovery of hand strength, but not necessarily manual dexterity (emphasizing the importance of physiotherapeutic programs designed to facilitate brain plasticity, motor re-learning and retraining following brain injury and stroke);
• that specific (and progressive) changes in motor maps occur over several weeks following damage to the primary motor area, and that these changes affect many motor areas in both hemispheres of the brain;

Over the last three years NRP scientists:

• Sarah Dunlop and Colleagues established the MAP (Move Again Program) network in WA, linking basic neuroscientists and allied health professionals working in spinal cord injury (SCI) across many institutes. MAP has resulted in a better understanding of the obstacles to exercise faced by individuals with SCI in WA and the commencement of multidisciplinary projects to address these obstacles as well as the recovery of upper limb function. MAP has leveraged major national funding to allow activities to continue and clinical studies to evolve into multi-centre randomized controlled trials across Australia.
• Garry Allison and John Buchanan established that following traumatic brain injury, a dynamic physiotherapy exercise protocol known as 'the running program', provides a better outcome for individuals on high level functional mobility tasks than usual (more time-intensive) physiotherapy outpatient services if participants are originally above a specific level of functional capacity. A model of care has been established for individuals at the end of an outpatient service delivery that optimises mobility and has potential for significant cost savings in rehabilitation centres.
• Gary Thickbroom and Colleagues, in their studies using transcranial magnetic stimulation following SCI, have developed new techniques (using triple pulse stimulation) and made significant discoveries in relation to excitability of the brain. The findings are of great importance in terms of designing brain stimulation protocols that will aid functional recovery after SCI.
• Stephan Schug, Michelle Byrnes and Colleagues discovered that a very high percentage of WA SCI patients experience pain, and that there were also areas of relative weakness in psychosocial aspects of clinical care and rehabilitation at the Sir George Bedbrook SCI Unit. The team succeeded in implementing additional, specific psychological assessments to identify pain, anxiety/depression and post-traumatic stress disorder in SCI patients, as well as programs to deliver improved levels of tailored psychological support and rehabilitation to those in need.