The Ken Parker Brain Research Laboratories

BMRI Buildings F, G and H. The Ken Parker Brain Research Laboratories are situated on levels 6 and 7 of Building F.

Following on from the earlier successes of the BMRI in establishing major laboratory, neuroimaging and clinical services infrastructure, The University of Sydney has now provided additional space for the next phase of basic laboratory development. Almost 2000-square metres was commissioned in 2007 to house ‘The Ken Parker Brain Research Laboratories’. These new state-of-the-art facilities will focus on the following three key areas:

• Brain cancers and glial diseases;
• Blood vessel diseases of the brain; and
• Chronic pain, migraine and other headache syndromes.

As with the earlier BMRI developments, our goal is to establish first class and internationally competitive research groups through a coordinated process of international recruitment, capital works development and integration with existing national and other BMRI research infrastructure. The two levels of The Ken Parker Brain Research Laboratories will require six million dollars for establishment of the necessary research infrastructure.

These new target areas for BMRI research focus on disorders that not only result in large degrees of premature death but also ongoing disability. They are areas that require renewed research efforts and are areas in which Australian-based research groups can reasonably be expected to make major international contributions.

As with our other developments, personnel support will be sought through a combination of national and international competitive research funds and position support by The University of Sydney Medical, Health Sciences and Science Faculties.

Floor plan of The Ken Parker Brain Research Laboratories (BMRI Building F Level 6) for chronic pain, migraine and vascular diseases.

The first level of the new laboratories will focus on a number of key brain disease processes that can result in disability and cognitive impairment at any stage of the life cycle. These are chronic pain, migraine headache and vascular diseases of the brain.

Chronic pain syndromes remain one of the most common but poorly understood neuropsychiatric syndromes. Current treatments are based largely on management strategies developed for acute pain due to obvious tissue injury or nerve damage. Despite tremendous investments, most have proved very disappointing in clinical practice. It is now clear that most have given insufficient attention to the ways in which the central nervous systems receives and processes pain messages beyond the phase of acute injury. New models of chronic pain and the underlying message systems in the central nervous system, offers new hope for the development of effective therapies.

Migraine headache has proved to be one of the most intriguing forms of recurrent and severe pain due to underlying changes in central nervous system function. A range of neurochemical, electrophysiological and blood vessel models exist for the condition. Traditionally, Australian neurology has been at the forefront of basic and applied research in this internationally-competitive field. In recent years some of our most successful research groups have moved overseas and we are now in a position to establish a platform for moving these operations back to Australia.

Research on blood vessel diseases of the brain has traditionally focused on those large arteries that are affected by clotting or bleeding and give rise to acute stroke syndromes. However, it is now clear that a wide range of neurological, dementia and psychiatric syndromes are caused by diseases affecting much smaller blood vessels that track through deep brain structures. These often develop slowly over some years and may be associated with a range of different genetic, lifestyle and other medical risk factors. Better understanding of these processes may help to prevent disorders like dementia, Parkinson’s disease and late-life depression.
Research on the first level of The Ken Parker Brain research laboratories will include the following brain vascular diseases:

• Vascular depression;
• Vascular dependent cognitive impairment;
• Stroke and vasospasm; and
• Migraine.

Vascular depression
The term ‘vascular depression’ describes a subset of vascular disorders that occur in old age as a consequence of cerebrovascular disease. There is a direct influence of vascular disease, in particular arteriosclerosis, on the incidence of depression. Depression and vascular disease share either a common pathophysiological process or genetic determinants. Vascular depression is the consequence of microvascular lesions particularly in prefrontal and subcortical regions.

Vascular dependent cognitive impairment
Vascular disease is the second most common cause of dementia after Alzheimer disease. The burden of illness is similar to that caused by Alzheimer disease but has been far less well studied. Some important advances have been made recently with the discovery of a monogenic form of vascular dementia and its causative gene Notch 3. In addition, magnetic resonance imaging studies are needed to provide a clear delineation of the various clinical subtypes. A most urgent need at present is to determine the synergistic interaction between vascular and classical Alzheimer pathologies in producing cognitive impairment.

Stroke and vasospasm
When a cerebral aneurysm ruptures, bleeding and clot formation occur around the surface of the brain, including several major blood vessels. The resulting condition, known as subarachnoid haemorrhage (SAH) often results in death or severe disability and is a significant cause of secondary stroke in these patients. Delayed cerebral vasospasm and impaired vasodilatation are critical complications that occur after SAH. Thus, from about three days after SAH, the cerebral blood vessels can undergo sustained constriction called cerebral vasospasm that is increases the rate of morbidity and mortality. Vasospasm also occurs in post-traumatic stress disorder and is sometimes a prelude to migraine headaches.

Migraine
Headaches in migraine are thought to be associated with a dilation of cranial blood vessels, particularly those in the dura mater, and an accompanying localized sterile inflammatory response. In many cases the headache phase of migraine is preceded by a condition called aura in which there is a disturbance of vision, consisting of bright spots and dazzling zigzag lines, sometimes accompanied by numbness and tingling of lips, face and hand as well as confused thinking. This aura is associated with a spreading depression of electrical activity in the cortex.

Floor plan for The Ken Parker Brain Research Laboratories (BMRI Building F Level 7) for brain cancers and glial diseases.

The second level of The Ken Parker Brain Research Laboratories will be devoted to basic research seeking to unravel the complex cellular processes that give rise to primary brain cancers and related glial cell diseases. Primary brain cancers remain one of the most devastating clinical syndromes to affect the central nervous system. Many are poorly responsive to current treatments and, hence, rapidly fatal. The ways in which the different cells of the brain become dysfunctional and give rise to malignant cancers is poorly understood. A great deal of work remains to be done on the basic biology of these cells and how the regulation of their turnover can be disrupted by disease or by other lifestyle factors.

Glial cells, comprising 70 per cent of all brain cells, were long thought to only act as nutrient supporters of neurons. This radically changed in the 1990s, as a consequence of three discoveries. First, astrocyte glial cells actively conduct information in the brain. Second, that astrocytes and microglia use transmitters and cytokines to modulate transmission of information in neural networks. Third, stem cells near the ventricular layers of the brain generate astrocytes and neurons, even in the mature brain.

These adult stem cells will form the focus of research of laboratories on this level. The research programs here will include:

• Glia - neuron adult stem cell therapy;
• Tumours and anti-tumour adult stem cell therapy;
• Multiple sclerosis and adult stem cell therapy, and
• Anti-inflammatory adult stem cell therapy.

Glia – neuron adult stem cell therapy
Adult neural stem cells may be grown to produce a particular nerve. We need to identify the signals that make stem cells differentiate into particular cell types. A further important research activity will involve attempts to identify how adult stem cells can be regulated to differentiate in such a way that they reform physically damaged circuitry, as in lesions of the spinal cord.

Tumours and anti-tumour stem cell therapy
This research program is concerned with the extent to which discoveries of the factors that determine the differentiation pathway of the cells to form glial cells illuminate the mechanisms that fail to regulate the proliferation of glial cells in tumours. Mesenchymal stem cells taken from the bone marrow of adult patients can have a gene inserted in them for interferon beta, a protein that kills tumour cells. Injection of these cells into the carotid artery of mice suffering from brain cancer is followed by the cells migrating to the tumour and killing it.

Multiple sclerosis and adult stem cell therapy
This research activity involves identifying the optimal conditions for using adult stem cells to generate glial cells that will take the place of those that degenerate in diseases such as multiple sclerosis - a form of adult stem cell therapy.

Anti-inflammatory adult stem cell therapy
Adult neural stem cells can secrete biochemicals that make neurons function better, promote survival, decrease inflammation and encourage the growth of blood vessels. An important research focus will involve identifying the triggers for the release of neuroinflammatory cytokines from glia, and how this can be prevented or overcome by the release of anti-inflammatory cytokines by adult stem cells.