Brain damage repair

Objective

A.BACKGROUND

It is a sad fact that lesions in the central nervous system are difficult to repair. While we can expect damage to body parts like the skin, bones or liver to heal upon proper treatment, repair of damage to the brain and spinal cord is often inadequate. The reasons are twofold: nerve cells do not replicate after birth, and severed nerve fibres lack the ability to grow through a damaged area and make functional contacts with other parts of the brain or spinal cord. This is the reason for the lasting nature of the symptoms of neurological patients, for example after stroke or traffic accidents. In addition to the human suffering, these conditions cost our societies enormous sums in care, institutional expenses and loss of work force.

Another major problem area for our society is the need to care for our physically and mentally handicapped persons. Many of these carry deficits due to a disturbed development of the nervous system caused by disease or damage inflicted during pregnancy or birth. Again, the deficits are of a lasting nature, with restricted possibilities for thorough repair, with the associated human and societal costs.
Time of opportunity

Fortunately, recent research suggests a dramatic change in this situation! A series of scientific discoveries point to radically improved possibilities for functional retraining, or even repair, of damaged brain and spinal cord tissue. Although brain repair now seems attainable in principle, much work remains in order to define the conditions required for a successful outcome and work out practical solutions.

Therefore, the situation is ripe for a concentrated attack of a problem of prime human, medical and societal importance. What is needed is a transnational combination of basic and clinical neurobiological research expertise in several European countries to develop the procedures necessary for achieving clinically important results.

Although individual projects in the brain repair field are financed through the EU Framework Programme, there appears to be no such European concentration on the effect of repair strategies on cognitive or mental functions. The ESF Neuroscience Programme is terminated. Further, the COST organization seems particularly suited to incorporate research efforts by a sufficient number of basic and clinical European laboratories.

Recent relevant research

Over the last few decades significant progress has been made in understanding why central nervous tissue is repaired so inefficiently. Several European research groups have made significant contributions to this field.

In the 1970s an English group showed that new synapses (functional couplings for transmission of impulses between nerve cells) could form on specific brain cells after partial lesions. Later, a Norwegian team discovered that intense training may cause formation of new synapses in adult rats. American research has found that the regular organization of sensory inputs and of motor output from the cerebral cortex, also called representational maps, may be rearranged following changes to peripheral nerves or muscles. Along the same line, American neuroscientists recently demonstrated that intense phonological training greatly improves the reading ability of a special type of dyslectic children, with dramatic enhancement of their linguistic and intellectual status. The improved insight represents a substantial challenge primarily to improve the reading and writing abilities of many dyslectic children. Secondarily, their intellectual development will be aided by their improved linguistic abilities.

A Canadian team discovered that brain and spinal cord cells have the ability to grow new nerve fibres several millimetres long. They will only do so, however, if they are allowed to grow into specially prepared nerve trunks in which the original nerve fibres are degenerated due to a previous crush, leaving the supporting cells (Schwann cells) intact. These form narrow cylinders into which the regenerating fibres migrate. After having grown through such nerve trunks into the brain or spinal cord, the migrating axons, after leaving their guiding Schwann tubes, proceed for a few millimetres only, and fail to make contact with prospective target cells.
A Swiss team discovered that another type of supporting cell secretes an inhibitory protein which is responsible for the arrest of the growing fibres. By an ingenious procedure, they made antibodies which neutralized the inhibitors, resulting in much improved growth of the regenerating nerve fibres. In its present form, this procedure appears difficult to apply to human patients. However, a Swedish group reported in 1996 that a combination of guiding nerve trunks and a chemical growth factor were able to guide nerve fibres from the brain across a large gap in the spinal cord of rats. These fibres made functional contacts with nerve cells in the distal stump of the spinal cord, and caused, after a period with intense training, impressive recovery. The best animals showed coordinated use of the hind limbs with moderately strong force development. Although the recovery is not perfect, it allows the animals to walk slowly and to climb ramps up to 45?.

However, early British and Russian research established that an isolated spinal cord contains an intact apparatus for rhythmic and coordinated limb movements and that this system can be activated by a tonic stream of impulses from the brain stem. Recently, a Swedish group showed that the rhythm may be activated by certain neurotransmitter molecules. Consequently, we need to know whether the repair attempts cited above represent re-establishment of connections or a more nonspecific activation of a distal network of nerve cells.

Much work remains to be done, both by basic and clinical neuroscientists. However, the short review above should indicate that a possible recovery of damage to the spinal cord does not appear unattainable any more. However, all scientists in the field agree that a concentrated effort of a number of research groups is required. A future benefit is that the new information can be transferred to other types of neuronal damage, notably those underlying cognitive and mental process deficits.
Another promising field is the prospect of reducing the damage and the functional deficit after a stroke. A drastically improved outcome requires a combined approach of fibrinolytic, pharmacological and physiotherapeutic procedures. New drugs may reduce the blood clot if applied sufficiently early, while other drugs may reduce the progressive damage that often follows during the first week after the insult. Intense, and carefully designed training by the patient under the close guidance of physiotherapy experts has been shown to give substantial recovery. However, much work is needed to improve our understanding of the whole process, in order to avoid unintended increase of the lesion, develop more efficient drugs, improve our ability to motivate the patient, and design effective training patterns. Again, the new knowledge is expected to be transferable to other areas, notably in the training of patients with cognitive deficits after brain insult.

Many of neurological and psychiatric patients suffer from effects of a neuro-developmental or a neuro-degenerative disorder. Recent research has opened up completely new vistas for improvement also for such cases. In Parkinsonian patients, suffering from a neuro-degenerative deficit in the number and efficiency of dopamine-containing nerve cells, a combined effort of Swedish and British groups has shown that transplantation of foetal dopamine-producing nerve cells can improve the disease condition significantly. Certain types of nerve cells can be transplanted to the anterior chamber of the eye, where they continue to live, send out nerve fibres to innervate appropriate target cells and deliver transmitter (chemical signal molecules at synapses). The cells can be directly inspected through the cornea. Recent research from many laboratories, with a particularly important contribution from German research, has highlighted the pivotal role of nerve growth factors for these recovery functions. Swedish researchers discovered that nerve cells containing catecholamines as transmitters (nor-adrenalin and dopamine) could be transplanted to another part of the brain where they not only survived and sent out nerve fibres, but also were able to contact their correct target cells in a precise manner.
In a French/Swedish collaboration, significant progress has been made in changing properties of certain neuroendocrine cells to produce dopamine, at the same time producing abundant quantities of capable cells and obviating the ethical problems associated with the use of foetal human tissue.

Another important approach is the application of modern imaging techniques (positron emission tomography, functional magnetic resonance imaging), allowing cognitive and mental processes to be studied in conscious man. Both normal and pathological conditions can be studied in detail. Particularly important studies have been made of speech generation and attention mechanisms by American groups, and of motor control by American and Swedish groups. A British group has provided spectacular demonstrations of the area of the brain which initiates and supports hallucinatory episodes in schizophrenic patients. A series of fundamental cognitive processes can now be studied, with the aim of understanding thought and memory processes in general, and pathological conditions like dementia, schizophrenia and affective disorders in particular. Importantly, the new imaging methods should allow a continuous evaluation of preventive and therapeutic measures in the repair process. A multidisciplinary approach is necessary, as can be implemented in a COST Action.

Finally, methods and concepts developed in molecular biology have deeply changed the outlook for diagnosis, prevention and treatment of neurological and psychiatric conditions. Application of such methods and thinking has already had a major impact on the repair processes in the nervous system. There is a tremendous potential for further development of repair opportunities by this approach.
B.OBJECTIVES AND BENEFITS

The main objective of the Action is to increase knowledge of the processes of successful repair of deficits or inflicted damage to the central nervous system (the brain and the spinal cord) to a level which will allow repair, or significant improvement, with particular emphasis on human cognitive and mental functions. This objective includes new insights into the basal biological processes required for growth and rearrangement in the central nervous system as well as an application of these principles to pathological conditions seen in damage and disease of the nervous system in animals and man.

A second objective is to develop new diagnostic approaches and methods for characterization of cognitive and mental diseases based upon modern technology.

The third objective is to develop new techniques and procedures for brain and spinal cord repair processes. This includes development of the drugs and instrumentation required for adequate nerve tissue repair. This objective may involve industrial development and implementation of drugs, instruments and computer adaptations.

The benefits from improved repair possibilities of central nervous system damage are hard to calculate. Since the toll of these diseases is amongst the heaviest known in medicine, even a moderate achievement of the objectives listed above could represent huge human and economical benefits. These will be welcomed, both from a compassionate human point of view as well as from a societal viewpoint. The latter is due to the high costs for medical care, hospitalization, building and running of institutions, social and medical remuneration to injured and mental patients and to loss of work force.
C.SCIENTIFIC PROGRAMME

In this Action, both basic and clinical studies of growth and repair processes in the nervous system are envisaged, in particular those underlying higher cognitive and mental functions. The research will include a wide range of studies of repair biology and medicine, including neuro-developmental and neuro-degenerative processes.

The scientific implementation will take the form of a double-pronged approach. The significant advances already seen in the field would be unthinkable without the many fundamental insights provided by basic neurobiological and medical research. A successful outcome of the COST Action, therefore, requires a significant contribution from high quality basic neurobiological research.

At the same time, the main objective is directed towards human patients. Consequently, a major portion of the initiative must engage clinical research laboratories. A proper balance between these two lines of attack seems important for the outcome.

Naturally, the detailed content of the COST Action will depend upon the plans of the participating scientific laboratories. A number of European neuroscience laboratories have made significant contributions to this research field and are likely to take part in the Action. Particularly significant contributions have been made by scientists from (in alphabetical order): Austria, Belgium, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, the Netherlands, Spain, Sweden, Switzerland and the United Kingdom.
Among the many possible themes that could be undertaken, the following tasks seem likely to constitute the centre of interest.

Basic neurobiology

Analyse the processes of formation of neural connections in young and adult brains.
Identify activity-dependent mechanisms in the formation of connections.
Define the role of the autonomic nervous system in the control of growth and development.
Clarify the biological properties of foetal nerve cells.
Identify neurotrophic factors, biology, modulation, and plastic effects in repair studies.
Analyse neuronal cell death, controlling factors, and its role in repair and transplantation.

Direct neuronal repair studies

Develop methods to promote effective repair of traumatic or degenerative damage.
Identify signal molecules involved in neural growth and repair.
Define the role of neurotrophic factors in development and repair.
Clarify the signals preventing or facilitating axonal growth and reinnervation of injured areas.
Develop functional imaging of growth and repair in the central nervous system.
Analyse neurotransmitter receptor mechanisms in injury of the central nervous system.
Identify neuron-glia interactions in development, lesions and repair.
Analyse the structural and functional recovery after early vs. late brain lesions.
Imaging

Develop imaging techniques to quantify repair brain processes.
Image cognitive processes (speech, attention, volition, learning, memory, imagery).
Image pathological neural processes (epilepsy, tremor, aphasia, stroke, headache).
Image repair processes (following stroke, transplantations, growth factor addition).

Cognition

Analyse the physiological and structural rearrangement after behavioural learning.
Define the learning and memory processes in children with learning disabilities.
Clarify the learning and memory improvement potential in patients with dementia.
Analyse the neurobiological basis of conscious behaviour, as background for repair.
Make computational models of normal and pathological motor and cognitive processes.
Make computational models of normal and pathological perceptual processes.
Analyse the neurobiology of perception, as baseline for repair effects.
Functional mapping of cortical areas in the human brain.
Generation of a computerized human atlas database for repair studies.
Cognition in the aged, is it a natural or pathological process?

D.ORGANIZATION AND TIMETABLE

The organization will follow the rules laid down in the Rules and Procedures for Implementing COST Actions (COST 400/94). The Management Committee (MC) will oversee the implementation of the Action. Instruments for such control may be the MC meetings and smaller meetings between laboratories taking part in related subsets of the overall programme. If practical, yearly meetings of the heads of participating laboratories and selected collaborators will be held, normally in conjunction with a major European neuroscience conference where already a number of the scientists plan to go (meetings of the European Neuroscience Association, or one of the five large national neuroscience meetings (France,
Germany, Italy, Spain and UK). When appropriate, younger colleagues will visit participating laboratories to learn and implement new techniques and procedures. As new results accumulate, one could plan for meetings with science and health politicians to discuss the progress. Such activity should be made in collaboration with COST, and according to COST procedures.

Timetable

The proposed timetable is six years. Anybody acquainted with the problems to be attacked will realize that this period is not sufficient to solve the major and difficult task at hand. However, significant advances are likely to be made during this period. Naturally, any extension will depend upon the progress achieved during the six year period.

E.ECONOMIC DIMENSION

The preparation of this COST Action has been made by the Chairman of the COST ad hoc Working Party for Neuroscience on the basis of the report produced by this Group, after deliberations in the Group and with input from its individual members. The Group had representatives from the following countries (in alphabetical order): Austria, Belgium, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom.

On the basis of such information and national estimates provided by the representatives of these countries, and taking into account the coordination costs to be covered over the COST budget of the European Commission, the overall cost of the activities to be carried out under the Action has been estimated, in 1996 prices, at roughly ECU 6,6 millions.
This estimate is based upon the assumption that a total of 10 scientific laboratories from at least 5 of the countries mentioned above participates in the Action. Any departure from this will change the total cost accordingly. It is likely that more than the necessary 5 countries will participate, making the total cost higher.

This estimation is based upon an assumed average cost from each participating laboratory of ECU 110 000 per year. This sum would cover 2 postdoctoral fellows (ECU 2 x 25 000), 1 technician (ECU 40 000) and a sum of ECU 20 000 for running expenses and/or equipment. The detailed allocation will, naturally, differ from one participating group to the next, and will differ somewhat between different countries depending upon cost level and governmental requirements (social expenditures, overhead etc.). With 10 participating laboratories the yearly expenditure will be ECU 1,1 million and the total cost of the Action, lasting six years, will therefore be ECU 6,6 million.

Programme(s)

IC-COST - European cooperation in the field of scientific and technical research (COST), 1971-

Topic(s)

7 - Medical Research

Call for proposal

Data not available

Funding Scheme

Data not available

Coordinator

N/A

EU contribution

No data

Address

Belgium

Total cost