The structure surrounding the brain

The CInAPCe Program promotes an unprecedented partnership or the mapping of epilepsy

It will begin to function by the start of 2007, the most detailed research effort ever carried out in the country directed towards an understanding of the working of the brain. One is dealing with the CInAPCe Program (standing for Inter-Institutional Research Support Concerning the Brain in Portuguese and alludes to homophone synapse, the location of contact between neurons), which is a network that brings together three dozen groups within six institutions in the state of Sào Paulo, covering diverse areas of knowledge that runs from neurology to computing, and from physics to genetics. The project’s starting point is the acquisition of four nuclear magnetic resonance (NMR) scan machines of high electromagnetic field, endowed with double the power of the previous generation that exist in Brazil. Combined with other tools, these machines will feed a major study into the mechanisms of epilepsy in the Brazilian population, and will also be directed towards the development of scientific investigative and diagnostic methods, as well as the treatment and prevention of the illness. Over the next four years the project is going to provide training and the formation of at least 300 researchers, among them 30 post doctorate studies, 100 doctorate degrees, 50 master’s degrees, 100 undergraduates and 20 technicians.

The nuclear magnetic resonance (NMR) machines of high electromagnetic field allow for the acquisition of brain images with definition and spatial resolution much higher than that currently available. They will also make possible the acquisition of images much faster. Today a limitation exists for carrying out very long examinations, since the patients’ collaboration within the claustrophobic NMR equipment only resists until a certain point in time. With the new acquisitions, a group of exams that would have lasted two hours – and which, for this reason were unviable – can now be done in 40 minutes at the maximum.

Each high electromagnetic field piece of equipment costs around US$ 2 million. One of them has already been purchased through a private partnership within the network, namely the Israelite Teaching and Research Institute, linked to the Albert Einstein Hospital of São Paulo. The other three machines will be bought through FAPESP funding and will arrive in the country by the end of this year. They are going to be installed at the Medical Sciences Faculty of Unicamp; at the Faculty of Medicine of the University of São Paulo (FMUSP), in the capital, and at USP’s School of Medicine in Ribeirão Preto (FMRP). “The hospitals of these institutions concentrate a casuistry of epilepsy that few centers in the world have at their disposal to study”, explains the neurologist Fernando Cendes, head of the Neuro-imaging Laboratory of the FCM-Unicamp, one of the project’s ideologists.

Multiplied capacity
With similar machines, the four institutions will manage to work simultaneously on research protocols. The capacity to recruit patients at each one of the four hospitals will be multiplied through working as a group. “The decision to purchase identical machines resulted exactly from the intension to stimulate group work”, says Luiz Eugênio Mello, the pro-rector of Graduation at the Federal University of São Paulo (UNIFESP), who is also one of the program’s coordinators. “A synergy of this magnitude would not be attained in any other manner”, he says. Nuclear magnetic resonance allows for the capture of various types of images, from the anatomy of the brain to its functional character. The theoretical basis of the method is the detection of the electromagnetic radiation emitted by atomic nuclei that have been submitted to an intense magnetic field and that had previously been excited by radio frequency pulses.

The white and grey matter of the brain possess different properties and concentrations of hydrogen protons. This gives the detected signals contrast conditions necessary for the definition of the anatomic structures. Also it is possible to study the metabolism and the working of the brain by way of spectroscopy via magnetic resonance, capable of dimensioning the presence of metabolites and cerebral neurotransmitters. As well, the functional magnetic resonance detects the areas of greater blood flow and oxygen consumption linked to the activation of specific determined cerebral regions, which allow for a mapping of the brain’s functioning during the execution of a determined task. The signal resolution depends on the magnetic field of the magnetic resonance and, indeed, the use of a high magnetic field brings about greater sensitivity.

The arrival of the new machines does not mean at all that the other equipment will not be used. On the contrary, the program aims to provide incentive towards research involving the combined use of technologies with the goal of developing better diagnostic tools. One of these investigative lines, just to give an example, is the combined use of functional magnetic resonance with the electroencephalogram (EEG). While the resonance can provide images of the brain during an epileptic crisis, the EEG, with electrodes located at different points on the head, is capable of informing the exact moment at which the crisis begins. The group use of these technologies is desirable, but there are technical problems that the CInAPCe Program researchers will attempt to overcome with the use of animal models. The main problem is that the magnetic fields of the EEG electrodes interfere with the sensitivity of the resonance.

A method that will be researched is that of Diffusion Tensor Imaging (DTI), which allows for the study of the connections between different areas of the brain by way of constant mapping by computer. Via this technique, the brain is transformed into a network of nerve fibers that connect different pieces of its territory. “Using the new machines, it will be possible to work in this cutting edge research area”, explains Luiz Eugênio Mello.

Other arrangements will also be put into practice in an articulated manner, such as systems combining functional magnetic resonance imaging (fMRI) with electroencephalography (EEG), or EEG with magnetic electroencephalography, among others. “Techniques such as these, at the stage in which we find ourselves, are now extremely useful for the study of the brain, some with wide ranging clinical application. All can be found in a clear development stage and there is a major scientific and technological effort in the sense of establishing arrangements in which these techniques are combined for the simultaneous acquisition of data”, says Roberto Covolan, a professor at the Gleb Wataghin Physics Institute of the State University of Campinas (Unicamp), who is also one of the program’s coordinators.

There are three companies in the world that manufacture commercial device that uses high electromagnetic field in nuclear magnetic resonance: General Electric, Philips and Siemens. Each group will have the liberty to purchase from whom they judge to be most adequate, assuming that the equipment can be operated in a network. The CInAPCe Program researchers will purchase the equipment from the companies that will allow for manipulation and improvement in the software designed by Brazilian professionals. The partnership contract will permit the creation of national competence and the purchase of  the necessary research techniques. This will attend to one of the project’s major objective, namely to promote technological development. On the USP campus at São Carlos a fifth resonance machine will be built, this one to study experimental models in rats and non-human primates. The physiological study of these models will be carried out by the Federal University of São Paulo (UNIFESP), which has a tradition in basic research into epilepsy. In an example of cooperation, a finding by the resonance machine network could be tested in an experimental model by the group from Sao Carlos and the animal’s brain tissue could then be sent on to UNIFESP for physiological study.

Advanced internet
Although situated in different cities, all of this equipment will work simultaneously in a virtual environment, since they will all be interlinked by an optical network of the highest velocity inaugurated last year, namely the KyaTera Project (Research Optical Platform for Advanced Internet Development). As the quantity of data generated will be very large, this fast network will allow for its transmission in an effective and safe manner. The impact of the network in the training of human resources will be powerful, according to the organizers of the CInAPCe Program. “Researchers from diverse area are going to work as a group and in a network, within a new environment, in which each will have to make the effort to understand the language of the other”, says Colovan. “The network will permit all of the post-graduate students at the different institutions to undergo training by way of video conferences, with the best specialists from each group – which would not be able to happen without the network”, says  Luiz Eugênio Mello. “If research into epilepsy was already strong in Brazil, this will make it even stronger”, he completes.

Multiple factors
Another of the concerns of the CInAPCe Program is the spreading of scientific knowledge. For this reason there will be cooperation with the entity Aspe (Health Assistance for Epilepsy Patients, in the Portuguese acronym), which is integrated into a global campaign led by the World Health Organization whose objective is to propagate information about epilepsy and to promote access to adequate treatment.

There has been notable progress in research into epilepsy over the last decade, given impulse by advances in non-invasive methods of obtaining brain images. But fundamental questions related to the illness are as yet not clarified. In truth, one is not dealing with a single illness. Under the umbrella of epilepsy there are a variety of pathologies that interfere in the dynamics of the brain and have as a common denominator the recurring emergence of crises. “This multiplicity of factors shows the need for the cooperation of specialists from different areas working on a common project”, explains professor Fernando Cendes. The complexity of brain activity requires a research effort of a multidisciplinary character. For this reason the most advanced centers in countries such as the United States stimulate collaboration between researchers of the exact sciences, technologies and biomedicine in the study of the brain’s processes. The goal is always to search for new responses about the dynamics of the brain and to improve the tools that currently exist.

The CInAPCe Program began to be developed at the end of the decade of the 90’s, with a wider objective and a more restricted spectrum of researchers. The original idea was to create an interdisciplinary research network within Unicamp in order to acquire cutting edge technology and to study the dynamics of the brain. “The inherent complexity of cerebral activity requires that research in this area covers a wide spectrum of activities, making use of ideas ranging from the most recently developed techniques for molecular biology to sophisticated methods for the functional mapping of the human brain”, explains Covolan. The intention of restricting the program to Unicamp was put aside during the year 2000, when the main proponents of the project, professors Covolan and Cendes, presented the idea to the then FAPESP president, Carlos Henrique de Brito Cruz, today the Foundation’s scientific director, and to the director of the Medical Sciences School of Unicamp, Mário Saad. They were advised to involve more institutions and to create a research network beyond the limits of Unicamp. They sought out other universities, and at the end of that year, they launched the idea of a state network.

Natural choice
When the study’s objective was limited in order to make the project more tangible, the choice of the theme of epilepsy was natural. The illness was the question most studied by the project’s participants. At the same time, the choice did not make up part of the original idea. “A good deal of what the researchers learned about the areas of the brain, such as the parts responsible for movement and language, came about starting from epileptic surgery”, says Cendes. “The mapping of the cortical functions before and during epileptic surgery offers the unique opportunity of studying the brains functions in vivo. Situations in which epilepsy also alters the memory will allow for a search for answers concerning the very process of memory formation itself”, he explains.

Epilepsy attacks 1% of the world’s population, of whom 80% of the victims live in under developed countries. The greater incidence among poor nations is attributed to varied reasons, from elevated case levels of infectious illnesses that affect the brain, as is the case with neurocysticercosis and meningitis, to lesions on the head brought about by car accidents and complications during birth.

During 2001 the program was taken to FAPESP, but it needed to overcome two obstacles. The first was the explosion in the US dollar exchange rate during 2002, which obliged the Foundation to freeze imports for a period of time. By the end of 2003 the situation had returned to normal and the project retook its course. The second challenge was to establish an ideal configuration for an initiative of unprecedented and multidisciplinary character. This was not an easy task. It was necessary to reach agreement, for example about the type of machine that had to be purchased. There was also the point of having a consensus about buying four identical high magnetic field machines to work in a network with the other types of equipment contemplated, such as the magnetic encephalograph or the tomography for positron emission put more to the side.

Three international evaluators, Brian Meldrum, an experimental neurology professor from King’s College in London, Bruce Pike, from the McConnell Brain Imaging Center in Montreal, and Ana Nobre, from Oxford University, assisted in the creation of directives. “The discussion revolved around the arrangement that would render the most for everyone. Some groups has experience and an interest in certain technologies and consequently it was necessary to reach a consensus”, says Luiz Eugênio Mello. Each participating institute must be able to count upon a researcher in the area of exact sciences and another in the area of biological sciences in command of each proposal, a pre-requisite in order to guarantee multidisciplinary genre.

The long period of time used in developing the project was not wasted. During this period it was discussed to exhaustion among its participants. “That was a time of engagement before the marriage that allowed for all of us to get to know each other”, suggests Fernando Cendes. “We’re learning to speak the same language. This is a project that was born mature.” The program was set to last four years. However, the idea is that at the end of this period, it will unfold into diverse projects about cerebral dynamics that will benefit from the expertise and infrastructure developed during the CInAPCe Program.