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Decade of the Brain
THIS ESSAY REVIEWS areas of
accomplishment and challenges in neuroscience research during the Decade of the
Brain: 1990 to 2000. Scientific progress, cultural and social change, and their
respective impact on neurosurgery and neurosurgeons are considered, along with
prospects for further advances in the 21st century.
This essay is a reflection regarding the
intellectual, technological, and political and social changes during the Decade
of the Brain: 1990 to 2000, and their impact on our lives and accomplishments
as clinical neuroscientists. The late United States Congressman Sylvio Conti
was the motivating congressional force for the advancement of legislation for
the Decade of the Brain. Part of the mechanism was the development of a
lobbying committee, the National Committee for Research in Neurological and
Communicable Diseases. This is an amalgam of societies, each with a particular
interest in brain disorders such as Parkinson's disease, von Hippel-Lindau
syndrome, neurofibromatosis, Alzheimer's disease, and so on. All join together
toward achievement of common goals: to increase federal involvement in
neuroscience research, to increase levels of federal funding, and to educate
the public with regard to neurological and neurosurgical diseases. Each year
during the Decade of the Brain, a different aspect of the neurol ogical
disorders that affect public health has been addressed. As a result, novel head
injury programs, epilepsy programs, brain tumor consortia, dementia research,
and a variety of initiatives have been developed that might not otherwise have
occurred.
During the past 10 years, effective therapy has been developed for multiple
sclerosis, diabetic neuropathy, migraine, and narcolepsy. A cochlear prosthesis
has been perfected that is effective for patients with congenital deafness.
These advances are sources of great satisfaction for the neuroscience
community. They reflect a prodigious amount of work by a large number of
talented people, as well as by many courageous patients who helped develop
these treatments.
Advances in pharmacotherapy have been astounding. The past decade has witnessed
the development of new and more effective antipsychotic, antiepileptic, and
antiviral agents. New drugs have revolutionized the care of diabetes and
hypertension. In neuroendocrinology, growth hormone replacement and growth
hormone receptor antagonists are used to treat acromegaly.
Technical and scientific advances during the Decade of the Brain presage
significant changes in our daily work as neurosurgeons. We perform endovascular
therapy for the treatment of aneurysms and vascular occlusive disease, spinal
implants and instrumentation, functional imaging of several varieties, and
image-guided surgery. We have used deep brain stimulation effectively for a
variety of movement disorders, and we have made advances in epilepsy surgery as
well as in current concepts of minimally invasive neurosurgery. Even Professor
Yaargil, who developed micro neurosurgery, probably would not have been able to
predict what has occurred and what continues to evolve as the concept of
minimally invasive neurosurgery (1). With sophisticated computer-based imaging,
we now have the ability to superimpose in three-dimensional space an epileptic
focus, a cortical lesion, and the electrodes that allow mapping of the spread
and propagation of an epileptic discharge (Fig. 1). We have modern
neurosurgical operating rooms with technical adjuncts such as endoscopes and
image-guided methodologies that allow us to serve patients so effectively.
Another major agenda for the Decade of the Brain has been the prevention of
neurological disorders. Stroke prevention has become a reality. The "brain
attack" concept has helped heighten public awareness of stroke, and treatment
has become possible through appropriate and rapid intervention. The "Think
First" program educates an increasing number of children and adolescents on
prevention and avoidance of head and spine injuries. Spinal bifida has been
almost eliminated through proper prenatal care. We can now prevent many of the
deadly aspects of human immunodeficiency virus infections. The research behind
these advances is fascinating. One can study a mouse embryo in a genetically
deficient animal with a neural tube defect. A Drosophila larva can provide the
substrate for major progress in developmental biology (Fig. 2), and the
resulting translational research can help prevent devastating problems in
children.
Perhaps more important than the technical advances are conceptual advances, a
few of which are listed in Table 1. The concept of stem cells in the nervous
system underlies the most exciting aspects of neurobiology for the coming
decade (4, 9). Figure 3 shows stem cells that were taken from a patient who
underwent a temporal lobotomy for epilepsy from the subependymal zone. This
work by Anita H�ttner, working in Ronald D.G. McKay's laboratory at the
National Institutes of Health, demonstrates the ability to culture stem cells
from an adult patient and proves that these cells can make synaptic
connections. The implications of new knowledge regarding stem cells and
plasticity are remarkable.
We know now that the mitochondrial genome can transmit neurological disease,
and much neurological research focuses on developing a greater understanding of
this process. We have learned a great deal regarding the genetic basis of
neoplasia and other forms of neurological disease. Examples of neuronal
plasticity are shown in Figures 4 and 5. We have remarkable new knowledge
regarding the plasticity involved when P2 axons grow to surround the olfactory
bulb, as well as concerning their targeting and movement. In the chick
forebrain, reconstruction of individual clones of differentiated neuronal stem
cells as they develop in the embryo can be visualized as clonal expansions of
individually differentiated neurons. It is staggering to reflect on the ways
the scientific basis of our work is changing and advancing. The NF-1 gene on
chromosome 17 is well characterized (Fig. 6), as is the genetic basis of von
Hippel-Lindau syndrome. Figure 7 shows a Purkinje cell with cytomegalovirus
transfection; viral transfer is critical to the concept of gene therapy.
It is also appropriate to consider the conceptual failures that persist as
problems at the end of the Decade of the Brain. These failures include the
following: 1) gene therapy, which seems so logical but has not yet achieved its
promise; 2) treatment of central nervous system injury: some progress has been
made, but not enough to produce a major impact in the public health arena; 3)
transplantation and regeneration: tremendous amounts of research and resources
have been directed toward this issue, but little in the way of practical
benefit has been achieved; 4) stroke therapy, stroke prevention, and protection
of the brain from ischemia; 5) prenatal surgery: very skilled surgeons have
performed wonderful operations, but the results are not generally acceptable at
the present time; 6) gloom therapy: after 30 years of research on the etiology
and management of gliomas, most of the same frustrations of 30 years ago
persist: and 7) mind-brain relationships, which we are just beginning to
understand as perha ps the most important humanistic aspect of the Decade of
the Brain.
A number of social and political changes have become hallmarks of the Decade of
the Brain. We have experienced the coronation of prospective randomized
clinical trials. One hesitates to submit an article, especially to the New
England Journal of Medicine, unless it is a prospective randomized clinical
trial (6, 7). This research methodology has proven effective in dispelling
myths and fostering progress. Outcomes research has become a major effort, and
many aspects of it are important to the public expectation of us as physicians.
"Designer drugs" have been developed. Pharmaceutical companies are capable of
identifying a problem, investigating the molecular biology relating to it, and
designing molecules that will effectively intervene. Unfortunately, designer
drugs are enormously expensive because research and development must be built
into their cost. Related to this issue is a disturbing trend toward patenting
molecules, genes, and even surgical techniques.
The changing role of academic neurosurgery is a complex subject, and the
influence of managed care is responsible for a number of negative influences.
Let us examine the phenomenon of the prospective randomized clinical trial.
What has it accomplished for us in this decade? The extracranial-intracranial
bypass was a casualty. Many researchers such as Thoralf M. Sundt, Jr., remained
concerned, particularly with the knowledge that a much greater number of
eligible patients were treated outside the trial than within it.
Nimodipine is widely promulgated for the treatment of vasospasm. We know, of
course, that it is not effective for spasm, but it seems to improve the outcome
and may reduce delayed ischemic neurological deficit (10). Spinal cord injury
is now treated almost universally with methylprednisolone. Such treatments have
become incorporated into common practice, and they have a financial impact on
our care of patients. However, I doubt that I have observed a single patient
who has had a better outcome because he or she received methylprednisolone in
the context of a spinal cord injury. Carmustine in polymer wafers (Gliadel;
Rh�ne-Poulenc Rorer Pharmaceuticals, Collegeville, PA) has been evaluated in a
prospective trial and produces marginal benefits for patients with malignant
glioma. Carotid endarterectomy trials confirm what has been suspected, but we
have not effectively capitalized on that knowledge.
Major ethical concerns have surfaced with regard to these trials. These include
questions as to whether a placebo-controlled trial can be justified, or whether
a sham operation may be performed on a human being; these may be necessary
measures to construct a scientifically sound prospective randomized trial.
These are thorny issues, as are those elicited by the outcomes movement and the
entire concept of evidence-based medicine. It is good that we have embraced new
end points such as quality of life, patient satisfaction, and cost. They are
important and in some ways as meaningful as survival, which traditionally has
been the focus of many tumor therapy clinical trials. We have learned how to
analyze and classify the data that we review. The problem with evidence-based
classification is that it often has no connection to the quality of the work.
The worth of an article is based on whether the research was performed
according to predetermined criteria. Meta-analysis is a popular method with the
same flaw,
because it assumes that all of the articles analyzed in a meta-analysis are of
equal value; however, that is almost never the case (2, 5, 7, 8). There has
been an associated devaluation of expert opinion. At times that may be
appropriate, but often it is not.
In addition, one must consider the impact of alternative medicine, which may be
a reflection of the public attitude toward science, medicine, and the entire
medical system. The Gloom Outcomes Project reports that nearly 50% of the
patients enrolled who had gliomas also had been receiving some form of
alternative medical therapy; this fact cannot and should not be ignored.
Other hallmarks of the Decade of the Brain are related to changes in
neurosurgery and the life and work of neurosurgeons. Some important trends
should be recognized. Sub specialization has flourished, probably because of the
vast amount of knowledge that has developed and the sophistication of the
techniques that we use. One notes the impact of fellowships on the training of
young neurosurgeons, which sometimes results in a diversion from the
traditional educational format, in which almost all of our residents performed
some investigative studies and gained an understanding of research paradigms
and processes. One of the challenges for those in neurosurgical education is
keeping the concept of the clinician investigator alive. Finally, many
laudatory lifestyle changes have occurred during this decade, including
diversity, maternity and paternity leave, and different goals for our residents
as they progress through different stages in their training.
During the Decade of the Brain, we have lost some degree of legitimate peer
review. Peer review is part of the essence of scientific progress, and our
neurosurgical journals do it rather well. The medical research establishment
once did it very well. However, some physicians now say, "I do not really want
to treat patients anymore; I make a lot more money performing drug trials."
Some colleagues obtain significant funding from instrument companies that use a
different type of "peer review" from that traditional to neuroscience (3, 11).
That some can profit from patents covering essentially secret research is
disturbing.
The movement of some surgical procedures out of the hospital setting is a
significant problem. The hospital setting has large numbers of built-in
controls. The ambulatory care setting and office setting have virtually none.
Therefore, another type of peer review is lost.
It is important for all of us to remember that as neurosurgeons, we are the
only clinical neuroscientists who work with the living brain, the living spine,
and the anatomic and physiological substrate of the human mind. That is a great
privilege and a great responsibility. It is also a wonderful opportunity for
neurosurgeons to play a pivotal role in directing and accomplishing the
advances in neuroscience during the decades to come in the 21st century (1).
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