Financial Anatomy of Neuroscience ResearchHoward Fields, MD, PhD

Your message and the articles by Moses and Martin, andDorsey et al., on the status of neuroscience research in theDecember 2006 issue of Annals were both interesting andtimely.1–3 You have identified a serious mismatch betweenthe expansion of funding for neuroscience research and thegeneration of new effective treatments for diseases of the ner-vous system. This mismatch suggests that the National Insti-tutes of Health and the neuroscience research communityhave failed either to direct research to clinical problems or totranslate disease-relevant discoveries into new treatments.The public has backed its faith in medical research with hugesums of money. To a certain degree, we, as stewards of thismassive medical research program, have not kept our end ofthe bargain. In part, this is because of the complexity of theproblems we are addressing. On the other hand, I think it isreasonable to question the degree to which the research dol-lar is actually being spent in the way the public intended.Despite significant positive accomplishments, a large propor-tion of NIH neuroscience grants support interesting andhigh-quality research that has no obvious clinical value. Thefact is that study sections often ignore the disease relevanceof the research proposals they review. As a member of twostudy sections, I speak from personal experience. The largepharmaceutical companies, although totally invested in therelevance of their research dollar, are handcuffed by attentionto market factors rather than disease mechanism. I havespent hours with major pharmaceutical and biotechnologycompanies trying to explain to them why clinical researchmust be more than therapeutic trials. National Institutes ofHealth and the pharmaceutical and biotechnology industryneed to invest in the study of disease mechanism in patients.Although academic and commercial entities often use animalmodels of disease to test their candidate therapies, such mod-els, particularly of nervous system disorders, can be notori-ously misleading. I need only mention the failure of animalmodels of pain, stroke, or brain injury to accurately predictthe therapeutic value of new pharmaceutical interventions.This is a problem that calls out for more mechanism-oriented research in patients.

The explosion of new, noninvasive methods to study pa-tients in the early stages of their diseases, for example, usinggenetic analysis and functional brain imaging, presents anunparalleled opportunity to study human disease mecha-nisms. Why has progress been so slow? Part of the problemis that clinicians are typically too busy (and too poorly com-pensated) in their practice to spend enough time with pa-tients. Without detailed examination of patients, it is diffi-cult to make the critical observations that can lead to anunderstanding of the underlying neurobiology of disease.Clearly, the financial pressures on practicing clinical neurol-ogists are a barrier to a better understanding of disease, andthus to development of new, more effective treatments. Oneapproach to support the study of disease mechanism wouldbe to establish neuroscience laboratories specifically designedfor human research and funded so that the clinician-scientistcan study patients in detail; test mechanistic hypotheses, forexample, using functional imaging; and then, ideally, take

this mechanistic information and hypothesis back to animalswhere more invasive cellular and molecular approaches canbe brought to bear. Note that the flow of hypothesis andexperiment in this case goes in both directions; there is con-tinuous and dynamic feedback between patient observationand laboratory experiment. But the key is that this research isdriven primarily by patient observation. Nowhere is this ap-proach more crucial than for diseases of the nervous system,especially degenerative and functional diseases. The brain isthe most unique human organ, and although some diseasescan be studied perfectly well in animals (eg, transmissiblediseases, toxicology, and so forth), the biggest challenge formost animal work on central nervous system diseases such asepilepsy, pain, movement, and cognitive/behavioral disordersis to show that a particular animal model has any relation tothe human disease. The optimal solution for this issue is tostudy patients with all available tools. Functional imagingwill be a major part of that effort, but careful clinical exam-ination of patients is the irreplaceable centerpiece. Unfortu-nately, there really is no financial mechanism to support thisvital class of research. It is typically too preliminary and an-ecdotal to satisfy a study section composed of laboratory-based scientists, especially if they are unfamiliar with the dis-ease in question. So an RO-1 grant is, in my experience,rarely, if ever, awarded for this type of work. Furthermore,because this early high-risk work typically has no obviousrelation to product development, commercial entities are re-luctant to support it. University hospitals must be run asbusinesses, and the public does not understand what isunique about this clinically driven experimental approach.Somehow, we must find a way to get this type of workfunded. Without it, true bidirectional translational work willcontinue to swim in a muddy pond, and the mismatch be-tween spending and effective new treatments will continue orworsen.

Department of Neurology and Physiology, University ofCalifornia, San Francisco, San Francisco, CA

References1. Johnston SC, Hauser SL. A status report on neuroscience re-

search, without grade inflation. Ann Neurol 2006;60:A9–A11.2. Moses H, Martin JB. What should be done to improve the pro-

ductivity of neurological research? Ann Neurol 2006;60:647–651.

3. Dorsey ER, Vitticore P, De Roulet J, et al. Financial anatomy ofneuroscience research. Ann Neurol 2006;60:652–659.

DOI: 10.1002/ana.21135

Primary Progressive Aphasia PathologyMarsel Mesulam, MD

Primary progressive aphasia (PPA) is diagnosed when a pro-gressive language impairment (fluent or nonfluent) emergesin relative isolation during the initial stages of a degenerativedisease that eventually leads to an aphasic dementia.1,2 Knibband colleagues’3 recent article offers another important con-tribution to this area by the Cambridge group. Using myPPA criteria,2,4 but liberalizing the 2-year period of symptomspecificity, they showed that approximately two of three cases

LETTERS/REPLIES

124 Annals of Neurology Vol 63 No 1 January 2008