In Professor Larson's experimentation, the region of
the brain stimulated is the periaqueductal gray area
(PAG). In a specific paper published in 1985 while
his project was being funded by the NIH, Professor
Larson says, "It has also been suggested that human
speech, being propositional in nature, is

fundamentally different from most types of animal
vocalizations and is controlled by different neural
mechanisms." In the same paper, he also says, "the
extent to which the PAG may be involved in normal
human speech remains to be determined," and "the PAG
may not be crucial for normal speech. In view of
the marginal and speculative nature of the PAG's
relationship to human speech and the general belief
that the diseases enumerated in Professor Larson's
justification for his grant are related to areas of
the brain other than the PAG, is not his statement of
justification an attempt to suggest that his research
has a relationship to human health that is, in fact,
probably non-existent?

Additionally, Professor Larson, himself, admits that
the PAG is not the only area involved in vocalization
and that the PAG may be only a link between the
limbic system of the brain and laryngeal and
respiratory systems. The limbic system is heavily

involved with emotions and the PAG itself is involved
with pain mechanisms. As the animals involved in
this study are clearly under a great deal of
emotional stress and experiencing pain, how can
Professor Larson know which of the effects he is
studying are due to pain and stress and which to
vocalization? At best, are not the results altered
in unknown ways by the stress the animal is
undergoing? Therefore, is there not significant
doubt that Professor Larson's data applies even to
the macaques involved, much less to humans?]

Answer. The merit of Dr. Larson's research and design was evaluated by the Sensory Disorders and Language Study Section that includes foremost experts in the study of voice, speech and language. The proposal received a favorable review and a high funding priority.

In the judgment of the expert review panel, the proposal demonstrated a strong and balanced approach to identifying the relationships among periaqueductal gray, nucleus retro-ambiguus and laryngeal motor neurons and should provide basic information regarding motor control of vocalization and offer greater insight into understanding disorders of motor speech control. It was considered important from the standpoint of understanding normal mechanisms of voice and speech. The investigators have shown that there are several functional types of cells among the periaqueductal gray neurons that are related to vocalization and have begun to define the properties of these cells. They have also obtained evidence that stimulation of different parts of the periaqueductal gray area may elicit different types of vocalizations and have begun to study patterns of muscle activity related to periaqueductal gray neuron stimulation.

They have obtained evidence, supported by data from other neuroanatomical laboratories, that the periaqueductal gray neurons project to the nucleus retro-ambiguus, instead of directly to the nucleus ambiguus.

Dr. Larson's research reflects a careful and meticulous approach to an important issue, accompanied by appropriate and adequate treatment of the animals involved in his research. This research is important to our understanding of the muscles and movements involved in vocalization, and has direct relevance to voice disorders, such as spasmodic dysphonia and speech disorders like the ones associated with Parkinson's disease. Continuation of this research is critical to our understanding of neurologically-based speech disorders and will ultimately have an impact upon our treatment of those affected.

Question. How is continued funding of this grant justified in light of the flawed aspects of this experiment and the minimal results produced to date?

[Background information Professor Larson cites a number of papers substantiating the relationships between the PAG and vocalization in a variety of animal species. As his results to date seem not to show much more than what is already known and copiously published, does not Professor Larson's research largely duplicate existing results? Is it not a waste of taxpayer money and productive of unnecessary animal suffering to fund this duplicative work?

In spite of the rather lengthy experimentation
Professor Larson has performed, his results seem
minimal almost to the point of triviality. Why is
the NIH rewarding such unproductive experimentation
by extending this grant? It seems, too, that the
taxpayers have been funding and funding generously,
Professor Larson's career since his days as a
graduate student 20 years ago with very little, if
anything, to show for that funding. Why does the NIH
allow this to continue? What are the NIH standards
for extending or terminating grants?]

Answer. The project will attempt to improve the understanding of mechanisms of vocal control by studying brainstem neuronal activity. This research is a part of a body of basic scientific research that provides important information in determining the pathophysiology of voice and speech disorders that cannot be conducted on human subjects, but may provide greater insight into human disorders. Charles Larson is recognized as one of the world's foremost authorities on the neural bases of vocalization. Over the last twenty years he has published more than twenty articles on related research.

Question. What assurances are there that the macaques involved in Professor Larson's experiments are being humanely treated as stipulated in the Animal Welfare Act?

[Background information Exactly how has Professor
Larson assured that each and every animal used in
each and every one of his experiments no pain or
discomfort? Detailed anesthetic protocols for the
past 2 years, as well as photocopies of the notes
substantiating these protocols and purchase orders of
the pharmacologic agents used should be provided.
What post-operative analgesic medicine is used?
Photocopies of notes substantiating the use of these
medications and purchase orders of the pharmacologic
agents used in any post-surgery procedure should be
provided.

What are the qualifications of all personnel administering and monitoring anesthetic protocols and performing surgical procedures?

Why cannot local citizens have contact with the
community representative serving on Northwestern
University's Animal Care and Use Committee, or even
know that person's name, despite numerous requests
from local residents and the Evanston, Illinois City
Council? Is not this withholding of information an
arrogant violation of the Animal Welfare Act as
amended by the Dole-Brown Amendment?]

Answer. Review groups at NIH and at Northwestern University have carefully considered this research and had no concerns regarding Dr. Larson's treatment of his animal subjects; the issue of pain was specifically addressed by the reviewers. The consideration of the treatment of animal subjects is a threetiered process. The Northwestern University Animal Care and Use Committee formally assures the NIH, under procedures outlined in both the Department of Agriculture Animal Welfare Act as amended and the Public Health Service Policy on Humane Care and Use of Laboratory Animals, that animal protocols regarding surgical procedures, medication, and recovery issues were judged to be appropriate. Additionally, the NIH Study Section, after receiving this clearance, reviewed and evaluated the scientific appropriateness as well as the issues related to animal care and use and made this report to the Institute prior to final consideration of the grant application. The final tier of the review is each Institute's own National Advisory Council.

Northwestern does not release the names of any of the committee members fearing for the safety of the individuals and their families due to death threats received in 1989 that were investigated by the FBI and other law enforcement organizations. However, Northwestern University does provide opportunities to address concerns to the committee members by communicating in care of the committee. The records about purchases and procedures would be the property of Northwestern University and requests for those kinds of materials should be directed to the Vice President for Research and Dean of the Graduate School, Dr. David H. Cohen. Questions about the Act can be answered most thoroughly by the Department of Agriculture, Animal and Plant Health Inspection Service, Regulatory Enforcement and Animal Care Office.

QUESTIONS SUBMITTTED BY SENATOR ARLEN SPECTER

Question.

RESEARCH FUNDING

Dr. Raub, in meetings with many of your

colleagues in the research community they have raised deep concern over young investigators becoming discouraged and leaving the research field because of an inability to compete successfully for limited research funds. What is the extent of this problem? Is funding the only factor contributing to this phenomenon?

Answer. The general perception in the scientific community of a funding crisis at the NIH often has focused on concern that young investigators are becoming discouraged about pursuing careers in biomedical research. In order to place the status of young investigators in perspective, a brief summary of the nature of this "funding crisis" is in order. The general perception of a crisis, has come about because the number of new and competing renewal research project grants that the NIH has been able to award in recent years has fallen below 6,000 grants. The principal reasons for these decreases are twofold. Costs of conducting research have escalated at a faster rate than have the funds appropriated for this purpose. In addition, besieged by concerns in the biomedical community that award periods were too short, the NIH began to increase the terms of awards, from an average of 3.4 years in 1985 to 4.2 years in 1990. The effect of this increase was the utilization of an increasing portion of the extramural budget for noncompeting awards, with fewer funds available to fund new and competing renewal awards. Despite decreases in competing awards, the total number of research project grants in the NIH portfolio continued to grow throughout most of this period.

This

About the time that the NIH began to lengthen the term of awards, the First Independent Research Support and Transition (FIRST) Award for beginning investigators was initiated. was a revision of the previous three-year New Investigator Research Award. The FIRST award provided for five years of support at a maximum level of $350 thousand for the entire period. Data collected since the initiation of this new instrument show that success rates for FIRST award applicants are much higher than are those for applicants for regular research project grants (RO1s). In fiscal year 1990, the success rates for the FIRST award and new RO1 award applicants were 27.6 and 16.7 percent, respectively. In that same fiscal year, the fourth full year that the award had been in effect, the NIH was supporting a total of 2,083 FIRST awards for $191.5 million.

Many beginning investigators choose to apply for an Rọ1 award, rather than a FIRST award, choosing to either avoid the dollar limitation or in the belief that they can be successful in competition with established investigators. In fiscal year 1989, the NIH awarded 335 first-time RO1s, compared to 502 FIRSTS, indicating that many beginning investigators were successful in this competition.

AIDS RESEARCH

Question. Dr. Raub, a recent study by the Institute of Medicine urged/recommended that funding for research on AIDS be increased immediately by $200,000,000. Are you familiar with this report and do you concur in its findings? What areas of research does the report indicate require additional resources? What progress has been made with the funds which have been appropriated over the last several years?

Answer. I am familiar with the Institute of Medicine (IOM) Report on the AIDS Program of the NIH. This study was performed at the request of the Associate Director for AIDS Research and the Office of AIDS Research, National Institutes of Health (NIH), for an unbiased, objective review of the NIH's AIDS research activities. As the study was ongoing and the report was being prepared, the NIH AIDS research program was continuing to evolve; thus, many of the changes recommended in the IOM report have already been implemented. Others will require further review for future action.

In general, the NIH concurs with the recommendations made in the IOM report. However, there are two areas of concern cited in the report regarding behavioral research and clinical trials that require NIH clarification. Specifically, the report identifies behavioral research as an area where the NIH should increase funding. We feel also that more can be done in this area. However, we believe the IOM panel's assessment of our level of funding for AIDS behavioral studies does not adequately reflect the level of this research actually being conducted. Behavioral research is conducted as a component of most of the major NIH-supported HIV epidemiological studies. In addition, other behavioral research such as risk assessment and research on nursing interventions would be captured under other budget categories, although directly relevant.

In the area of clinical trials, the IOM panel expressed concern that the AIDS Clinical Trials Group (ACTG) network may not be able to keep pace with the ever increasing requirements for expansion and modification of its focus and activities. We have given considerable thought to this evolutionary process, are constantly evaluating the program, and have taken several steps to ensure both flexibility and responsiveness to changing scientific priorities. Two of the most recent changes within the clinical trials program include the recompetition of the adult units of the ACTG, which will provide for performancebased funding for research grant recipients, and the implementation of the Division of AIDS "DAIDS Initiative" within the National Institute of Allergy and Infectious Diseases (NIAID), which will provide greater flexibility and more rapid evaluation of therapeutic agents and treatment approaches.

The NIH intends to use the IOM report as a planning tool in its development of a long-range strategy for AIDS research activities. Like the panel, we believe that NIH AIDS research should continue to receive high scientific priority so that the challenges presented by AIDS can be met.